The relationship between Bisphenols exposure and intestinal flora: a systematic review and meta-analysis

The relationship between Bisphenols exposure and intestinal flora: a systematic review and meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The relationship between Bisphenols exposure and intestinal flora: a systematic review and meta-analysis Tian Wang, Suju Sun, Yancheng Feng, Zhiwang Guo, Hao Wang, Liqin Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1948177/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract A growing number of studies have indicate that Bisphenols (BPs) have an effect on gut microbial community, including alter gut microbial diversity and composition. Due to limited sample size and some varied results, a review is needed to add credibility to the conclusion of BPs influence on gut microbial community. Literature search was implemented based on PubMed,Wed of Science, Science Direct, SinoMed, CNKI database from inception date to February 24,2022. Nineteen eligible articles (BPs exposure on rodent animal experiment studies) were included to our review and all literature’s references were traced back. Meta analysis were conducted to synthesis 5 alpha diversity index(observed species, chao, ace, Shannon, Simpson index), narrative synthesis approach was selected to synthesis composition of gut microbial in BPs group. Results suggest Simpson index significantly increase after BPs intervention. In subgroup analysis, Simpson significantly increase in low dose group( dosage ≦ 0.20mg/kg), observed species significantly decrease in long term group(duration > 5 weeks), chao index decrease in short term group and increase in long term group, chao and Shannon decrease in intestine sample group. To conclude, BPs exposure may decrease the abundance and diversity of gut microbial especially probiotic. BPs gut microbial relative abundance diversity Figures Figure 1 1. Introduction BPs are organic compounds that been widely used in many industrial applications to produce epoxy resin and polycarbonate plastic (PC) since 1960s [ 45 ] . It has significantly promote the development of industrial whereas brings great deals of detrimental effects to human health and contaminant our environment as a result of common use of plastic product. Because of widely used in producing plastic product, BPs have pollute soil, water and atmosphere environment, it can be intake through oral, dermal contact and respiratory inhalation. BPs as one of the most widespread exoestrogens, exposure of BPs may increase the risk of suffer from reproductive disease due to its phytoestrogen effect and bind to the estrogen receptor [ 37 ][ 38 ] . Result from He’s research suggest that homeostasis of host is very sensitive to BPs at relative low dose [ 3 ] . In Chao’s study, low dose BPs exposure impairs synaptic plasticity and cognitive function [ 35 ] , similar result also be found in Zhang’s study [ 36 ] . High throughput sequencing revealed that BPs increase relative abundance of Firmicutes、Tenericutes and Proteobacteria in rats fecal, decrease relative abundance of Bacteroides. BPs exposure alter abundance and diversity gut microbial as well as composition of gut microbial in rats [ 2 ] . An increasing importance has been attached to function of intestinal microbial, which is deemed as the second brain of human in some research [ 28 ][ 29 ] . The superficial area of intestinal mucosa in adult can reach about 300 square meters, which is human’s largest organ to interact with external environment [ 44 ] . Totally there are about 100 trillion bacteria in body of adult, 80% of which located in intestine, about ten times as many as cells in human body. Weight of gut microbiota in adult is more than 1kg under health circumstance, containing more than one thousand microbial species consist of 3.3 million gene. Heterogeneity of gut microbial between individuals varied from 80–90%. Gut microbial plays an important role in precisely reflect human metabolism status and endocrine homeostasis and sensitive to alteration of content of serum biochemical substance [ 17 ] , as such gut microbial are deemed as a crucial indicator used to reflect host health status at an early exposure stage [ 1 ] . Gut dysbiosis may result in disequilibrium of host homeostasis, including hypertension, cancer, hepatic disease, Hutchinson-Gilford Progeria syndrome, immune disease and endocrine function disorder [ 25 ][ 26 ] . A surging number of studies have suggested the relationship of composition of gut microbial and BPs intervention. BPA intervention significantly change the composition of intestine microbiota in colon, abundance of BPA degrading bacteria increase (such as Microbacterium and Alcaligenes) [ 3 ] . Bacteria significantly altered at the phylum, class and genus level from BPA intervention. Sub-acute (16 days) BPA exposure significantly altered the alpha diversity after BPA exposure [ 4 ] . Javurek result indicate that increase in Proteobacteria which is associated with intestinal inflammation may persist in filial generation because gut microbial dysbiosis caused by BPA intervention has also exist in offspring from control group [ 5 ] . BPA exposure cause generational and sex-dependent gut microbiome changes. Several of the bacteria whose relative abundance increased with BPA exposure (such as Bacteroides, Mollicutes, Prevotellaceae, Erysipelotrichaceae, Akkermansia, Methanobrevibacter, Sutterella ) are pro-inflammatory and associated with several diseases, especially inflammatory bowel disease (IBD), metabolic disorders and reproductive cancer [ 5 ] . Probiotic like Akkermansia, Lachnospiraceae and Bifidobacterium decrease from BPs exposure [ 7 , 9 , 12 ] . Diversity of gut microbial also reflected by BPs exposure [ 4 , 5 , 11 ] . Alpha diversity indices consist of observed species, Chao index, Ace index, Shannon index and Simpson index. Chao index estimate amount of observed species of community base on chao1 algorithm [ 52 ] . Ace index evaluate total quantity of species, value of Ace and Chao index are positively correlate with species richness. Shannon index is used to assess diversity of microbial. Greater Shannon index value indicates higher diversity of microbial community. Simpson index reflect status of dominant species in community, greater simpson index value implies lower diversity. Since result of studies revealing the relationship of composition at different taxonomy level (phylum, class, genus and species) as well as alpha diversity of gut microbial and BPs exposure are different from each other. Research focusing on influence of BPs on diversity of gut microbial suggest that observed species went decrease after BPs exposure [ 2 , 5 , 10 ] . Chao index decrease after BPs exposure [11,13−15] . Ace index decrease after BPs exposure [ 13 , 15 ] . Shannon index decrease after BPs exposure [ 7 , 10 , 12 , 13 ] . Simpson index increase after BPs exposure [ 1 – 3 , 7 , 15 ] . It is necessary for us to carried out a systematic review and meta analysis for 5 alpha diversity index (observed species, chao index, Ace index, Shannon index, Simpson index) to enlarge the sample size and acquire more accurate evidence. Most studies focusing on BPs effect on composition and diversity of intestine flora are animal experiment research so far, as such we carried out animal experiment review. 2. Methods We conducted systematic review according to protocol registered on PROSPERO and registration number is CRD42022300159. This systematic review and meta analysis was implemented in line with predetermined criteria outlined by the PRISMA guidelines. In accordance with a predetermined Population (including animal species)-Exposure-Comparator-Outcome (PECO) guidelines. Literature in which rodents were exposed to BPs, with control group set as comparison. Outcomes clearly demonstrate diversity and composition of gut microbial (relative abundance of genera at different taxonomic levels) are eligible for inclusion. 2.1. Search Strategy PubMed, Wed of Science, Science Direct, SinoMed, CNKI databases were searched by 2 independent investigators for relevant articles published from database inception date to February 24, 2022. The search of articles was carried out by the following retrieval strategies: (1) BPs OR 4,4-dihydroxy-2,2- diphenylpropane OR 2,2-bis (4-hydroxyphenyl) propane OR diphenylolpropane; (2) mouse OR mice OR rabbit OR rats; (3) gut microbiota OR intestine flora OR gut microbiome OR fecal microbiota; and (3) terms (1) and (2). 2.2. Specific inclusion and exclusion criteria Studies were included if they meet with following criteria: (1)Study was design as randomized controlled trial; (2) Experimental animal were rodent (including rat, mice and rabbit), there were no limitations on strain, gender and age; (3) Experimental group was exposed to BPs (dissolved in corn oil or DMSO), intervention means (mainly via oral administer),intervention duration and dosage of BPs were clearly reported in method section; (4) Control group receive vehicle or no treatment, baseline character among groups were not significantly different; (5) Outcome indicator including relative abundance of genera at different taxonomic level (phylum,class,genus,species), diversity of gut microbial (alpha diversity); (6) Publication type allow for primary research,journal article and dissertation. Exclusion criteria are described as follows: (1) Publication type were review or meeting abstract; (2) Subject were not rodents, vitro experiments;(3) Study focus on river sediment or soil bacteria bio-degradation capacity for BPs; (4)Outcome data of study are incomplete or unclear; (5) Duplicate articles. 2.3. Data extraction Data were extracted from eligible articles according to inclusion and exclusion criteria. A standardized template from Cochrane Handbook for Systematic Reviews of Interventions was used to extract data ,including study ID, first author name,language, publish year, publication type, geographical location, study design, intervention manner(dosage, duration, pathway), sample size of each group, information of animal (strains,age,gender), published journal,outcome indicator (mean ± standard deviation).Two paired reviewers independently extracted this information from each included study and resolved any disagreements through discussion. 2.4. Risk of bias assessment We evaluated the risk of bias of each study using the Systematic Review Center for Laboratory Animal Experimentation’s (SYRCLE) risk of bias tool [ 27 ] . There are ten domains included in this scale that evaluate selection bias, performance bias, detection bias, attrition bias, reporting bias, and other sources of bias of study, respectively. Quality reviewers select ‘yes’, ‘no’ or ‘unclear’ for each domain (Yes indicates low risk of bias in this domain and results of study are deemed reliable. No represents a significant risk of bias in the study. Unclear stands for susceptible bias to some degree but insufficient to influence result). 2.5. Statistical analysis Meta and metafor package from software R (version 4.1.1) were applied to measure the significance of heterogeneity, describe outcome indicators (mean ± standard deviation), estimate pooled-effect(data synthesis), generate forest plot, sensitivity analyse to probe source of heterogeneity and assess publication bias (funnel plot). P ≤ 0.10 were considered significant in heterogeneity test and α level set at 0.05 for other statistical test. Fail safe number were calculated to probe stability of pooled analysis. 3. Results In total, 1109 articles were identified from the 5 database searches. After removing duplicate publications, 666 articles without repetition were screened for eligibility. Of the 463 studies were excluded after title and abstract review, 203 articles were carried out full text review for eligibility. According to the preliminary defined inclusion and exclusion criteria 184 research were excluded. Eventually, 19 literature satisfied with the inclusion criteria and adopted for systematic review (Fig. 1 ). Table 1 summarizes the study characteristics, study design and outcome indicators. 3.1. Study Characteristics All eligible studies was rodents animal researches. BPs intervention means were gavage and oral administer. The dose of BPs varied from 0.005 to 100 mg/kg, and the duration of intervention ranging from 2 to 24 weeks. Sample tissues includes intestine contents and feces. The main selected indicators in the meta-analysis were alpha diversity and relative abundance of genera at different taxonomic level (phylum, class, genus and species). Other information that were important for the objective including the first author’s name, animal age, and sample size of both control and experimental groups were extracted (Table 1 ). Table 1 Characteristic of included studies Author Country Language Publish type Species Age (week) Study design Publish year Journal Dosage (mg/kg) Duration (week) Sample size (C/T) Lai K.P. China English J CD 1 mice 3 Completely randomized design 4 groups 2016 Environmental Pollution 1.2 10 4/4 Tang Juan China Chinese D SD rat 8 Completely randomized design4groups 2017 Nanjing Agricultural University 50 4 6/6 He Jianbo China Chinese D SD rat 7 Completely randomized design6groups 2019 Hangzhou Normal University 100 6 7/7 Joella Xu U.S. English J NOD mice 16 Completely randomized design2groups 2019 Organ toxicity and mechanism 0.3 22 20/20 Angela B. Javurek U.S. English J California mice 10 Completely randomized design3groups 2016 Gut Microbes 50 6 12/10 Jennifer AA DeLuca U.S. English J C57BL/6 mice 10 Completely randomized design4groups 2018 Experimental Biology and Medicine 0.05 2 12/10 Dan Feng China English J CD 1 mice 5 Completely randomized design2groups 2020 Environmental Pollution 0.05 24 8/8 DENG Yuanyuan China Chinese J C57BL/6J mice 6 Completely randomized design2groups 2020 Nanjing Medical University 0.05 4 10/10 Lavanya Reddivari U.S. English J Dutch-Belted rabbit 6 Completely randomized design2groups 2017 American society for microbiology 0.2 3 4/4 Graciel Diamante U.S. English J C57BL/6J mice 8 Completely randomized design2groups 2020 Environment international 0.005 3 8/8 Joella Xu U.S. English J NOD mice 10 Completely randomized design2groups 2019 ARCHIVES OF TOXICOLOGY 0.03 6 15/15 Sarabjit Kaur U.S. English J California mice 11 Completely randomized design4groups 2020 Scientific Reports 50 2 20/20 Ling Feng China English CD 1 mice 3 Completely randomized design2groups 2019 Environmental Pollution 0.05 10 10/10 Ming-Kuei Shih China English J SD rat 15 Completely randomized design5groups 2021 Molecules 0.05 5 14/13 Yinhua Ni China English J C57BL/6 mice 7 Completely randomized design5 groups 2021 Chemosphere 50 22 6/6 Yann Malaisé France English J C3H/HeN mice 7 Completely randomized design2 groups 2017 Scientific reports 0.05 5 NR Jin-Xian Liao China English J SD rat 15 Completely randomized design4 groups 2021 International Journal of Molecular Sciences 0.05 5 4 ~ 8 per group Matthew V. Gomez U.S. English J CD 1 mice 20 Completely randomized design5 groups 2020 Society of toxicology 0.2 5 19/17 Chen Yuran China Chinese J Balb /c - nu mice 5 Completely randomized design5 groups 2022 JiangXi Science 0.2 6 6/6 3.2. Quality assessment of study Risk of bias was assessed using Systematic Review Center for Laboratory Animal Experimentation(SYRCLE) quality-assessment tools. Result indicate that generation of assignment allocation sequence were reported in 10 publications which concerned to be at low risk. Baseline characteristics of animals from control and experiment group were deemed as homogeneity in 7 identified studies. Of 1 publication’s allocation concealment was sufficient and correct. 12 studies were complied with randomly attribute housing (individual polypropylene cage) for subject. Only 1 article clearly demonstrate performance blinding of investigator in method design section. There were 10 articles meet with random outcome assessment. Blinding of outcome assessment was considered low risk in 2 eligible studies. In each study entire animals were included for final analysis, so incomplete outcome data domain were deemed as low risk for all included studies. Primary result as well as secondary result details from all selected studies were reported in accordance with protocol and no significant bias arouse from other domain. On the whole, nine literature was considered to have middle risk of bias, eight studies were deemed as low risk and two researches were regarded high risk of bias (Table 2 ). Table 2 SYRCLE risk of bias tool for studies assessment References Sequence generation Baseline characteristic Allocation concealment Random housing Performance Blinding Random outcome assessment Blinding of outcome assessment Incomplete outcome data Selective outcome reporting Other sources of bias Lai 2016 U U U Y U U U Y Y Y Tang 2017 U Y U Y U Y U Y Y Y He 2019 U Y U Y U U U Y Y Y Xu 2019 U Y U Y U U U Y Y Y Javurek 2016 Y U U Y U U U Y Y Y .DeLuca 2018 Y Y Y U Y Y Y Y Y Y Feng 2020 Y Y U Y U U U Y Y Y Deng 2020 Y U U Y U U U Y Y Y Lavanya 2017 Y Y U Y U U U Y Y Y Graciel 2020 U U U U U Y U Y Y Y Joella 2019 Y Y U Y U Y U Y Y Y Sarabjit 2020 Y U U Y U Y U Y Y Y Ling 2019 Y U U Y U Y U Y Y Y Shih 2021 Y U U Y U U U Y Y Y Ni 2021 Y U U U U Y U Y Y Y Malaisé 2017 U U U N Y Y Y Y Y Y Liao 2021 U Y U U U Y U Y Y Y Matthew 2020 N U U U U Y U Y Y Y Chen 2022 Y Y U U U Y U Y Y Y 3.3. Heterogeneity test and pooled analysis Observed species, Chao index, Ace index, Shannon index and Simpson index were selected to reflect alpha diversity of gut microbial. Alpha diversity consist of comprehensive indices that reflect richness and diversity of specific domain or ecology system. All tags were clustered to OTU at 97% sequence similarity (16S rRNA sequencing was conducted on bacterial DNA extracted from fecal or intestine sample). Heterogeneity test indicate five indices have significant heterogeneity (Table 3 ), so random effect model was chosen for pooled analysis. According to result of pooled analysis, observed species, chao index and Shannon index slightly decrease after BPs exposure. Ace index moderately increase in BPs treatment group. Simpson index significantly increase in BPs intervention group. Our result suggest that BPs reduce diversity of gut microbial (Supplementary Fig. S1). We use fail-safe number to probe stability of result of pooled analysis, the fail-safe number of Simpson index was 26, so the result is reliable. Table 3 Influence of BPs on alpha diversity of gut microbial Indicators Studies ( N ) Animals ( N ) Heterogeneity test Effect model Meta analysis result I 2 (%) P SMD 95% CI P observed species 6 78 90.7 < 0.001 Random effects model -1.385 -4.217 ~ 1.447 0.338 Chao index 10 238 89.6 < 0.001 Random effects model -0.991 -2.523 ~ 0.541 0.205 Ace index 4 56 60.5 0.055 Random effects model 0.355 -0.537 ~ 1.248 0.435 Shannon index 10 172 82.1 < 0.001 Random effects model -0.462 -1.371 ~ 0.447 0.319 Simpson index 6 74 49.3 0.079 Random effects model 0.945 0.213 ~ 1.676 0.011 3.4. Funnel plot and sensitivity analysis Begg rank correlation test was carried out examine the asymmetry of funnel plot (Supplementary Fig. S2). Publication bias were not significant for all alpha indicators( P > 0.05) (Supplementary Table S1), hence results of meta analysis are not influenced by publication bias and reliable. Sensitivity analysis was conducted to determine impact of each study on pooled analysis result(Supplementary Fig. S3). In observed species pooled analysis, Tang, He and Chen’s studies obviously affect result of pooled analysis. In result of synthesis of Chao index, result of Tang, He’s researches was significantly different from pooled result. Tang, Ling and Ni’s Ace result have significant difference compared to other studies. He, Javurek and Feng’s Shannon outcome were obviously varied from other researches. Only Ni’s Simpson result was distinct from other outcome. 3.5. Subgroup analysis was applied to explore effects of different BPs dose, intervention duration and sample tissue 3.5.1. Subgroup analysis for different BPs dosage To figure out different dosage of BPs influence on alpha diversity of gut microbial, subgroup analysis for different dose of BPs was conducted (Table 4 ). Simpson index in low dose group were significantly increased after BPs exposure ( P = 0.001). Other alpha diversity indicators (observed species, Chao, Ace, Shannon) exhibit no significant changes after BPs exposure. Table 4 Subgroup analysis for different dosage of BPs Indicators Dosage ≦ 0.20mg/kg Dosage > 0.20mg/kg Studies ( N ) SMD 95% CI P Studies ( N ) SMD 95% CI P Observed species 3 0.518 -2.795 ~ 3.831 0.759 3 -3.437 -7.402 ~ 0.528 0.089 Chao 5 -0.116 -1.327 ~ 1.095 0.851 5 -2.323 -5.603 ~ 0.958 0.165 Ace 2 0.637 -0.479 ~ 1.752 0.263 2 0.049 -1.675 ~ 1.773 0.955 Shannon 5 -0.679 -1.671 ~ 0.313 0.180 5 -0.285 -1.951 ~ 1.382 0.738 Simpson 3 1.262 0.517 ~ 2.007 0.001 3 0.684 -0.772 ~ 2.141 0.357 Table 5 Subgroup analysis for different duration of intervention Indicators Duration ≦ 5 weeks Duration > 5 weeks Studies ( N ) SMD 95% CI P Studies ( N ) SMD 95% CI P Observed species 4 -1.610 -6.061 ~ 2.840 0.478 2 -1.104 -2.089~-0.120 0.028 Chao 6 -0.477 -0.853~-0.102 0.013 4 0.621 0.168 ~ 1.075 0.007 Ace 2 0.450 -0.436 ~ 1.335 0.320 2 0.204 -1.750 ~ 2.157 0.838 Shannon 5 -0.420 -1.676 ~ 0.837 0.513 5 -0.506 -1.959 ~ 0.946 0.494 Simpson 3 1.270 0.538 ~ 2.002 0.001 3 0.609 -0.702 ~ 1.921 0.362 Table 6 Subgroup analysis for different sample type Indicators Sample = fecal Sample = intestine Studies ( N ) SMD 95% CI P Studies ( N ) SMD 95% CI P Chao 7 -1.371 -3.860 ~ 1.118 0.280 3 -0.555 -1.067~-0.043 0.034 Ace 2 0.445 -0.384 ~ 1.275 0.293 2 0.204 -1.750 ~ 2.157 0.838 Shannon 7 -0.310 -1.609 ~ 0.990 0.640 3 -0.904 -1.576~-0.233 0.008 Simpson 4 1.302 0.688 ~ 1.915 < 0.001 2 0.187 -1.582 ~ 1.956 0.836 * only 1 article have observed species from intestine sample group, so observed species is excluded 3.5.2. Subgroup analysis for different intervention duration BPs effect on alpha diversity of intestinal flora in short duration group was distinct from which in long duration group (Table 5 ). Observed species was significantly decrease in long term BPs exposure group ( P = 0.028). Chao was significantly decrease in short term BPs exposure ( P = 0.013). Value of Chao index was significantly grow in long term BPs exposure group ( P = 0.007). Simpson index was significantly increase after short term BPs exposure ( P = 0.001). Compared to control group observed species and Shannon index were slightly decrease in short term BPs exposure group. Ace and Simpson indicators were marginally increase in long term BPs exposure group. Shannon decrease a bit in long term BPs exposure group. 3.5.3. Subgroup analysis for different sample tissue Two group have different changes of alpha diversity caused by BPs exposure (Table 6 ). In fecal sample group, Simpson index significantly increase after BPs intervention ( SMD = 1.302, P < 0.001), fail-safe number is 25. Observed species was not analyzed because of limited number of study. Ace index slightly increase for BPs intervention ( SMD = 0.445, P = 0.293). In intestine sample group, chao and Shannon index were significantly decrease due to BPs exposure ( SMD = -0.555, P = 0.034 and SMD =-0.904, P = 0.008, respectively). 3.5.4. Fail-safe number of subgroup analysis result Fail-safe number of Simpson index from low dose group was 10, which indicate a stable result. Observed species and chao index from long term group fail-safe number were 3, which suggest result is unsteady. Chao index and Simpson index from short term group were 56 and 12, respectively. Fail-safe number of Chao index and Shannon index from intestine group were 3 and 5, respectively. 3.6. Narrative synthesis for alteration of gut microbiota composition after BPs treatment BPs can influence composition of gut microbial from the phylum to genus levels (Supplementary Table S2). 3.6.1. BPs change the composition of intestinal flora at phylum level Firmicutes and Bacteroidetes were the most abundant phyla in colonic mucosal tissues of both control and BPA intervention mice [ 13 ] . Compared to control group, relative abundance of Proteobacteria, Bacteroidetes and phylum Tenericutes in intestine/fecal samples were mainly affected by BPs exposure. Many result indicates that BPs exposure up-regulate the level of Proteobacteria [ 1 ][ 2 ][ 15 ] , but in Matthew study, Proteobacteria was decreased from the low dose BPs exposure, studies also revealed that increase level of Proteobacteria is positively associated with the occurrence of intestinal inflammation. Abundance of Bacteroidetes and phylum Tenericutes decrease from BPs group [ 1 ][ 2 ][ 18 ] , specifically Bacteroidetes markedly increase in high dose group but significantly decrease in low dose group (50mg/kg) [ 3 ] . Tenericutes was significantly down-regulate in both high dose and low dose group for male mice(0.03mg/kg and 0.3mg/kg, respectively) [ 18 ] . BPs intervention significantly increase the relative abundance of Firmicutes [ 15 ] and Fusobacteria [ 2 ][ 3 ][ 7 ] , yet in He’s study, phylum Firmicutes significantly decrease in middle and high dose group (100 and 1000mg/kg) [ 3 ] . Also in Matthew’s study, phylum Firmicutes decrease from the high dose (0.3mg/kg) [ 18 ] . Verrucomicrobia in middle and high dose group was increase drastically [ 3 ] . Juvenile BPs intervention promote the level of Verrucomicrobia increase [ 11 ] . The relative abundance of Verrucomicrobia was positive correlation with BPs concentration in a dose-response relationship in males group [ 15 ] . However, in Feng’s study, the abundance of Verrucomicrobia was decrease distinctly from BPs exposure group [ 7 ] . The high dose BPs (0.3mg/kg) increased the level of Cyanobacteria and TM7 [ 18 ] . BPs decrease the relative abundance of Gemmatimonadetes, OD1 and Nitrospirae which were lower in type 2 diabetes and/or anti-inflammatory [ 11 ] . The Bacteroidetes to Firmicutes (B:F) ratio is well acknowledged to play a crucial part in maintaining normal intestinal homeostasis. A reduction of Bacteroidetes:Firmicutes ratio can be found in obesity, inflammatory bowel disease and autism spectrum disorder patients [ 46 , 47 ] . The Bacteroidetes:Firmicutes ratio was increased in the high dose BPs group from both sub-acute and chronic exposure (27 and 122 days, respectively) [ 4 ] . But other research revealed that, the Bacteroidetes:Firmicutes ratio reduced dramatically because of BPs induce the relative abundance of Firmicutes markedly increase, and Bacteroidetes significantly decrease [ 7 , 14 ] . However, in Joella’s study, Bacteroidetes:Firmicutes ratio were not significantly altered from BPA exposure [ 11 ] . 3.6.2. BPs change the composition of intestinal flora at class level Compared to control group, BPA exposure induce abundance of Bacteroidia markedly decrease [ 19 ] , but in Joella’s study, Bacteroidia increase among all BPs doses group [ 4 ] . In comparison with standard control group, BPA intervention induce the relative abundance of class Epsilonproteobacteria increase 2.88 folds, Class Clostridia and Mollicutes were less than their counterpart in standard control group (0.43 times and 0.0047 times, respectively) [ 1 ] . Clostridia class was markedly increase in BPA exposure group [ 19 ] . Similar result in Joella’s study, Mollicutes was down-regulate in both low and high dose BPs group [ 4 ] . However in Javurek’s result, BPA intervention result in population of Mollicutes class increase which is positive correlated with alteration of endocrine in male group [ 5 ] . Among all BPA doses, the relative abundance of Betaproteobacteria decreased [ 4 ] . The content of Bacilli class was decrease significantly in both low dose and high dose group (0.03mg/kg and 0.3mg/kg, respectively) [ 4 ] . In the high dose BPs group (0.3mg/kg) Erysipelotrichi and Verrucomicrobia decreased compared to the control group [ 4 ][ 18 ] . Compared to control group, the relative abundance of Alpha proteobacteria were decline in both low and high dose BPA intervention group (5mg/kg and 50mg/kg, respectively) [ 5 ][ 11 ] . 3.6.3. BPs change the composition of intestinal flora at family and genus level Bacteroidales, S24-7 family, Bacteroides, Lactobacillus, Fusobacterium and Escherichia-Shigella were the most common intestine flora in BPA exposure group and their relative abundance were greater than 1% [ 3 ] . The content of Helicobacter in BPA exposure group was 4.13 times more than that in control group [ 1 ][ 12 ][ 19 ] . Coprococcus comes reduce to zero in BPA intervention group [ 1 ][ 12 ] . The relative abundance of Eubacterium dolichum [ 2 ][ 12 ] , Clostridiumviride [ 1 ][ 15 ][ 16 ] and Lactobacillus [10,17−19] were decrease after BPA exposure (decrease by 61 percent, 78 percent and 69 percent, respectively). The abundance of Romboutsia, Aerococcus and Alistipes significantly decrease in BPA intervention group. Ruminiclostridium, Esicherichia-shigella and collinsella markedly increase after BPA exposure [ 2 ] . Odoribacter and Rikenellaceae increase after BPA exposure [ 4 ][ 12 ][ 13 ][ 15 ] . Bacteroides [ 3 ][ 4 ][ 9 ][ 12 ][ 19 ] , Clostridiales [ 4 ][ 12 ][ 14 ][ 15 ][ 18 ] , Ruminococcaceae [ 4 ][ 9 ][ 10 ][ 11 ][ 18 ] , Sutterella [ 4 ][ 5 ] and Turicibacter [ 4 ][ 11 ] were decrease from sub-acute BPA exposure. But in Yann study, Clostridium butyricum and Clostridium Cluster XIVa significantly increase after BPA intervention [ 16 ] . Different result also be found in Javurek’s study, the level of Sutterella were up-regulate in male BPA exposure group [ 5 ] . Campylobacterales increase in chronic exposure group. Anaeroplasma and Campylobacter decrease in chronic exposure group (0.3mg/kg) [ 4 ] . Akkermansia, Erysipelotrichaceae and Lachnospiraceae [ 18 ] significantly decrease in BPA chronic intervention group in comparison with control group [ 4 ][ 12 ][ 15 ] . The relative abundance of Akkermansia significantly decreased in BPA group which is negative correlate with the occurrence of obesity, diabetes and inflammatory bowel disease (IBD) [ 7 ][ 12 ] . The relative abundance of Akkermansia decreased from 12–2.6% in F 1 generation BPA exposure group which suggest BPA in utero of dam may have an effect on intestinal environment of offspring [ 9 ] . BPA exposure elevate the level of endotoxin, inflammation response and hepatic lipid content may lead to abundance of Akkermansia reduce and poor intestinal barrier function [ 7 ] . But in Javurek and Matthew’s study, Akkermansia were up-regulate in BPA exposure group [ 5 ][ 18 ] . Lactococcus was decrease and Mogibacteriaceae were increase in female BPA exposure group [ 5 ][ 12 ][ 18 ] . Methanobrevibacter was up-regulate in male BPA exposure group [ 5 ][ 9 ] , Desulfovibrio were decrease in male BPA exposure group [ 5 ][ 12 ] . Acinetobacter significantly increase from BPs exposure in comparison with control group [ 8 ][ 9 ] . Dorea and Bilophila increase in the cecum of F 1 generation BPA exposure group [ 9 ] . Oscillospira decrease from P 0 generation BPA exposure group in comparison with control group, its relative abundance larger than 1% [ 9 ][ 12 ][ 13 ][ 17 ] . But in Joella and Ni’s study, Oscillospira increase from female low dose group (5mg/kg) [ 11 ][ 15 ] . Jeotgalicoccus increase in P 0 generation BPA intervention group [ 9 ] . Prevotella was quiet few in female control group and cannot be detected in BPA exposure group [ 10 ][ 13 ][ 17 ] . Increased abundances of Oscillospira, Ruminococcus, Jeotgalicoccus and Lachnospiraceae in BPA treatment which could promote type 1 diabetes pathogenesis and/or inflammation [ 11 ] . Juvenile BPA exposure up-regulate abundances of unclassified RF32 , Anaerofustis and Rhodospirillales might also be anti-inflammatory and/or protective factor of type 1 diabetes [ 11 ] . Alteration of composition of gut microbial in adult mice group after four month BPA exposure is different from that in juvenile mice group, this suggest age of mice and duration of intervention may effect species alteration [ 11 ] . Blautia [ 12 ] , Dehalobacterium [ 12 ][ 17 ] and Enterobacteriaceae [ 12 ] increase in female low dose group (5mg/kg). Anaerostipes decrease from female low dose group (5mg/kg) [ 12 ] . Allobaculum increase from female high dose group (50mg/kg) and decrease from male high dose BPA intervention [ 12 ][ 17 ] . Bacteroidales and S24-7 decrease in female high dose, male high dose BPA intervention group and male low dose BPA intervention group (50mg/kg) [ 12 ] . The abundance of Porphyromonadaceae, Coriobacteriaceae [ 18 ] , Peptostreptococcaceae and Parabacteroides were increase in male low dose intervention group(5mg/kg) and male high dose group (50mg/kg) [ 12 ][ 15 ] . Carnobacteriaceae and Cyanobacteria decrease in male low dose BPA intervention group [ 12 ] . BPA exposure increase the abundance of Subdoligranulum [ 13 ] . BPA exposure decrease diversity of gut microbial and alter composition of gut microbial which affect physiology function of host [ 13 ] . Result indicate that BPA induce gut microbial dysbiosis [ 14 ] . Marvinbryantia markedly decrease from male BPA treatment group [ 15 ] . Ruminiclostridium and Tyzzerella significantly increase in 50mg/kg BPA exposure group [ 15 ] . Muribaculum and Parasutterella [ 19 ] decrease in both male and female BPA treatment group [ 15 ] . Bifidobacterium was the most important contributor for the observed differences between groups and BPA significantly decrease abundance of Bifidobacterium [ 16 ] . C. ruminantium markedly increase from male BPA intervention group in comparison to control group [ 17 ] . Adlercreutzia decrease from male BPA exposure group [ 17 ] . Composition of gut microbiota in offspring may be attributed to the transfer of BPA from maternal rats to offspring through umbilical cord blood during pregnancy and/or through breast milk during breastfeeding [ 17 ] . Additionally, BPA induced liver damage observed in offspring may also affect the diversity of intestinal microbial through the gut–liver axis [ 17 ] . Candidatus Arthromitus, Streptococcus agalactiae and Alkaliphilus increase after BPs exposure [ 18 ] . Abundance of Alloprevotella in BPs group slightly different from which in control group [ 19 ] . 4. Discussion Our pooled analysis result suggest that BPs exposure can lead to changes in diversity and composition of gut microbial. Diversity of gut microbiota reduced in BPs treatment group. Simpson index significantly increase after BPA exposure. Value of Simpson index reflect status of dominant species and greater Simpson index value implies lower diversity. Based on subgroup analysis result, changes in alpha diversity of gut microbial are likely to have association with dosage and duration of BPs exposure. Simpson index was significantly increase from low dose group but slightly increase from high dose group, our result is consistent with other studies [10,20−23] . Character of BPs is similar with serum endogenous hormone effect, which are hint yet high efficiency [ 42 ] , as such diversity of gut microbial is more sensitive to low dose BPs intervention. In Feng’s study, Simpson index significantly increase from short duration group [ 7 ] , which is same with our subgroup analysis result. Value of Chao index is positively correlate with abundance of microbial species, Chao index was markedly decrease from short term exposure but significantly increase in long term exposure, which indicate short duration BPs exposure decrease the abundance of gut microbial and long period BPs exposure increase the abundance of gut microbial, our result is similar with He and Joella’s research [ 3 , 4 ] . Chao index and Shannon significantly decrease in intestine sample group. Simpson index significantly increase in fecal sample group. Fecal has long been typical sample for gut microbial study due to its readily available, however, fecal sample isn’t always the optimum choice for analyzing low intestine resident flora, what’s more, different part of fecal contains various type of flora (anaerobic bacteria locate at internal and aerobic bacteria locate at external of fecal). Until today there is still lack of research utilizing intestine sample to study gut microbial of animals cause intestine sample is difficult to acquire, as such these research are less representative [ 48 ] . Our result indicate that Observe species significant decrease in long term group but Ace index have no significant change after BPs exposure. Lai’s research indicate observed species decrease after BPs exposure [ 1 , 10 , 19 ] , which reflect richness of species decrease, but other studies suggest observed species increase after BPs exposure [ 2 , 3 , 7 ] . In Ni’s study, Ace index increase after BPs intervention [ 15 ] , but in Tang’s study, Ace index decrease in BPs group [ 2 , 13 , 19 ] , Ace index reflect the abundance of intestine flora. An increasing number of studies have revealed that the composition of intestinal microbial in BPs exposure group have significant alteration at phylum, class, order, family and genus taxa in comparison with control group. BPs exposure induce pro-inflammatory bacteria increase and probiotic decrease, shifted composition of gut microbial may lead to several disease, for example, BPs exposure increased Jeotgalicoccus which is adverse factor for intestine health [ 11 ] . Esicherichia-shigella might be pathogen of nonalcoholic fatty liver disease (NAFLD), which increase from BPs exposure group [ 2 , 49 ] . Akkermansia decrease from BPs exposure group, reduction of Akkermansia is positively associate with obesity, type 2 diabetes and cardiovascular disease [ 7 , 9 , 12 ] . Lachnospiraceae is a potential probiotic exists in healthy condition intestine and play an important role in dietary fiber metabolism, Lachnospiraceae abundance decrease from BPs exposure [ 18 ] . Lactobacillus decrease from BPs exposure, which ferment carbohydrate to lactic acid and promote digestive system health [10,17−19] . Bifidobacterium significantly decrease from BPs intervention [ 16 ] , which is protective factor against inflammatory bowel disease and Alzheimer's disease cognitive impairment [ 50 , 51 ] . There are some limitations in our systematic review. Firstly, the cause-effect relationships of dysbiosis and disease still need further study to determine. Secondly, our review merely included rodents studies to investigate the relationship between BPs exposure and alteration of composition and diversity of intestinal microbial, however, there are many in vitro studies, epidemiological survey and mammal studies been excluded. Thirdly, the specific situation of dysbiosis differ between animals and human, our result is based on animal research, as such extrapolation result with human disease need cautiously determined. 5. Conclusion To conclude, BPs exposure altered the composition of gut microbial at several taxonomic level and significantly decrease diversity of gut microbial. However, causal association between gut dysbiosis and homeostasis imbalance still need more evidence to confirm. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests. References Lai KP, Chung YT, Li R, Wan HT, Wong CK (2016) Bisphenol A alters gut microbiome: Comparative metagenomics analysis. Environ Pollut 218:923–930. doi: 10.1016/j.envpol.2016.08.039 TangJuan. Several environmental endocrine disruptors affect liver and small intestine injury and alter fecal microbial composition in rats. [D].2017. NanJing Agricultural University,PhD dissertation He Jianbo. Correlation study between the changes of intestinal microflora and oxidative damage of small intestine under Tetrabromobisphenol A stress in rats.[D].2019. 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Oncol Translational Med 7(06):269–274 Supplementary Files SupplementaryMaterial.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1948177","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":128134098,"identity":"c0ca079e-cce5-4571-9432-8d27cb7753bf","order_by":0,"name":"Tian Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIie3PMWsCMRTA8XcEMp1mfUKxm3Og4CT2qyQc6KLgVDI43BHJDa109WM4drzjIFPU1fHuG9StQ0HdLea6OeQ3vz/vPYAgeECUZWnxrUZjxnRZC7X0J12ssmbjJklvYxNeO+tP+jDVLx1TRdtiNug1K9LiMCgNdgwhUDiqZEqB5e/ifkIyg7in3Uiv7VF+PQG63da/hb/F1zX7yVE6ChznvkQaFBQjA7PhQhrSKtG8MDz6uCbQLsEya1InEkSboHA29v7y/JnX1a86j18Pujz9qGWf5ev7yY34f+NBEATBny6ydE4+BRxeYAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-0412-7773","institution":"Hebei Medical University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Tian","middleName":"","lastName":"Wang","suffix":""},{"id":128134099,"identity":"ef58040e-7f90-443f-bb1d-e171e1de67b4","order_by":1,"name":"Suju Sun","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Suju","middleName":"","lastName":"Sun","suffix":""},{"id":128134100,"identity":"8bed190f-5474-4095-bcc5-45123a0861b0","order_by":2,"name":"Yancheng Feng","email":"","orcid":"","institution":"Xi'an Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yancheng","middleName":"","lastName":"Feng","suffix":""},{"id":128134101,"identity":"2f3eddeb-d32a-481e-9b7d-4b99c196c04e","order_by":3,"name":"Zhiwang Guo","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhiwang","middleName":"","lastName":"Guo","suffix":""},{"id":128134102,"identity":"0c4d99e0-6a04-4482-8969-424ee28f169a","order_by":4,"name":"Hao Wang","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hao","middleName":"","lastName":"Wang","suffix":""},{"id":128134103,"identity":"ece72b87-0fb6-409d-9f14-8c711c9fa30b","order_by":5,"name":"Liqin Wang","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Liqin","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2022-08-10 08:44:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1948177/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1948177/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":25145658,"identity":"2b4b28f5-3e4d-4fc7-8281-1611d99b7c07","added_by":"auto","created_at":"2022-08-12 15:56:31","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":76643,"visible":true,"origin":"","legend":"\u003cp\u003ePreferred Reporting Items for Systematic Reviews and Meta-\u003c/p\u003e\u003cp\u003eAnalyses (PRISMA) Flow Diagram.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1948177/v1/52a2f34f974c370222f4b99b.jpg"},{"id":31348680,"identity":"8e7ee019-6a08-4494-95f8-a486f0484bf8","added_by":"auto","created_at":"2023-01-10 08:00:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":696660,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1948177/v1/d655630b-3189-47e8-9c67-a10b59003ced.pdf"},{"id":25145659,"identity":"dac84b6e-dc05-4264-a64d-c6b83e588349","added_by":"auto","created_at":"2022-08-12 15:56:32","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":896208,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-1948177/v1/639764ffdd1144b64083dfe7.docx"}],"financialInterests":"","formattedTitle":"The relationship between Bisphenols exposure and intestinal flora: a systematic review and meta-analysis","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eBPs are organic compounds that been widely used in many industrial applications to produce epoxy resin and polycarbonate plastic (PC) since 1960s\u003csup\u003e[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/sup\u003e. It has significantly promote the development of industrial whereas brings great deals of detrimental effects to human health and contaminant our environment as a result of common use of plastic product. Because of widely used in producing plastic product, BPs have pollute soil, water and atmosphere environment, it can be intake through oral, dermal contact and respiratory inhalation. BPs as one of the most widespread exoestrogens, exposure of BPs may increase the risk of suffer from reproductive disease due to its phytoestrogen effect and bind to the estrogen receptor\u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e][\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eResult from He\u0026rsquo;s research suggest that homeostasis of host is very sensitive to BPs at relative low dose\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. In Chao\u0026rsquo;s study, low dose BPs exposure impairs synaptic plasticity and cognitive function\u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e, similar result also be found in Zhang\u0026rsquo;s study\u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e. High throughput sequencing revealed that BPs increase relative abundance of Firmicutes、Tenericutes and Proteobacteria in rats fecal, decrease relative abundance of Bacteroides. BPs exposure alter abundance and diversity gut microbial as well as composition of gut microbial in rats\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. An increasing importance has been attached to function of intestinal microbial, which is deemed as the second brain of human in some research \u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e][\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e. The superficial area of intestinal mucosa in adult can reach about 300 square meters, which is human\u0026rsquo;s largest organ to interact with external environment\u003csup\u003e[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/sup\u003e. Totally there are about 100 trillion bacteria in body of adult, 80% of which located in intestine, about ten times as many as cells in human body. Weight of gut microbiota in adult is more than 1kg under health circumstance, containing more than one thousand microbial species consist of 3.3\u0026nbsp;million gene. Heterogeneity of gut microbial between individuals varied from 80\u0026ndash;90%. Gut microbial plays an important role in precisely reflect human metabolism status and endocrine homeostasis and sensitive to alteration of content of serum biochemical substance\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e, as such gut microbial are deemed as a crucial indicator used to reflect host health status at an early exposure stage \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Gut dysbiosis may result in disequilibrium of host homeostasis, including hypertension, cancer, hepatic disease, Hutchinson-Gilford Progeria syndrome, immune disease and endocrine function disorder\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e][\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eA surging number of studies have suggested the relationship of composition of gut microbial and BPs intervention. BPA intervention significantly change the composition of intestine microbiota in colon, abundance of BPA degrading bacteria increase (such as Microbacterium and Alcaligenes) \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Bacteria significantly altered at the phylum, class and genus level from BPA intervention. Sub-acute (16 days) BPA exposure significantly altered the alpha diversity after BPA exposure\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Javurek result indicate that increase in Proteobacteria which is associated with intestinal inflammation may persist in filial generation because gut microbial dysbiosis caused by BPA intervention has also exist in offspring from control group \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. BPA exposure cause generational and sex-dependent gut microbiome changes. Several of the bacteria whose relative abundance increased with BPA exposure (such as Bacteroides, Mollicutes, Prevotellaceae, Erysipelotrichaceae, Akkermansia, Methanobrevibacter, Sutterella ) are pro-inflammatory and associated with several diseases, especially inflammatory bowel disease (IBD), metabolic disorders and reproductive cancer \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Probiotic like Akkermansia, Lachnospiraceae and Bifidobacterium decrease from BPs exposure\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e .\u003c/p\u003e \u003cp\u003eDiversity of gut microbial also reflected by BPs exposure\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Alpha diversity indices consist of observed species, Chao index, Ace index, Shannon index and Simpson index. Chao index estimate amount of observed species of community base on chao1 algorithm\u003csup\u003e[\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]\u003c/sup\u003e. Ace index evaluate total quantity of species, value of Ace and Chao index are positively correlate with species richness. Shannon index is used to assess diversity of microbial. Greater Shannon index value indicates higher diversity of microbial community. Simpson index reflect status of dominant species in community, greater simpson index value implies lower diversity. Since result of studies revealing the relationship of composition at different taxonomy level (phylum, class, genus and species) as well as alpha diversity of gut microbial and BPs exposure are different from each other. Research focusing on influence of BPs on diversity of gut microbial suggest that observed species went decrease after BPs exposure\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. Chao index decrease after BPs exposure\u003csup\u003e[11,13\u0026minus;15]\u003c/sup\u003e. Ace index decrease after BPs exposure\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Shannon index decrease after BPs exposure\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Simpson index increase after BPs exposure\u003csup\u003e[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. It is necessary for us to carried out a systematic review and meta analysis for 5 alpha diversity index (observed species, chao index, Ace index, Shannon index, Simpson index) to enlarge the sample size and acquire more accurate evidence.\u003c/p\u003e \u003cp\u003eMost studies focusing on BPs effect on composition and diversity of intestine flora are animal experiment research so far, as such we carried out animal experiment review.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003eWe conducted systematic review according to protocol registered on PROSPERO and registration number is CRD42022300159. This systematic review and meta analysis was implemented in line with predetermined criteria outlined by the PRISMA guidelines. In accordance with a predetermined Population (including animal species)-Exposure-Comparator-Outcome (PECO) guidelines. Literature in which rodents were exposed to BPs, with control group set as comparison. Outcomes clearly demonstrate diversity and composition of gut microbial (relative abundance of genera at different taxonomic levels) are eligible for inclusion.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Search Strategy\u003c/h2\u003e \u003cp\u003ePubMed, Wed of Science, Science Direct, SinoMed, CNKI databases were searched by 2 independent investigators for relevant articles published from database inception date to February 24, 2022. The search of articles was carried out by the following retrieval strategies: (1) BPs OR 4,4-dihydroxy-2,2- diphenylpropane OR 2,2-bis (4-hydroxyphenyl) propane OR diphenylolpropane; (2) mouse OR mice OR rabbit OR rats; (3) gut microbiota OR intestine flora OR gut microbiome OR fecal microbiota; and (3) terms (1) and (2).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Specific inclusion and exclusion criteria\u003c/h2\u003e \u003cp\u003eStudies were included if they meet with following criteria: (1)Study was design as randomized controlled trial; (2) Experimental animal were rodent (including rat, mice and rabbit), there were no limitations on strain, gender and age; (3) Experimental group was exposed to BPs (dissolved in corn oil or DMSO), intervention means (mainly via oral administer),intervention duration and dosage of BPs were clearly reported in method section; (4) Control group receive vehicle or no treatment, baseline character among groups were not significantly different; (5) Outcome indicator including relative abundance of genera at different taxonomic level (phylum,class,genus,species), diversity of gut microbial (alpha diversity); (6) Publication type allow for primary research,journal article and dissertation. Exclusion criteria are described as follows: (1) Publication type were review or meeting abstract; (2) Subject were not rodents, vitro experiments;(3) Study focus on river sediment or soil bacteria bio-degradation capacity for BPs; (4)Outcome data of study are incomplete or unclear; (5) Duplicate articles.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Data extraction\u003c/h2\u003e \u003cp\u003eData were extracted from eligible articles according to inclusion and exclusion criteria. A standardized template from Cochrane Handbook for Systematic Reviews of Interventions was used to extract data ,including study ID, first author name,language, publish year, publication type, geographical location, study design, intervention manner(dosage, duration, pathway), sample size of each group, information of animal (strains,age,gender), published journal,outcome indicator (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation).Two paired reviewers independently extracted this information from each included study and resolved any disagreements through discussion.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Risk of bias assessment\u003c/h2\u003e \u003cp\u003eWe evaluated the risk of bias of each study using the Systematic Review Center for Laboratory Animal Experimentation\u0026rsquo;s (SYRCLE) risk of bias tool \u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. There are ten domains included in this scale that evaluate selection bias, performance bias, detection bias, attrition bias, reporting bias, and other sources of bias of study, respectively. Quality reviewers select \u0026lsquo;yes\u0026rsquo;, \u0026lsquo;no\u0026rsquo; or \u0026lsquo;unclear\u0026rsquo; for each domain (Yes indicates low risk of bias in this domain and results of study are deemed reliable. No represents a significant risk of bias in the study. Unclear stands for susceptible bias to some degree but insufficient to influence result).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5. Statistical analysis\u003c/h2\u003e \u003cp\u003eMeta and metafor package from software R (version 4.1.1) were applied to measure the significance of heterogeneity, describe outcome indicators (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation), estimate pooled-effect(data synthesis), generate forest plot, sensitivity analyse to probe source of heterogeneity and assess publication bias (funnel plot). \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026le;\u0026thinsp;0.10 were considered significant in heterogeneity test and α level set at 0.05 for other statistical test. Fail safe number were calculated to probe stability of pooled analysis.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eIn total, 1109 articles were identified from the 5 database searches. After removing duplicate publications, 666 articles without repetition were screened for eligibility. Of the 463 studies were excluded after title and abstract review, 203 articles were carried out full text review for eligibility. According to the preliminary defined inclusion and exclusion criteria 184 research were excluded. Eventually, 19 literature satisfied with the inclusion criteria and adopted for systematic review (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the study characteristics, study design and outcome indicators.\u003c/p\u003e\n\u003cdiv class=\"Section2\" id=\"Sec9\"\u003e\n \u003ch2\u003e3.1. Study Characteristics\u003c/h2\u003e\n \u003cp\u003eAll eligible studies was rodents animal researches. BPs intervention means were gavage and oral administer. The dose of BPs varied from 0.005 to 100 mg/kg, and the duration of intervention ranging from 2 to 24 weeks. Sample tissues includes intestine contents and feces. The main selected indicators in the meta-analysis were alpha diversity and relative abundance of genera at different taxonomic level (phylum, class, genus and species). Other information that were important for the objective including the first author\u0026rsquo;s name, animal age, and sample size of both control and experimental groups were extracted (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCharacteristic of included studies\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"12\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAuthor\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCountry\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLanguage\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePublish type\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSpecies\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003cp\u003e(week)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStudy design\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePublish year\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eJournal\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDosage\u003c/p\u003e\n \u003cp\u003e(mg/kg)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDuration\u003c/p\u003e\n \u003cp\u003e(week)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSample size\u003c/p\u003e\n \u003cp\u003e(C/T)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLai K.P.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEnglish\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCD 1 mice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletely randomized design 4 groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEnvironmental Pollution\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4/4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTang Juan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChinese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSD rat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletely randomized design4groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNanjing Agricultural University\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6/6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHe Jianbo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChinese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSD rat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletely randomized design6groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHangzhou Normal University\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7/7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJoella Xu\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU.S.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEnglish\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNOD mice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletely randomized design2groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOrgan toxicity and mechanism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20/20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAngela B. Javurek\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU.S.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEnglish\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCalifornia mice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletely randomized design3groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGut Microbes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12/10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJennifer AA DeLuca\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU.S.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEnglish\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eC57BL/6 mice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletely randomized design4groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExperimental Biology and Medicine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12/10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDan Feng\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEnglish\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCD 1 mice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletely randomized design2groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEnvironmental Pollution\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8/8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDENG Yuanyuan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChinese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eC57BL/6J mice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletely randomized design2groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNanjing Medical University\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10/10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLavanya Reddivari\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU.S.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEnglish\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDutch-Belted rabbit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletely randomized design2groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAmerican society for microbiology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4/4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGraciel Diamante\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU.S.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEnglish\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eC57BL/6J mice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletely randomized design2groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEnvironment international\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8/8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJoella Xu\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU.S.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEnglish\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNOD mice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletely randomized design2groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eARCHIVES OF TOXICOLOGY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15/15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSarabjit Kaur\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU.S.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEnglish\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCalifornia mice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletely randomized design4groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eScientific Reports\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20/20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLing Feng\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEnglish\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCD 1 mice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletely randomized design2groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEnvironmental Pollution\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10/10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMing-Kuei Shih\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEnglish\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSD rat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletely randomized design5groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMolecules\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14/13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYinhua Ni\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEnglish\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eC57BL/6 mice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletely randomized design5 groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChemosphere\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6/6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYann Malais\u0026eacute;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFrance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEnglish\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eC3H/HeN mice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletely randomized design2 groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eScientific reports\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJin-Xian Liao\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEnglish\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSD rat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletely randomized design4 groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInternational Journal of Molecular Sciences\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u0026thinsp;~\u0026thinsp;8 per group\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMatthew V. Gomez\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU.S.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEnglish\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCD 1 mice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletely randomized design5 groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSociety of toxicology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19/17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChen Yuran\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChinese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBalb /c - nu mice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompletely randomized design5 groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJiangXi\u003c/p\u003e\n \u003cp\u003eScience\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6/6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec10\"\u003e\n \u003ch2\u003e3.2. Quality assessment of study\u003c/h2\u003e\n \u003cp\u003eRisk of bias was assessed using Systematic Review Center for Laboratory Animal Experimentation(SYRCLE) quality-assessment tools. Result indicate that generation of assignment allocation sequence were reported in 10 publications which concerned to be at low risk. Baseline characteristics of animals from control and experiment group were deemed as homogeneity in 7 identified studies. Of 1 publication\u0026rsquo;s allocation concealment was sufficient and correct. 12 studies were complied with randomly attribute housing (individual polypropylene cage) for subject. Only 1 article clearly demonstrate performance blinding of investigator in method design section. There were 10 articles meet with random outcome assessment. Blinding of outcome assessment was considered low risk in 2 eligible studies. In each study entire animals were included for final analysis, so incomplete outcome data domain were deemed as low risk for all included studies. Primary result as well as secondary result details from all selected studies were reported in accordance with protocol and no significant bias arouse from other domain. On the whole, nine literature was considered to have middle risk of bias, eight studies were deemed as low risk and two researches were regarded high risk of bias (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSYRCLE risk of bias tool for studies assessment\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"11\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eReferences\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSequence\u003c/p\u003e\n \u003cp\u003egeneration\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003cp\u003echaracteristic\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAllocation\u003c/p\u003e\n \u003cp\u003econcealment\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRandom\u003c/p\u003e\n \u003cp\u003ehousing\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePerformance\u003c/p\u003e\n \u003cp\u003eBlinding\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRandom outcome assessment\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBlinding of\u003c/p\u003e\n \u003cp\u003eoutcome assessment\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIncomplete\u003c/p\u003e\n \u003cp\u003eoutcome data\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSelective outcome\u003c/p\u003e\n \u003cp\u003ereporting\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOther sources of bias\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLai 2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTang 2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHe 2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eXu 2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJavurek 2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n 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2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFeng 2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n 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2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGraciel 2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n 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2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLing 2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eShih 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNi 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMalais\u0026eacute; 2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLiao 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMatthew 2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChen 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec11\"\u003e\n \u003ch2\u003e3.3. Heterogeneity test and pooled analysis\u003c/h2\u003e\n \u003cp\u003eObserved species, Chao index, Ace index, Shannon index and Simpson index were selected to reflect alpha diversity of gut microbial. Alpha diversity consist of comprehensive indices that reflect richness and diversity of specific domain or ecology system. All tags were clustered to OTU at 97% sequence similarity (16S rRNA sequencing was conducted on bacterial DNA extracted from fecal or intestine sample).\u003c/p\u003e\n \u003cp\u003eHeterogeneity test indicate five indices have significant heterogeneity (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e), so random effect model was chosen for pooled analysis. According to result of pooled analysis, observed species, chao index and Shannon index slightly decrease after BPs exposure. Ace index moderately increase in BPs treatment group. Simpson index significantly increase in BPs intervention group. Our result suggest that BPs reduce diversity of gut microbial (Supplementary Fig. S1).\u003c/p\u003e\n \u003cp\u003eWe use fail-safe number to probe stability of result of pooled analysis, the fail-safe number of Simpson index was 26, so the result is reliable.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab3\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eInfluence of BPs on alpha diversity of gut microbial\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"9\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eIndicators\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eStudies\u003c/p\u003e\n \u003cp\u003e(\u003cem\u003eN\u003c/em\u003e)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eAnimals\u003c/p\u003e\n \u003cp\u003e(\u003cem\u003eN\u003c/em\u003e)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eHeterogeneity test\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eEffect model\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eMeta analysis result\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e(%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eSMD\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95%\u003cem\u003eCI\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eobserved species\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e90.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRandom effects model\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.385\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-4.217\u0026thinsp;~\u0026thinsp;1.447\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.338\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChao index\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e238\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e89.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRandom effects model\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.991\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-2.523\u0026thinsp;~\u0026thinsp;0.541\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.205\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAce index\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e60.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.055\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRandom effects model\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.355\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.537\u0026thinsp;~\u0026thinsp;1.248\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.435\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eShannon index\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e172\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e82.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRandom effects model\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.462\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.371\u0026thinsp;~\u0026thinsp;0.447\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.319\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSimpson\u003c/p\u003e\n \u003cp\u003eindex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e49.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.079\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRandom effects model\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.945\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.213\u0026thinsp;~\u0026thinsp;1.676\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec12\"\u003e\n \u003ch2\u003e3.4. Funnel plot and sensitivity analysis\u003c/h2\u003e\n \u003cp\u003eBegg rank correlation test was carried out examine the asymmetry of funnel plot (Supplementary Fig. S2). Publication bias were not significant for all alpha indicators(\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Supplementary Table S1), hence results of meta analysis are not influenced by publication bias and reliable.\u003c/p\u003e\n \u003cp\u003eSensitivity analysis was conducted to determine impact of each study on pooled analysis result(Supplementary Fig. S3). In observed species pooled analysis, Tang, He and Chen\u0026rsquo;s studies obviously affect result of pooled analysis. In result of synthesis of Chao index, result of Tang, He\u0026rsquo;s researches was significantly different from pooled result. Tang, Ling and Ni\u0026rsquo;s Ace result have significant difference compared to other studies. He, Javurek and Feng\u0026rsquo;s Shannon outcome were obviously varied from other researches. Only Ni\u0026rsquo;s Simpson result was distinct from other outcome.\u003c/p\u003e\n \u003ch2\u003e3.5. Subgroup analysis was applied to explore effects of different BPs dose, intervention duration and sample tissue\u003c/h2\u003e\n \u003cdiv class=\"Section3\" id=\"Sec13\"\u003e\n \u003ch2\u003e3.5.1. Subgroup analysis for different BPs dosage\u003c/h2\u003e\n \u003cp\u003eTo figure out different dosage of BPs influence on alpha diversity of gut microbial, subgroup analysis for different dose of BPs was conducted (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Simpson index in low dose group were significantly increased after BPs exposure (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). Other alpha diversity indicators (observed species, Chao, Ace, Shannon) exhibit no significant changes after BPs exposure.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab4\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSubgroup analysis for different dosage of BPs\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"9\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eIndicators\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eDosage\u0026thinsp;≦\u0026thinsp;0.20mg/kg\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eDosage\u0026thinsp;\u0026gt;\u0026thinsp;0.20mg/kg\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudies\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(\u003c/strong\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eN\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eSMD\u003c/span\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e95%\u003c/strong\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eCI\u003c/span\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eP\u003c/span\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudies\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(\u003c/strong\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eN\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eSMD\u003c/span\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e95%\u003c/strong\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eCI\u003c/span\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eP\u003c/span\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eObserved species\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.518\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-2.795\u0026thinsp;~\u0026thinsp;3.831\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.759\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-3.437\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-7.402\u0026thinsp;~\u0026thinsp;0.528\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.089\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChao\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.116\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.327\u0026thinsp;~\u0026thinsp;1.095\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.851\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-2.323\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-5.603\u0026thinsp;~\u0026thinsp;0.958\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.165\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAce\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.637\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.479\u0026thinsp;~\u0026thinsp;1.752\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.263\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.049\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.675\u0026thinsp;~\u0026thinsp;1.773\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.955\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eShannon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.679\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.671\u0026thinsp;~\u0026thinsp;0.313\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.180\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.285\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.951\u0026thinsp;~\u0026thinsp;1.382\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.738\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSimpson\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.262\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.517\u0026thinsp;~\u0026thinsp;2.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.684\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.772\u0026thinsp;~\u0026thinsp;2.141\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.357\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab5\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSubgroup analysis for different duration of intervention\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"9\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eIndicators\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eDuration\u0026thinsp;≦\u0026thinsp;5 weeks\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eDuration\u0026thinsp;\u0026gt;\u0026thinsp;5 weeks\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudies\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(\u003c/strong\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eN\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eSMD\u003c/span\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e95%\u003c/strong\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eCI\u003c/span\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eP\u003c/span\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudies\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(\u003c/strong\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eN\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eSMD\u003c/span\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e95%\u003c/strong\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eCI\u003c/span\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eP\u003c/span\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eObserved species\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.610\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-6.061\u0026thinsp;~\u0026thinsp;2.840\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.478\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.104\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.089~-0.120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.028\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChao\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.477\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.853~-0.102\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.621\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.168\u0026thinsp;~\u0026thinsp;1.075\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAce\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.450\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.436\u0026thinsp;~\u0026thinsp;1.335\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.320\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.204\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.750\u0026thinsp;~\u0026thinsp;2.157\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.838\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eShannon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.420\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.676\u0026thinsp;~\u0026thinsp;0.837\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.513\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.506\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.959\u0026thinsp;~\u0026thinsp;0.946\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.494\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSimpson\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.270\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.538\u0026thinsp;~\u0026thinsp;2.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.609\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.702\u0026thinsp;~\u0026thinsp;1.921\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.362\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab6\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSubgroup analysis for different sample type\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"9\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eIndicators\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eSample\u0026thinsp;=\u0026thinsp;fecal\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eSample\u0026thinsp;=\u0026thinsp;intestine\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudies\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(\u003c/strong\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eN\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eSMD\u003c/span\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e95%\u003c/strong\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eCI\u003c/span\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eP\u003c/span\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudies\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(\u003c/strong\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eN\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eSMD\u003c/span\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e95%\u003c/strong\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eCI\u003c/span\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003eP\u003c/span\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChao\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.371\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-3.860\u0026thinsp;~\u0026thinsp;1.118\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.280\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.555\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.067~-0.043\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.034\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAce\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.445\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.384\u0026thinsp;~\u0026thinsp;1.275\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.293\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.204\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.750\u0026thinsp;~\u0026thinsp;2.157\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.838\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eShannon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.310\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.609\u0026thinsp;~\u0026thinsp;0.990\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.640\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.904\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.576~-0.233\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSimpson\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.302\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.688\u0026thinsp;~\u0026thinsp;1.915\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.187\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.582\u0026thinsp;~\u0026thinsp;1.956\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.836\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\"\u003e* only 1 article have observed species from intestine sample group, so observed species is excluded\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec14\"\u003e\n \u003ch2\u003e3.5.2. Subgroup analysis for different intervention duration\u003c/h2\u003e\n \u003cp\u003eBPs effect on alpha diversity of intestinal flora in short duration group was distinct from which in long duration group (Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e). Observed species was significantly decrease in long term BPs exposure group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.028). Chao was significantly decrease in short term BPs exposure (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013). Value of Chao index was significantly grow in long term BPs exposure group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007). Simpson index was significantly increase after short term BPs exposure (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). Compared to control group observed species and Shannon index were slightly decrease in short term BPs exposure group. Ace and Simpson indicators were marginally increase in long term BPs exposure group. Shannon decrease a bit in long term BPs exposure group.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec15\"\u003e\n \u003ch2\u003e3.5.3. Subgroup analysis for different sample tissue\u003c/h2\u003e\n \u003cp\u003eTwo group have different changes of alpha diversity caused by BPs exposure (Table \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e). In fecal sample group, Simpson index significantly increase after BPs intervention (\u003cem\u003eSMD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.302, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), fail-safe number is 25. Observed species was not analyzed because of limited number of study. Ace index slightly increase for BPs intervention (\u003cem\u003eSMD\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.445, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.293). In intestine sample group, chao and Shannon index were significantly decrease due to BPs exposure (\u003cem\u003eSMD\u003c/em\u003e= -0.555, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.034 and \u003cem\u003eSMD\u003c/em\u003e=-0.904, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008, respectively).\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec16\"\u003e\n \u003ch2\u003e3.5.4. Fail-safe number of subgroup analysis result\u003c/h2\u003e\n \u003cp\u003eFail-safe number of Simpson index from low dose group was 10, which indicate a stable result. Observed species and chao index from long term group fail-safe number were 3, which suggest result is unsteady. Chao index and Simpson index from short term group were 56 and 12, respectively. Fail-safe number of Chao index and Shannon index from intestine group were 3 and 5, respectively.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec17\"\u003e\n \u003ch2\u003e3.6. Narrative synthesis for alteration of gut microbiota composition after BPs treatment\u003c/h2\u003e\n \u003cp\u003eBPs can influence composition of gut microbial from the phylum to genus levels (Supplementary Table S2).\u003c/p\u003e\n \u003cdiv class=\"Section3\" id=\"Sec18\"\u003e\n \u003ch2\u003e3.6.1. BPs change the composition of intestinal flora at phylum level\u003c/h2\u003e\n \u003cp\u003eFirmicutes and Bacteroidetes were the most abundant phyla in colonic mucosal tissues of both control and BPA intervention mice\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Compared to control group, relative abundance of Proteobacteria, Bacteroidetes and phylum Tenericutes in intestine/fecal samples were mainly affected by BPs exposure. Many result indicates that BPs exposure up-regulate the level of Proteobacteria\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e, but in Matthew study, Proteobacteria was decreased from the low dose BPs exposure, studies also revealed that increase level of Proteobacteria is positively associated with the occurrence of intestinal inflammation. Abundance of Bacteroidetes and phylum Tenericutes decrease from BPs group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e, specifically Bacteroidetes markedly increase in high dose group but significantly decrease in low dose group (50mg/kg)\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Tenericutes was significantly down-regulate in both high dose and low dose group for male mice(0.03mg/kg and 0.3mg/kg, respectively)\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. BPs intervention significantly increase the relative abundance of Firmicutes\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e and Fusobacteria\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e, yet in He\u0026rsquo;s study, phylum Firmicutes significantly decrease in middle and high dose group (100 and 1000mg/kg)\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Also in Matthew\u0026rsquo;s study, phylum Firmicutes decrease from the high dose (0.3mg/kg)\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Verrucomicrobia in middle and high dose group was increase drastically\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Juvenile BPs intervention promote the level of Verrucomicrobia increase \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. The relative abundance of Verrucomicrobia was positive correlation with BPs concentration in a dose-response relationship in males group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. However, in Feng\u0026rsquo;s study, the abundance of Verrucomicrobia was decrease distinctly from BPs exposure group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. The high dose BPs (0.3mg/kg) increased the level of Cyanobacteria and TM7\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. BPs decrease the relative abundance of Gemmatimonadetes, OD1 and Nitrospirae which were lower in type 2 diabetes and/or anti-inflammatory\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eThe Bacteroidetes to Firmicutes (B:F) ratio is well acknowledged to play a crucial part in maintaining normal intestinal homeostasis. A reduction of Bacteroidetes:Firmicutes ratio can be found in obesity, inflammatory bowel disease and autism spectrum disorder patients\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e]\u003c/sup\u003e. The Bacteroidetes:Firmicutes ratio was increased in the high dose BPs group from both sub-acute and chronic exposure (27 and 122 days, respectively)\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. But other research revealed that, the Bacteroidetes:Firmicutes ratio reduced dramatically because of BPs induce the relative abundance of Firmicutes markedly increase, and Bacteroidetes significantly decrease\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. However, in Joella\u0026rsquo;s study, Bacteroidetes:Firmicutes ratio were not significantly altered from BPA exposure \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec19\"\u003e\n \u003ch2\u003e3.6.2. BPs change the composition of intestinal flora at class level\u003c/h2\u003e\n \u003cp\u003eCompared to control group, BPA exposure induce abundance of Bacteroidia markedly decrease\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e, but in Joella\u0026rsquo;s study, Bacteroidia increase among all BPs doses group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. In comparison with standard control group, BPA intervention induce the relative abundance of class Epsilonproteobacteria increase 2.88 folds, Class Clostridia and Mollicutes were less than their counterpart in standard control group (0.43 times and 0.0047 times, respectively)\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Clostridia class was markedly increase in BPA exposure group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Similar result in Joella\u0026rsquo;s study, Mollicutes was down-regulate in both low and high dose BPs group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. However in Javurek\u0026rsquo;s result, BPA intervention result in population of Mollicutes class increase which is positive correlated with alteration of endocrine in male group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Among all BPA doses, the relative abundance of Betaproteobacteria decreased\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. The content of Bacilli class was decrease significantly in both low dose and high dose group (0.03mg/kg and 0.3mg/kg, respectively)\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. In the high dose BPs group (0.3mg/kg) Erysipelotrichi and Verrucomicrobia decreased compared to the control group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Compared to control group, the relative abundance of Alpha proteobacteria were decline in both low and high dose BPA intervention group (5mg/kg and 50mg/kg, respectively)\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec20\"\u003e\n \u003ch2\u003e3.6.3. BPs change the composition of intestinal flora at family and genus level\u003c/h2\u003e\n \u003cp\u003eBacteroidales, \u003cem\u003eS24-7\u003c/em\u003e family, Bacteroides, Lactobacillus, Fusobacterium and Escherichia-Shigella were the most common intestine flora in BPA exposure group and their relative abundance were greater than 1% \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. The content of Helicobacter in BPA exposure group was 4.13 times more than that in control group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Coprococcus comes reduce to zero in BPA intervention group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. The relative abundance of Eubacterium dolichum\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e, Clostridiumviride\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e and Lactobacillus\u003csup\u003e[10,17\u0026minus;19]\u003c/sup\u003e were decrease after BPA exposure (decrease by 61 percent, 78 percent and 69 percent, respectively).\u003c/p\u003e\n \u003cp\u003eThe abundance of Romboutsia, Aerococcus and Alistipes significantly decrease in BPA intervention group. Ruminiclostridium, Esicherichia-shigella and collinsella markedly increase after BPA exposure\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Odoribacter and Rikenellaceae increase after BPA exposure\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Bacteroides\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e, Clostridiales\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e, Ruminococcaceae\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e, Sutterella\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e and Turicibacter \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003ewere decrease from sub-acute BPA exposure. But in Yann study, Clostridium butyricum and Clostridium Cluster XIVa significantly increase after BPA intervention \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Different result also be found in Javurek\u0026rsquo;s study, the level of Sutterella were up-regulate in male BPA exposure group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Campylobacterales increase in chronic exposure group. Anaeroplasma and Campylobacter decrease in chronic exposure group (0.3mg/kg)\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Akkermansia, Erysipelotrichaceae and Lachnospiraceae\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e significantly decrease in BPA chronic intervention group in comparison with control group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eThe relative abundance of Akkermansia significantly decreased in BPA group which is negative correlate with the occurrence of obesity, diabetes and inflammatory bowel disease (IBD)\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. The relative abundance of Akkermansia decreased from 12\u0026ndash;2.6% in F\u003csub\u003e1\u003c/sub\u003e generation BPA exposure group which suggest BPA in utero of dam may have an effect on intestinal environment of offspring \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. BPA exposure elevate the level of endotoxin, inflammation response and hepatic lipid content may lead to abundance of Akkermansia reduce and poor intestinal barrier function\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. But in Javurek and Matthew\u0026rsquo;s study, Akkermansia were up-regulate in BPA exposure group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eLactococcus was decrease and Mogibacteriaceae were increase in female BPA exposure group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Methanobrevibacter was up-regulate in male BPA exposure group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e, Desulfovibrio were decrease in male BPA exposure group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Acinetobacter significantly increase from BPs exposure in comparison with control group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Dorea and Bilophila increase in the cecum of F\u003csub\u003e1\u003c/sub\u003e generation BPA exposure group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Oscillospira decrease from P\u003csub\u003e0\u003c/sub\u003e generation BPA exposure group in comparison with control group, its relative abundance larger than 1%\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. But in Joella and Ni\u0026rsquo;s study, Oscillospira increase from female low dose group (5mg/kg)\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Jeotgalicoccus increase in P\u003csub\u003e0\u003c/sub\u003e generation BPA intervention group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Prevotella was quiet few in female control group and cannot be detected in BPA exposure group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Increased abundances of Oscillospira, Ruminococcus, Jeotgalicoccus and Lachnospiraceae in BPA treatment which could promote type 1 diabetes pathogenesis and/or inflammation\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eJuvenile BPA exposure up-regulate abundances of unclassified \u003cem\u003eRF32\u003c/em\u003e, Anaerofustis and Rhodospirillales might also be anti-inflammatory and/or protective factor of type 1 diabetes\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Alteration of composition of gut microbial in adult mice group after four month BPA exposure is different from that in juvenile mice group, this suggest age of mice and duration of intervention may effect species alteration\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eBlautia\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e, Dehalobacterium\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e and Enterobacteriaceae\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003eincrease in female low dose group (5mg/kg). Anaerostipes decrease from female low dose group (5mg/kg) \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Allobaculum increase from female high dose group (50mg/kg) and decrease from male high dose BPA intervention \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Bacteroidales and \u003cem\u003eS24-7\u003c/em\u003e decrease in female high dose, male high dose BPA intervention group and male low dose BPA intervention group (50mg/kg)\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. The abundance of Porphyromonadaceae, Coriobacteriaceae\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e, Peptostreptococcaceae and Parabacteroides were increase in male low dose intervention group(5mg/kg) and male high dose group (50mg/kg)\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e][\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Carnobacteriaceae and Cyanobacteria decrease in male low dose BPA intervention group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. BPA exposure increase the abundance of Subdoligranulum\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eBPA exposure decrease diversity of gut microbial and alter composition of gut microbial which affect physiology function of host\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Result indicate that BPA induce gut microbial dysbiosis\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Marvinbryantia markedly decrease from male BPA treatment group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Ruminiclostridium and Tyzzerella significantly increase in 50mg/kg BPA exposure group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Muribaculum and Parasutterella\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e decrease in both male and female BPA treatment group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Bifidobacterium was the most important contributor for the observed differences between groups and BPA significantly decrease abundance of Bifidobacterium \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. C. ruminantium markedly increase from male BPA intervention group in comparison to control group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Adlercreutzia decrease from male BPA exposure group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eComposition of gut microbiota in offspring may be attributed to the transfer of BPA from maternal rats to offspring through umbilical cord blood during pregnancy and/or through breast milk during breastfeeding\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Additionally, BPA induced liver damage observed in offspring may also affect the diversity of intestinal microbial through the gut\u0026ndash;liver axis\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Candidatus Arthromitus, Streptococcus agalactiae and Alkaliphilus increase after BPs exposure\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Abundance of Alloprevotella in BPs group slightly different from which in control group\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eOur pooled analysis result suggest that BPs exposure can lead to changes in diversity and composition of gut microbial. Diversity of gut microbiota reduced in BPs treatment group.\u003c/p\u003e \u003cp\u003eSimpson index significantly increase after BPA exposure. Value of Simpson index reflect status of dominant species and greater Simpson index value implies lower diversity. Based on subgroup analysis result, changes in alpha diversity of gut microbial are likely to have association with dosage and duration of BPs exposure. Simpson index was significantly increase from low dose group but slightly increase from high dose group, our result is consistent with other studies\u003csup\u003e[10,20\u0026minus;23]\u003c/sup\u003e. Character of BPs is similar with serum endogenous hormone effect, which are hint yet high efficiency\u003csup\u003e[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/sup\u003e, as such diversity of gut microbial is more sensitive to low dose BPs intervention. In Feng\u0026rsquo;s study, Simpson index significantly increase from short duration group\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e, which is same with our subgroup analysis result.\u003c/p\u003e \u003cp\u003eValue of Chao index is positively correlate with abundance of microbial species, Chao index was markedly decrease from short term exposure but significantly increase in long term exposure, which indicate short duration BPs exposure decrease the abundance of gut microbial and long period BPs exposure increase the abundance of gut microbial, our result is similar with He and Joella\u0026rsquo;s research\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eChao index and Shannon significantly decrease in intestine sample group. Simpson index significantly increase in fecal sample group. Fecal has long been typical sample for gut microbial study due to its readily available, however, fecal sample isn\u0026rsquo;t always the optimum choice for analyzing low intestine resident flora, what\u0026rsquo;s more, different part of fecal contains various type of flora (anaerobic bacteria locate at internal and aerobic bacteria locate at external of fecal). Until today there is still lack of research utilizing intestine sample to study gut microbial of animals cause intestine sample is difficult to acquire, as such these research are less representative\u003csup\u003e[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur result indicate that Observe species significant decrease in long term group but Ace index have no significant change after BPs exposure. Lai\u0026rsquo;s research indicate observed species decrease after BPs exposure\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e, which reflect richness of species decrease, but other studies suggest observed species increase after BPs exposure\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. In Ni\u0026rsquo;s study, Ace index increase after BPs intervention\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e, but in Tang\u0026rsquo;s study, Ace index decrease in BPs group\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e, Ace index reflect the abundance of intestine flora.\u003c/p\u003e \u003cp\u003eAn increasing number of studies have revealed that the composition of intestinal microbial in BPs exposure group have significant alteration at phylum, class, order, family and genus taxa in comparison with control group. BPs exposure induce pro-inflammatory bacteria increase and probiotic decrease, shifted composition of gut microbial may lead to several disease, for example, BPs exposure increased Jeotgalicoccus which is adverse factor for intestine health\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Esicherichia-shigella might be pathogen of nonalcoholic fatty liver disease (NAFLD), which increase from BPs exposure group \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]\u003c/sup\u003e. Akkermansia decrease from BPs exposure group, reduction of Akkermansia is positively associate with obesity, type 2 diabetes and cardiovascular disease\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Lachnospiraceae is a potential probiotic exists in healthy condition intestine and play an important role in dietary fiber metabolism, Lachnospiraceae abundance decrease from BPs exposure\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Lactobacillus decrease from BPs exposure, which ferment carbohydrate to lactic acid and promote digestive system health\u003csup\u003e[10,17\u0026minus;19]\u003c/sup\u003e. Bifidobacterium significantly decrease from BPs intervention\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e, which is protective factor against inflammatory bowel disease and Alzheimer's disease cognitive impairment\u003csup\u003e[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThere are some limitations in our systematic review. Firstly, the cause-effect relationships of dysbiosis and disease still need further study to determine. Secondly, our review merely included rodents studies to investigate the relationship between BPs exposure and alteration of composition and diversity of intestinal microbial, however, there are many in vitro studies, epidemiological survey and mammal studies been excluded. Thirdly, the specific situation of dysbiosis differ between animals and human, our result is based on animal research, as such extrapolation result with human disease need cautiously determined.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eTo conclude, BPs exposure altered the composition of gut microbial at several taxonomic level and significantly decrease diversity of gut microbial. However, causal association between gut dysbiosis and homeostasis imbalance still need more evidence to confirm.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u0026nbsp; Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication \u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u0026nbsp; The authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLai KP, Chung YT, Li R, Wan HT, Wong CK (2016) Bisphenol A alters gut microbiome: Comparative metagenomics analysis. 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Oncol Translational Med 7(06):269\u0026ndash;274\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"BPs, gut microbial, relative abundance, diversity","lastPublishedDoi":"10.21203/rs.3.rs-1948177/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1948177/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eA growing number of studies have indicate that Bisphenols (BPs) have an effect on gut microbial community, including alter gut microbial diversity and composition. Due to limited sample size and some varied results, a review is needed to add credibility to the conclusion of BPs influence on gut microbial community. Literature search was implemented based on PubMed,Wed of Science, Science Direct, SinoMed, CNKI database from inception date to February 24,2022. Nineteen eligible articles (BPs exposure on rodent animal experiment studies) were included to our review and all literature\u0026rsquo;s references were traced back. Meta analysis were conducted to synthesis 5 alpha diversity index(observed species, chao, ace, Shannon, Simpson index), narrative synthesis approach was selected to synthesis composition of gut microbial in BPs group. Results suggest Simpson index significantly increase after BPs intervention. In subgroup analysis, Simpson significantly increase in low dose group( dosage\u0026thinsp;≦\u0026thinsp;0.20mg/kg), observed species significantly decrease in long term group(duration\u0026thinsp;\u0026gt;\u0026thinsp;5 weeks), chao index decrease in short term group and increase in long term group, chao and Shannon decrease in intestine sample group. To conclude, BPs exposure may decrease the abundance and diversity of gut microbial especially probiotic.\u003c/p\u003e","manuscriptTitle":"The relationship between Bisphenols exposure and intestinal flora: a systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-08-12 15:56:30","doi":"10.21203/rs.3.rs-1948177/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"befb28fa-6f4d-4231-b2da-f562bb4e445c","owner":[],"postedDate":"August 12th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-01-10T08:00:34+00:00","versionOfRecord":[],"versionCreatedAt":"2022-08-12 15:56:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1948177","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1948177","identity":"rs-1948177","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}