The diversity of factors influencing human digestive microbiota in healthy adults and their interaction: A scoping review

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The objective of this study was to perform a scoping review that gathers and updates the information available about factors that affect human digestive microbiota in healthy adults. It is also reviewed if other factors are considered and if some type of interaction between them is studied. We searched in MEDLINE, Web of Science, Scielo, PROSPERO, and Cochrane databases. Two authors independently reviewed study eligibility and data extraction. Articles were classified based on the main factor studied upon one of the following categories: diet, habits, environment, or chemical exposure. Results The literature search provided a total of 73 studies that met the inclusion criteria. The presence of data about the influence of diet, habits, environment, and exposition to chemicals on digestive microbiota were registered. Analysis of the studies indicates that the assessment of risk factors is often focused on a specific aspect (diet, habits, environment, and chemicals) and the study of the interaction between factors is up to now not sufficiently investigated. In addition, there are some situations probably relevant to the human digestive microbiota that are not being assessed (snacking, intermittent fasting, type of sport practiced, living with pets or working with animals, type of transportation daily used, home cleaning habits, treatments with radiotherapy, immune suppressants, corticosteroids). Conclusions Little is known about the impact of the combined interaction of possible risk factors (diet, habits, environment, and chemical exposure) of dysbiosis in human digestive microbiota. Further studies are encouraged to evaluate more broadly the interactions between the risk factors that may influence the diversity of the human digestive microbiota. All of them are factors that act together every day on our health. gut microbiota dysbiosis diet lifestyle environment chemicals Figures Figure 1 INTRODUCTION Knowledge about human microbiota has taken a growing interest in studies due to its impact on health. It has also been described that some factors, such as diet, consumption of prebiotics and probiotics, medication, living places, physical activity, socioeconomic status, alcohol and tobacco consumption, and stress, have an impact on the digestive microbiota. 1, 2, 3, 4, 5, 6, 7, 8 In these studies, the data collection consists of microbiological and genetic analyses on feces or saliva. Several of them also use a questionnaire about habits and other circumstances of the participants that may impact the microbiota composition and diversity. 8, 9 Up to now, there are some details that have been investigated that could be relevant to investigate. Some factors described affecting human microbiota are familiar environment and dental care. 7,9 Working activity and place, living with pets and frequent contact with animals such as fish, chickens, or cows with their specific microbiota, are sources of microorganisms. 10, 11 To the best of our knowledge, these factors have not been included yet in research to study the human digestive microbiota. We conducted a scoping review to compile the factors described in the literature that influence the human digestive microbiota. Our objective was to review these factors that have an impact and may lead to dysbiosis in healthy adults. Due to the influence of the digestive microbiota on health, a profound knowledge of the factors that influence the human microbiota and its interactions would pave the way for preventive health care. MATERIALS AND METHODS This scoping review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and meta-analyses (PRISMA) guidelines for Scoping Review (PRISMA-ScR). 12 Eligibility criteria Inclusion criteria Original research articles included in the scoping review were studies involving healthy human adults older than 19 years describing factors that influence in digestive microbiota (including oral, gastric, or intestinal microbiota) leading to dysbiosis. We have classified these factors into four categories: -DIET: characteristics of the diet, type of food consumed, nutritional supplements, pro and prebiotics, specific diets. -CHEMICALS: commonly used drugs, antibiotics, vitamins, herbal products, herbicides, pesticides. -ENVIRONMENT: rural or urban, type of accommodation, cohabiting family, work activity, workplace, pets, household cleaning, means of transportation frequently used. -HABITS: sleep, physical activity, tobacco, alcohol, drugs. We selected papers published from 1 January 1950 to 30 September 2023 in English or Spanish. We included any research articles (no design restriction), systematic reviews, or meta-analysis, with or without questionnaires. We did not include conference abstracts. Exclusion criteria Studies about humans younger than 19 years, menopause, gestation, and digestive diseases and their pathogeny, diagnosis, or treatment (intestinal inflammatory diseases, celiac disease, gastric or oral diseases, eating disorders, parasitic diseases, fecal transplant). We also excluded studies about any other diseases such as mental, nervous system, kidney, skin, eyes, respiratory system, liver, pancreas, blood, obesity, metabolic syndrome, diabetes, COVID, HIV, or cancer. Literature search strategy Bibliographic search was made in five scientific databases: Web of Science (WoS), PubMed, Scielo, Cochrane, and PROSPERO. After considering synonyms, keywords selected were: “Gastrointestinal microbiome”, “Gastrointestinal or gut or enteric or intestine or stomach or oral or mouth”, “Microbiome or microbiota or flora or microflora or bacteria”, “Dysbiosis or dysymbiosis or dysbacteriosis”. The final search strategy used was: ((Gastrointestinal OR gut OR intestine OR enteric OR stomach OR oral OR mouth) AND (microbiome OR microflora OR flora OR microbiota OR bacteria)) AND ((intestinal OR gut OR enteric) AND (dysbiosis OR dys-symbiosis OR dysbacteriosis)). Eligibility assessment and data extraction Literature search results were uploaded to the bibliography management tool Mendeley, and duplicates were removed. Screening by title and abstract was done by two trained review authors (BPL, CM) based on the inclusion and exclusion criteria. The full text of the selected references was retrieved, and BPL and CM screened them according to the selection criteria. The entire process was carried out independently and by blinding the reviewers. Disagreements were resolved by discussion and consensus. Additional studies found by non-systematic search and relevant to the researchers have been included. Data extraction included the following: First author, year of publication, number of participants, age, diet, habit, environment, chemical-related factors, and questionnaire item-descriptions. RESULTS We retrieved a total of 2864 references. After eliminating duplicates (996) with the bibliographic tool Mendeley it remained 1868 references. 73 studies fulfilled the criteria for inclusion. The search strategy and selection of publications are shown in Figure 1. [Here Figure 1] Of the total of 73 studies, 50 are research studies, and 22 are reviews or meta-analysis papers. Every research study found was classified into one of the following four categories of factors: -DIET: 22 papers addressing probiotics, prebiotics, sweeteners, type of foods, ultra-processed food, specific diets (Mediterranean diet, vegan diet), fermented foods, plant-based food polyphenols, or protein supplements (Table 1) -HABITS: 7 studies about sleep, physical activity, tobacco, alcohol, or drugs (Table 2). -ENVIRONMENT: 11 articles regarding rural/urban environment, living near a mine, nursing homes, cohabiting family (partner, children, parents, grandparents), short hospitalization periods, long ocean voyages, or exposure to high altitudes (Table 3). -CHEMICALS: 10 papers about antibiotics, methamphetamine, opioids, metformin, vitamin D, proton-pump inhibitors, herbicides, fungicides, titanium oxide nanoparticles, or herbal treatments (, Table 4). One study addressed two or more of these categories and was included in the discussion. 70 First, a review was made of the results related to the factors studied in every paper. In 41 of these research studies questionnaires were used. In Tables 1 to 4, questions of the questionnaires used in every study are split into the four categories mentioned (diet, habits, environment, and chemicals) and data of these four categories retrieved in every study were recorded. Diet Overall, diet was the most studied factor about its influence on digestive microbiota (43% of the papers included in the scoping review) (Table 1). In the literature reviewed, probiotics have been shown to influence digestive microbiota to prevent or treat some diseases, decrease dysbiosis due to age, or help to maintain a normal microbiota in a meat-based diet. 13, 14. 15 Besides, the effect of commercial probiotics in healthy subjects was proven to increase the diversity of the oral cavity. 16 Fermented food has taken greater importance due to its relationship with positive microbiota changes and other effects such as reduction of academic stress and inflammatory markers. 17, 18, 19 The intake of dietary fibre with different prebiotics also influences digestive microbiota. A diet rich in fiber increases the levels of beneficial bacteria and short-chain fatty acids (SCFA). 20, 21, 22 Supplementing with milk oligosaccharides, a prebiotic based on resistant starch, induces the growth of beneficial bifidobacteria. 23, 24 It has also been described that a greater intake of dietary fiber from cereals, fruits, and vegetables is associated with shifts in gut microbiome composition and a reduction of C-reactive protein. 25 Inulin consumption modified the microbiota composition with higher microbial diversity 26 . Dietary addition of L. casei , B. breve and a prebiotic product, results in an improvement of intestinal physiologic traits and an increase of total fecal bifidobacteria 27 . Polyphenols also have been shown to affect the gut microbiota. Some of them have protective effects of the goblet cells of the intestinal mucosa. Other polyphenols have been shown to increase the counts of Lactobacillus and Bifidobacterium and improve gut and host health. 28, 29 The type of diet has also been related to gut microbiota status. High adherence to Southern European Atlantic Diet produces a greater number of total bacteria, Actinobacteria , Lactobacillus, and Bifidobacterium genus. 30 Significant correlations between bacterial taxa and Mediterranean Diet adherence were observed in centenarians, nonagenarians, and younger subjects. 31 Microbiota associated to Mediterranean diet was enriched with beneficial bacteria that induces anti-inflammatory status and reduces the risk of developing gut diseases. 32 Individual foods have also been shown to influence digestive microbiota. Green tea liquid consumed daily decreased Bacteroidetes in feces and pathogenic bacteria in saliva. 33 A diet heavily based on beans and dairy products reduced gut diversity with less beneficial bacteria. 34 A long-term protein supplementation may have a negative effect on gut microbiota and increase the risk of intestinal diseases. 35, 36 Nevertheless, natural plant extracts with polyphenols, prebiotics, probiotics, and regular physical exercise improved gut microbiota, reducing dysbiosis produced by High Protein Diet (HPD). 36 Consumption of more than five servings per day of ultra-processed food produced a decrease in microbiota diversity 37 . Sesame seed snacks and plant-based smoothies produced a notable increase in endogenous antioxidants in plasma and an improvement in gut microbiota. 38 Pure saccharin supplementation did not alter gut microbial diversity, while Vitamin D supplementation increased the overall diversity of gut microbiota in healthy females with vitamin D deficiency. 39, 40 Food additives also affect gut microbiota composition. Some sweeteners and some emulsifiers may alter microbiota. Food preservatives increase the growth of proinflammatory bacteria, while anti-inflammatory bacteria decrease. Acidifiers can reduce coliform presence and increase lactic acid bacteria, and colorants can reduce microbiota diversity in vitro . Nevertheless, the long-term impact of food additives on gut microbiota needs to be examined 41 . [Here Table 1] Habits As shown in Table 2, there are different types of habits that influence digestive microbiota, such as physical activity, which has been shown to increase microbial diversity. 42 The quality of sleep also influences the microbiota, although not in all the circumstances. The microbiome is resistant to changes after consecutive days of sleeping restriction. 43 However, an acute sleep-wake cycle shift of 2 to 4 hours (subjects postpone their regular sleeping time for 2 to 4 hours) affects the functional profiles of gut microbes and interactions among them 44 . Alcohol consumption or smoking or the combination of both cause gut microbiota dysbiosis in healthy men. Noteworthy, smoking alone causes more severe dysbiosis than drinking alone. 45 Furthermore, smoking habits also modified oral microbiota diversity and heavy episodic drinking is associated with a specific stool type phenotype (Bristol stool scale). 46 Consumption of heroin, ephedrine, and methamphetamine produced changes in the microbiota. Bacterial diversity was higher in SUD (substance use disorders) and this increases with the length of substance abuse. 47 Intestinal colonization by oral bacteria has been demonstrated; therefore, oral hygiene becomes more important 46,48 . In fact, the salivary microbiome was affected by denture use 46 . [Here Table 2] Environment The environment is also an important factor to study in this context (Table 3). References retrieved have shown different sources of influence on gut microbiota. Blastocystis , a component of gut microbiota, has a higher prevalence in non-westernized individuals 49 . Differences in gut microbiota composition were found in individuals with the same ethnicity but coming from different Italian regions. 50 Medication and time spent in the nursing home contributed to microbiota dysbiosis more than age and frailty. The microbiota of residents who had lived in the nursing home for more than 1 year were enriched in inflammatory and pathogenic species and reduced in anti-inflammatory and symbiotic species. 51 Nevertheless, it has been described that short-term hospitalization did not impact the richness or structure of the salivary microbiome. 52 Indoor spaces often harbor unique microbial communities. Indoor air in residences contained a greater number of culturable bacteria than outdoor air. Differences in bacterial flora in settled dust in two buildings were greater than differences between seasons. Bacterial communities on surfaces in offices were different between cities, and the microbiota in a home were identifiable by family. Humans are also major sources of bacteria in indoor air. 53 As for the quality of the environment, long-term exposure to metals in residents near a mining and smelting area produced different profiles of gut microbiota. These effects were higher in men because of mining and smelting activity. 54 Currently, it is under discussion whether air pollution due to emissions from factories, chimneys, or livestock also affects gut microbiota since it may be trapped in the food. Some studies showed that gut microbiota metabolized the inorganic arsenic into toxic metabolites. Currently, there are some chemicals and pesticides that are considered microbiota-disrupting chemicals. 55 The living altitude also influences the microbiota composition, which was enriched in Prevotella and Bacteroidetes in subjects living in high altitudes (>1500m) while Faecalibacterium and Blautia were increased in the low altitude group (<1500m). 56 Microbiota diversity can also change due to traveling. Sun et al., (2022) reported that a 135-day sea expedition produced “seafaring syndrome” (SS) with abnormal defecation, frequent insomnia, poor sleeping quality, and overeating. Noteworthy, a significant correlation between the gut microbiome perturbation and this syndrome was found. 57 Cohabitation with other people also influences digestive microbiota. Microbial dysbiosis might be caused in healthy partners cohabiting with Ulcerous Colitis patients and anxiety and stress are related to reduced diversity. 58, 59 People with larger social networks tend to have a more diverse microbiome. Cohabiting time affected strain sharing more than age or genetics. 60 A high similarity in the oral microbiota composition was found between members of the same family, higher between twins, parents, or brothers, and less or none between grandparents and grandchildren. There was also a similarity between classmates. 9 [Here Table 3] Chemicals Chemicals have proven to be important factors that influence digestive microbiota (Table 4). Non steroidal anti-inflammatory drugs (NSAID) provoke changes in gut microbiota. Bacterial population in the gastrointestinal tract reflects the combination of medications and varied with the type of NSAID that people take 61 . Proton Pump Inhibitors (PPI) have been associated with a decrease in microbiota diversity and an increase of Lactobacilus , Steptococcus , Staphylococcus and E.coli. 62 , 63 Antibiotics are clearly an important factor that changes gut microbiota characteristics. Azithromycin alters the diversity of the salivary microbiome and delays the recovery of the diversity of gut microbiota after a treatment. 64 Moxifloxacin reduced bacterial diversity, which is not recovered until 16 to 21 days 65 . S. boulardii treatment can mitigate some antibiotic-induced microbiota changes (dysbiosis). 66 Metformine has an effect of reduction of gut microbiome diversity already after 24 hours of administration. 67 Decreased diversity of Shanon and Chao indices was observed in methadone-treated subjects. 68 Also, essential oils may be considered as a factor that influences the gut microbiome. Notably, a component of these oils, geraniol, has proven to increase butyrate-producer bacteria and improve intestinal dysbiosis. 69 [Here Table 4] Diet, chemicals, environment, and/or habits interaction Summing up, diet, chemicals, environment, and habits have been described as influencing the digestive microbiota. These factors are typically considered individually without considering the interactions between them. Diet, sleep quality, medications, supplements, physical activity, and psychological status are considered possible causes of dysbiosis. 70, 71, 72 However, it is also very important to study the interactions between factors on the microbiota quality. Boisseau et al. (2022) found that the microbiota of athletes is different from the rest of the population. Diets and treatments could be the origin of these differences. However, it is also known that exercise improves microbiota in sedentary people, but excessive practice does not improve microbiota and even worsens health. Nevertheless, there are no studies on humans that search for the interaction between diet and physical activity. 6 Also, a positive interaction was found between diet, physical exercise, and HPD. Natural plant extracts with polyphenols, prebiotics, probiotics, and regular physical exercise improved gut microbiota, reducing dysbiosis produced by HPD 36 . DISCUSSION Of the 73 articles that meet the inclusion criteria, the majority described the influence of diet, habits, chemicals, or environment independently affecting the gut microbiota. All the factors reviewed act together in people´s daily lives. Therefore, the existence of an interaction between them is something that should be considered. In fact, in almost all the studies analyzed, the questionnaires given to the participants contain questions about all or some of these factors in order to exclude their influence from the results. In the group of 19 papers about diet influence (Table 1 ) data were collected about diet (16/19), habits (12/19), environment (3/19), and chemicals (7/19) In addition to checking the consumption of foods whose influence on the diet is proven, such as fermented foods, 17, 18, 19 it would be interesting to investigate more about whether there is a difference between homemade and commercial fermentation meals since there are already many elaborate fermentation products on the market whose microorganism content is probably different from the homemade ones. Information in this regard can be collected in the questionnaire (homemade or commercial). The positive effects of some types of diet rich in vegetables have been proven. 30, 31, 32, 33 Therefore, it is also necessary to ask about the frequency of consumption since we can eat vegetables, but not in an appropriate frequency to notice positive effects. 34 It would be also interesting to investigate about the consumption of diets high in proteins or protein supplements and their duration, given that, in some cases, it can negatively influence the digestive microbiota. 35 UP foods should also be checked since high consumption has been seen to affect the diversity of the digestive microbiota. 37 Treatments with vitamin D are becoming more common in the population. Since this also influences the digestive microbiota, 40 should be considered. Furthermore, the influence of some nutritional habits, such as snacking, intermittent fasting, and the number of daily intakes were not included in any of the questionnaires. Herein, we suggest including snacking as another factor to be considered. Snacking behavior is a practice that can be done with different types of foods and therefore can contribute to improving diet but also to worsening it. 72 Other factors that may be suitable to include were intermittent fasting and the number of daily intakes. These are habits that may influence the function of the digestive tract at different rhythms and frequencies, and this may affect the environment of microbiota. The 6 papers that analyze habits influence (Table 2 ) data were retrieved about diet (5/6), habits (5/6), environment (1/6), and chemicals (2/6). Furthermore, these questionnaires do not consider the type of sport practiced. This is important to consider since team sports and sports in contact with water must be possible sources of different microbiota. Furthermore, none of these questionnaires considers body and hair hygiene, analyzing both frequency and time spent washing it. This may affect skin microbiota and, consequently, the digestive microbiota too. In the 7 papers addressing the environmental factors (Table 3 ), data were recorded about diet (7/7), habits (7/7), environment (3/7), and chemicals (1/7). However, there were not retrieved other circumstances related to the environment. Living with pets may influence the human microbiota due to the interaction with their own specific microbiota. Domestic dogs share the house with the owners. Its microbiota has a taxonomic similarity with humans, much larger than mice or pig. 73, 74 Living or working with another type of animals may influence the human microbiota, too, due to their different specific microbiota. The microbiome of teleost fish, broiler chicken, and clam (Agropecten ventricosus) is different from the microbiome of mammals. 10, 75, 76 Cows that consume more pastures have a higher amount of Firmicutes and Bacteroidetes , while cows that consume more concentrated food have the inverse proportion. 11 Not only microorganisms from pets but also parasites may alter gut conditions and contribute to intestinal dysbiosis. 77, 78 There are many professions developed in contact with animals and or with people with different microbiota composition, such as livestock, veterinary, fishing, agriculture, slaughterhouse, medicine, nursing, physiotherapy, nursing homes, public transport driver, police, prisons, schools, nurseries, masseuse, aesthetic centers (manicures, pedicures, tattoo artists, hairdressers), research laboratories with animal or biological material, zoos. We have not found any research about the influence of these kinds of environments on digestive microbiota, but they probably have some role in its variation. Moreover, the type of transportation daily used (individual, public) may also be an important source of variation of the microbiota taken from the environment. Place of work may also be an influencing factor since different environments can harbor different microbiota: home, office, industry, field, ship, plane, educational center, and transports such as trucks and taxis. Home cleaning is a daily action that can also modify the home microbiome, and coexistence with domestic animals or working with them are also important data to collect in a questionnaire for microbiota research. Pesticides also modify the microbiota of the animals. It has been described that long-term (lifelong) exposure to a low dose of a glyphosate herbicide (GBH-RUp) in drinking water led to significant changes in the intestinal microbiome composition in mice. 79 Daily contact with pesticides may be important for people working in aquaculture, poultry farming, and livestock farming. Another possible source of variation in the human microbiota environment may be home cleaning habits. Cleaning of chicken sponges significantly affected its microbiome structure. The authors of this study visualize the role of kitchen sponges as microbial hot spot in building the environment with the capability to collect and spread bacteria. 80 The environment has a high microbial diversity. Sites like home, offices, industry, and transport have very different physicochemical conditions. The role of the ambient microbiome in the skin and digestive microbiota is evident but not well understood nowadays. 81 The 8 papers regarding the chemical factors (Table 4 ) collected data about diet (5/8), habits (2/8), environment (1/8), and chemicals (7/8). Noteworthy, none of these questionnaires consider some type of therapy that could also affect the digestive microbiome, such as radiotherapy. 82 There are also other treatments widely used as opioids, 83 immune suppressants, corticosteroids, and anovulatory that should be considered. Almost all the studies included in this review investigated one of these factors and have provided evidence about their impact on our inner microbiota. However, further studies are necessary to obtain more data about the interaction between these aforementioned factors to shed light on their implications for the quality of the digestive microbiota. Of all the articles reviewed, only one considers studying the interaction between factors. Boisseau et al. ( 6 ) reviewed the relationship between diet and physical activity. In humans, short-term changes in diet affect microbiota but in a transient way. A high fat content causes a decrease in Bifidobacteria , while protein increase bifidobacteria and lactobacillus , and carbohydrates increase Bifidobacteria and reduce Bacteroides . On the other hand, the microbiota of athletes is different of the rest of the population. Diets and treatments could be the origin of these differences. However, it is also known that exercise improves microbiota in sedentary people, but an excessive practice does not improve microbiota and even worsen health. Nevertheless, there are no studies on humans that search about the interaction between diet and physical activity. This can be extensive to the other factors. For example, it is possible that different changes in the microbiota of different individuals due to probiotic consumption could be due to differences in some other factor studied in this review. CONCLUSIONS Summing up, diet, chemicals, environment, and habits have been described to influence in the digestive microbiota. These factors are typically considered individually without considering the interactions between them. Furthermore, as shown in this review some cases that could influence human digestive microbiota are not yet studied. However, further studies are necessary to obtain more data about the influence on digestive microbiota of these aforementioned factors and about the interaction between all of them to shed light on their implications for the quality of the digestive microbiota. There is a great variety of questionnaires used in research about human digestive microbiota. It would be helpful to use a standardized tool that help to collect data about these factors. Declarations Ethics approval and consent to participate Not applicable Consent for publication Not applicable Availability of data and materials Not applicable Competing interests The authors declare that they have no competing interests Funding The financial support for the publication of this paper is made by Universidad Internacional de La Rioja. The role of the sponsor of this review was restricted to providing economic support, and it were not involved in the study process, manuscript preparation, or submission. Authors´contributions BPLL: Conceptualization, data curation, formal analysis, investigation, methodology, writing original draft and edition. CMR: Data curation, formal analysis, investigation, methodology, writing review and edition, validation. EGF: Formal analysis, methodology, supervision, validation, writing review. Acknowledgements Not applicable References McBurney MI, Davis C, Fraser CM, et al. 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Gut microbiota and old age: Modulating factors and interventions for healthy longevity. Exp Gerontol . 2020;141. Redondo-Useros N, Nova E, González-Zancada N, Díaz LE, Gómez-Martínez S, Marcos A. Microbiota and lifestyle: A special focus on diet. Nutrients . 2020;12(6):1-54. doi:10.3390/nu12061776 Hernandez J, Rhimi S, Kriaa A, et al. Domestic Environment and Gut Microbiota: Lessons from Pet Dogs. Microorganisms . 2022;10(5). doi:10.3390/microorganisms10050949 Soriano Ferrer C. La Microbiota Intestinal En Perros y Gatos y Su Relación Con El Sistema Inmunitario Asociado. Trabajo Fin de Grado. Zaragoza; 2021. Peinado Martínez MJ. Efectos de Nuevos Aditivos Alimentarios Sobre La Composición de La Microbiota Digestiva En Pollos Broiler. Tesis Doctoral. Tesis Doctoral. (Universidad de Granada, ed.). Granada, España; 2015. http://hdl.handle.net/10481/42252. Mazón-Suástegui JM, Tovar-Ramírez D, Ortiz-Cornejo NL, et al. Efecto de medicamentos homeopáticos sobre crecimiento, supervivencia y microbiota gastrointestinal, en juveniles del pectínido Argopecten ventricosus. Rev MVZ Cordoba . 2019;24(3):7328-7338. doi:10.21897/rmvz.1536 Piazzesi A, Putignani L. Impact of helminth–microbiome interactions on childhood health and development—A clinical perspective. Parasite Immunol . 2023;45(4). doi:10.1111/pim.12949 Garcia-Bonete MJ, Rajan A, Suriano F, Layunta E. The Underrated Gut Microbiota Helminths, Bacteriophages, Fungi, and Archaea. Life . 2023;13(8). doi:10.3390/life13081765 Del Castilo I, Neumann AS, Lemos FS, et al. Lifelong Exposure to a Low-Dose of the Glyphosate-Based Herbicide RoundUp® Causes Intestinal Damage, Gut Dysbiosis, and Behavioral Changes in Mice. Int J Mol Sci . 2022;23(10). doi:10.3390/ijms23105583 Cardinale M, Kaiser D, Lueders T, Schnell S, Egert M. Microbiome analysis and confocal microscopy of used kitchen sponges reveal massive colonization by Acinetobacter, Moraxella and Chryseobacterium species. Sci Rep . 2017;7(1). doi:10.1038/s41598-017-06055-9 Gebrayel P, Nicco C, Al Khodor S, et al. Microbiota medicine: towards clinical revolution. J Transl Med . 2022;20(1). doi:10.1186/s12967-022-03296-9 Ren H, Wu Q, Sun Z, Fang M, Liu J, Luo J. Research progress and treatment of radiation enteritis and gut microbiota. Radiat Oncol J . 2023;41(2):61-68. doi:10.3857/roj.2023.00346 Satish S, Abu Y, Gomez D, Kumar Dutta R, Roy S. HIV, opioid use, and alterations to the gut microbiome: elucidating independent and synergistic effects. Front Immunol . 2023;14. doi:10.3389/fimmu.2023.1156862 Tables Tables 1 to 4 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files Table1.docx Table2.docx Table3.docx Table4.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-4663650","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":325240861,"identity":"86d7f05f-393e-49bd-8c89-ebc25e986424","order_by":0,"name":"Begoña 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(UNIR)","correspondingAuthor":false,"prefix":"","firstName":"Celia","middleName":"Medrano","lastName":"Rodríguez","suffix":""},{"id":325240866,"identity":"a3cf4493-45de-4191-9e54-4394aa314054","order_by":2,"name":"Eduardo González Fraile","email":"","orcid":"","institution":"Universidad Internacional de La Rioja (UNIR)","correspondingAuthor":false,"prefix":"","firstName":"Eduardo","middleName":"González","lastName":"Fraile","suffix":""}],"badges":[],"createdAt":"2024-06-30 16:38:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4663650/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4663650/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":61065949,"identity":"21257139-62d2-43ec-bfb9-3efd1a015601","added_by":"auto","created_at":"2024-07-25 07:38:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":122304,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA flow chart of the search, identification, and screening process of the scoping review about factors that affect human digestive microbiota in healthy adults.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4663650/v1/0f85235c40aae59e92a2f336.png"},{"id":73048966,"identity":"91498df3-3796-4dba-98ba-e792c373b978","added_by":"auto","created_at":"2025-01-06 09:09:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":585060,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4663650/v1/e9e48777-d18b-4ab7-adec-ae844ca60523.pdf"},{"id":61065965,"identity":"246b8af8-707c-421c-ac0a-3d3a2db6eb2c","added_by":"auto","created_at":"2024-07-25 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07:38:32","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":47943,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-4663650/v1/dd05a95fa8ca6b1c263cf358.docx"},{"id":61065966,"identity":"4132deb2-116b-4507-8539-e009ccbf28d4","added_by":"auto","created_at":"2024-07-25 07:38:35","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":43204,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.docx","url":"https://assets-eu.researchsquare.com/files/rs-4663650/v1/19688232824605c54f919b3e.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The diversity of factors influencing human digestive microbiota in healthy adults and their interaction: A scoping review","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eKnowledge about human microbiota has taken a growing interest in studies due to its impact on health. It has also been described that some factors, such as diet, consumption of prebiotics and probiotics, medication, living places, physical activity, socioeconomic status, alcohol and tobacco consumption, and stress, have an impact on the digestive microbiota. \u003csup\u003e1, 2, 3, 4, 5, 6, 7, 8\u003c/sup\u003e In these studies, the data collection consists of microbiological and genetic analyses on feces or saliva. Several of them also use a questionnaire about habits and other circumstances of the participants that may impact the microbiota composition and diversity. \u003csup\u003e8, 9\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eUp to now, there are some details that have been investigated that could be relevant to investigate. Some factors described affecting human microbiota are familiar environment and dental care.\u003csup\u003e7,9\u003c/sup\u003e Working activity and place, living with pets and frequent contact with animals such as fish, chickens, or cows with their specific microbiota, are sources of microorganisms. \u003csup\u003e10, 11\u003c/sup\u003e To the best of our knowledge, these factors have not been included yet in research to study the human digestive microbiota.\u003c/p\u003e \u003cp\u003eWe conducted a scoping review to compile the factors described in the literature that influence the human digestive microbiota. Our objective was to review these factors that have an impact and may lead to dysbiosis in healthy adults. Due to the influence of the digestive microbiota on health, a profound knowledge of the factors that influence the human microbiota and its interactions would pave the way for preventive health care.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eThis scoping review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and meta-analyses (PRISMA) guidelines for Scoping Review (PRISMA-ScR). \u003csup\u003e12\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eEligibility criteria\u003c/p\u003e\n\u003cp\u003eInclusion criteria\u003c/p\u003e\n\u003cp\u003eOriginal research articles included in the scoping review\u0026nbsp;were studies involving healthy human adults older than 19 years describing factors that influence in digestive microbiota (including oral, gastric, or intestinal microbiota) leading to dysbiosis. We have classified these factors into four categories:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e-DIET: characteristics of the diet, type of food consumed, nutritional supplements, pro and prebiotics, specific diets.\u003c/p\u003e\n\u003cp\u003e-CHEMICALS: commonly used drugs, antibiotics, vitamins, herbal products, herbicides, pesticides.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e-ENVIRONMENT: rural or urban, type of accommodation, cohabiting family, work activity, workplace, pets, household cleaning, means of transportation frequently used.\u003c/p\u003e\n\u003cp\u003e-HABITS: sleep, physical activity, tobacco, alcohol, drugs.\u003c/p\u003e\n\u003cp\u003eWe selected papers published from 1 January 1950 to 30 September 2023 in English or Spanish. We included any research articles (no design restriction), systematic reviews, or meta-analysis, with or without questionnaires. We did not include conference abstracts.\u003c/p\u003e\n\u003cp\u003eExclusion criteria\u003c/p\u003e\n\u003cp\u003eStudies about humans younger than 19 years, menopause, gestation, and digestive diseases and their pathogeny, diagnosis, or treatment (intestinal inflammatory diseases, celiac disease, gastric or oral diseases, eating disorders, parasitic diseases, fecal transplant). We also excluded studies about any other diseases such as mental, nervous system, kidney, skin, eyes, respiratory system, liver, pancreas, blood, obesity, metabolic syndrome, diabetes, COVID, HIV, or cancer.\u003c/p\u003e\n\u003cp\u003eLiterature search strategy\u003c/p\u003e\n\u003cp\u003eBibliographic search was made in five scientific databases: Web of Science (WoS), PubMed, Scielo, Cochrane, and PROSPERO.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAfter considering synonyms, keywords selected were: “Gastrointestinal microbiome”, “Gastrointestinal or gut or enteric or intestine or stomach or oral or mouth”, “Microbiome or microbiota or flora or microflora or bacteria”, “Dysbiosis or dysymbiosis or dysbacteriosis”. The final search strategy used was: ((Gastrointestinal OR gut OR intestine OR enteric OR stomach OR oral OR mouth) AND (microbiome OR microflora OR flora OR microbiota OR bacteria)) AND ((intestinal OR gut OR enteric) AND (dysbiosis OR dys-symbiosis OR dysbacteriosis)).\u003c/p\u003e\n\u003cp\u003eEligibility assessment and data extraction\u003c/p\u003e\n\u003cp\u003eLiterature search results were uploaded to the bibliography management tool Mendeley, and duplicates were removed. Screening by title and abstract was done by two trained review authors (BPL, CM) based on the inclusion and exclusion criteria. The full text of the selected references was retrieved, and BPL and CM screened them according to the selection criteria. The entire process was carried out independently and by blinding the reviewers. Disagreements were resolved by discussion and consensus.\u003c/p\u003e\n\u003cp\u003eAdditional studies found by non-systematic search and relevant to the researchers have been included.\u003c/p\u003e\n\u003cp\u003eData extraction included the following: First author, year of publication, number of participants, age, diet, habit, environment, chemical-related factors, and questionnaire item-descriptions.\u0026nbsp;\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eWe retrieved a total of 2864 references. After eliminating duplicates (996) with the bibliographic tool Mendeley it remained 1868 references. 73\u0026nbsp;studies fulfilled the criteria for inclusion.\u0026nbsp;The search strategy and selection of publications are shown in Figure 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e[Here Figure 1]\u003c/p\u003e\n\u003cp\u003eOf the total of 73 studies, 50 are research studies, and 22 are reviews or meta-analysis papers. Every research study found was classified into one of the following four categories of factors:\u003c/p\u003e\n\u003cp\u003e-DIET: 22 papers addressing probiotics, prebiotics, sweeteners, type of foods, ultra-processed food, specific diets (Mediterranean diet, vegan diet), fermented foods, plant-based food polyphenols, or protein supplements (Table 1)\u003c/p\u003e\n\u003cp\u003e-HABITS: 7 studies about sleep, physical activity, tobacco, alcohol, or drugs (Table 2).\u003c/p\u003e\n\u003cp\u003e-ENVIRONMENT: 11 articles regarding rural/urban environment, living near a mine, nursing homes, cohabiting family (partner, children, parents, grandparents), short hospitalization periods, long ocean voyages, or exposure to high altitudes (Table 3).\u003c/p\u003e\n\u003cp\u003e-CHEMICALS: 10 papers about antibiotics, methamphetamine, opioids, metformin, vitamin D, proton-pump inhibitors, herbicides, fungicides, titanium oxide nanoparticles, or herbal treatments (, Table 4).\u003c/p\u003e\n\u003cp\u003eOne study addressed two or more of these categories and was included in the discussion.\u003csup\u003e70\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eFirst, a review was made of the results related to the factors studied in every paper. In 41 of these research studies questionnaires were used. In Tables 1 to 4, questions of the questionnaires used in every study are split into the four categories mentioned (diet, habits, environment, and chemicals) and data of these four categories retrieved in every study were recorded.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDiet\u003c/p\u003e\n\u003cp\u003eOverall, diet was the most studied factor about its influence on digestive microbiota (43% of the papers included in the scoping \u0026nbsp;review) (Table 1). In the literature reviewed, probiotics have been shown to influence digestive microbiota to prevent or treat some diseases, decrease dysbiosis due to age, or help to maintain a normal microbiota in a meat-based diet. \u003csup\u003e13, 14. 15\u003c/sup\u003e Besides, the effect of commercial probiotics in healthy subjects was proven to increase the diversity of the oral cavity.\u003csup\u003e16\u003c/sup\u003e Fermented food has taken greater importance due to its relationship with positive microbiota changes and other effects such as reduction of academic stress and inflammatory markers. \u003csup\u003e17, 18, 19\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe intake of dietary fibre with different prebiotics also influences digestive microbiota. A diet rich in fiber increases the levels of beneficial bacteria and short-chain fatty acids (SCFA). \u003csup\u003e20, 21, 22\u003c/sup\u003e Supplementing with milk oligosaccharides, a prebiotic based on resistant starch, induces the growth of beneficial bifidobacteria. \u003csup\u003e23, 24\u003c/sup\u003e It has also been described that a greater intake of dietary fiber from cereals, fruits, and vegetables is associated with shifts in gut microbiome composition and a reduction of C-reactive protein. \u003csup\u003e25\u003c/sup\u003e Inulin consumption modified the microbiota composition with higher microbial diversity \u003csup\u003e26\u003c/sup\u003e. Dietary addition of \u003cem\u003eL. casei\u003c/em\u003e, \u003cem\u003eB. breve\u003c/em\u003e and a prebiotic product, results in an improvement of intestinal physiologic traits and an increase of total fecal bifidobacteria \u003csup\u003e27\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003ePolyphenols also have been shown to affect the gut microbiota. Some of them have protective effects of the goblet cells of the intestinal mucosa. Other polyphenols have been shown to increase the counts of \u003cem\u003eLactobacillus\u003c/em\u003e and \u003cem\u003eBifidobacterium\u003c/em\u003e and improve gut and host health. \u003csup\u003e28, 29\u003c/sup\u003e The type of diet has also been related to gut microbiota status. High adherence to Southern European Atlantic Diet produces a greater number of total bacteria, \u003cem\u003eActinobacteria\u003c/em\u003e, \u003cem\u003eLactobacillus,\u003c/em\u003e and \u003cem\u003eBifidobacterium\u003c/em\u003e genus.\u003csup\u003e30\u003c/sup\u003e Significant correlations between bacterial taxa and Mediterranean Diet adherence were observed in centenarians, nonagenarians, and younger subjects.\u003csup\u003e31\u003c/sup\u003e Microbiota associated to Mediterranean diet was enriched with beneficial bacteria that induces anti-inflammatory status and reduces the risk of developing gut diseases. \u003csup\u003e32\u003c/sup\u003e Individual foods have also been shown to influence digestive microbiota. Green tea liquid consumed daily decreased \u003cem\u003eBacteroidetes\u003c/em\u003e in feces and pathogenic bacteria in saliva. \u003csup\u003e33\u003c/sup\u003e A diet heavily based on beans and dairy products reduced gut diversity with less beneficial bacteria.\u003csup\u003e34\u003c/sup\u003e A long-term protein supplementation may have a negative effect on gut microbiota and increase the risk of intestinal diseases.\u003csup\u003e35, 36\u003c/sup\u003e Nevertheless, natural plant extracts with polyphenols, prebiotics, probiotics, and regular physical exercise improved gut microbiota, reducing dysbiosis produced by High Protein Diet (HPD). \u003csup\u003e36\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eConsumption of more than five servings per day of ultra-processed food produced a decrease in microbiota diversity \u003csup\u003e37\u003c/sup\u003e. Sesame seed snacks and plant-based smoothies produced a notable increase in endogenous antioxidants in plasma and an improvement in gut microbiota. \u003csup\u003e38\u003c/sup\u003e \u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePure saccharin supplementation did not alter gut microbial diversity, while Vitamin D supplementation increased the overall diversity of gut microbiota in healthy females with vitamin D deficiency. \u003csup\u003e39, 40\u003c/sup\u003e Food additives also affect gut microbiota composition. Some sweeteners and some emulsifiers may alter microbiota. Food preservatives increase the growth of proinflammatory bacteria, while anti-inflammatory bacteria decrease. Acidifiers can reduce coliform presence and increase lactic acid bacteria, and colorants can reduce microbiota diversity \u003cem\u003ein vitro\u003c/em\u003e. Nevertheless, the long-term impact of food additives on gut microbiota needs to be examined \u003csup\u003e41\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e[Here Table 1]\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHabits\u003c/p\u003e\n\u003cp\u003eAs shown in Table 2, there are different types of habits that influence digestive microbiota, such as physical activity, which has been shown to increase microbial diversity. \u003csup\u003e42\u003c/sup\u003e The quality of sleep also influences the microbiota, although not in all the circumstances. The microbiome is resistant to changes after consecutive days of sleeping restriction. \u003csup\u003e43\u003c/sup\u003e However, an acute sleep-wake cycle shift of 2 to 4 hours (subjects postpone their regular sleeping time for 2 to 4 hours) affects the functional profiles of gut microbes and interactions among them \u003csup\u003e44\u003c/sup\u003e. Alcohol consumption or smoking or the combination of both cause gut microbiota dysbiosis in healthy men. Noteworthy, smoking alone causes more severe dysbiosis than drinking alone. \u003csup\u003e45\u003c/sup\u003e Furthermore, smoking habits also modified oral microbiota diversity and heavy episodic drinking is associated with a specific stool type phenotype (Bristol stool scale). \u003csup\u003e46\u003c/sup\u003e\u0026nbsp; Consumption of heroin, ephedrine, and methamphetamine produced changes in the microbiota. Bacterial diversity was higher in SUD (substance use disorders) and this increases with the length of substance abuse.\u003csup\u003e47\u003c/sup\u003e Intestinal colonization by oral bacteria has been demonstrated; therefore, oral hygiene becomes more important \u003csup\u003e46,48\u003c/sup\u003e. In fact, the salivary microbiome was affected by denture use \u003csup\u003e46\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e[Here Table 2]\u003c/p\u003e\n\u003cp\u003eEnvironment\u003c/p\u003e\n\u003cp\u003eThe environment is also an important factor to study in this context (Table 3). References retrieved have shown different sources of influence on gut microbiota. \u003cem\u003eBlastocystis\u003c/em\u003e, a component of gut microbiota, has a higher prevalence in non-westernized individuals \u003csup\u003e49\u003c/sup\u003e. Differences in gut microbiota composition were found in individuals with the same ethnicity but coming from different Italian regions. \u003csup\u003e50\u003c/sup\u003e Medication and time spent in the nursing home contributed to microbiota dysbiosis more than age and frailty. The microbiota of residents who had lived in the nursing home for more than 1 year were enriched in inflammatory and pathogenic species and reduced in anti-inflammatory and symbiotic species. \u003csup\u003e51\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eNevertheless, it has been described that short-term hospitalization did not impact the richness or structure of the salivary microbiome.\u003csup\u003e52\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eIndoor spaces often harbor unique microbial communities. Indoor air in residences contained a greater number of culturable bacteria than outdoor air. Differences in bacterial flora in settled dust in two buildings were greater than differences between seasons. Bacterial communities on surfaces in offices were different between cities, and the microbiota in a home were identifiable by family. Humans are also major sources of bacteria in indoor air. \u003csup\u003e53\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs for the quality of the environment, long-term exposure to metals in residents near a mining and smelting area produced different profiles of gut microbiota. These effects were higher in men because of mining and smelting activity.\u003csup\u003e54\u003c/sup\u003e Currently, it is under discussion whether air pollution due to emissions from factories, chimneys, or livestock also affects gut microbiota since it may be trapped in the food. Some studies showed that gut microbiota metabolized the inorganic arsenic into toxic metabolites. Currently, there are some chemicals and pesticides that are considered microbiota-disrupting chemicals. \u003csup\u003e55\u003c/sup\u003e The living altitude also influences the microbiota composition, which was enriched in \u003cem\u003ePrevotella\u003c/em\u003e and \u003cem\u003eBacteroidetes\u003c/em\u003e in subjects living in high altitudes (\u0026gt;1500m) while \u003cem\u003eFaecalibacterium\u003c/em\u003e and \u003cem\u003eBlautia\u003c/em\u003e were increased in the low altitude group (\u0026lt;1500m). \u003csup\u003e56\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eMicrobiota diversity can also change due to traveling. Sun et al., (2022) reported that a 135-day sea expedition produced \u0026ldquo;seafaring syndrome\u0026rdquo; (SS) with abnormal defecation, frequent insomnia, poor sleeping quality, and overeating. Noteworthy, a significant correlation between the gut microbiome perturbation and this syndrome was found. \u003csup\u003e57\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eCohabitation with other people also influences digestive microbiota. Microbial dysbiosis might be caused in healthy partners cohabiting with Ulcerous Colitis patients and anxiety and stress are related to reduced diversity. \u003csup\u003e58, 59\u003c/sup\u003e People with larger social networks tend to have a more diverse microbiome. Cohabiting time affected strain sharing more than age or genetics. \u003csup\u003e60\u003c/sup\u003e A high similarity in the oral microbiota composition was found between members of the same family, higher between twins, parents, or brothers, and less or none between grandparents and grandchildren. There was also a similarity between classmates. \u003csup\u003e9\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e[Here Table 3]\u003c/p\u003e\n\u003cp\u003eChemicals\u003c/p\u003e\n\u003cp\u003eChemicals have proven to be important factors that influence digestive microbiota (Table 4). Non steroidal anti-inflammatory drugs (NSAID) provoke changes in gut microbiota. Bacterial population in the gastrointestinal tract reflects the combination of medications and varied with the type of NSAID that people take \u003csup\u003e61\u003c/sup\u003e. Proton Pump Inhibitors (PPI) have been associated with a decrease in microbiota diversity and an increase of \u003cem\u003eLactobacilus\u003c/em\u003e, \u003cem\u003eSteptococcus\u003c/em\u003e, \u003cem\u003eStaphylococcus\u003c/em\u003e and \u003cem\u003eE.coli.\u0026nbsp;\u003c/em\u003e\u003csup\u003e62\u003c/sup\u003e\u003csup\u003e, 63\u003c/sup\u003e Antibiotics are clearly an important factor that changes gut microbiota characteristics. Azithromycin alters the diversity of the salivary microbiome and delays the recovery of the diversity of gut microbiota after a treatment. \u003csup\u003e64\u003c/sup\u003e Moxifloxacin reduced bacterial diversity, which is not recovered until 16 to 21 days \u003csup\u003e65\u003c/sup\u003e. \u0026nbsp;\u003cem\u003eS. boulardii\u003c/em\u003e treatment can mitigate some antibiotic-induced microbiota changes (dysbiosis).\u003csup\u003e66\u003c/sup\u003e Metformine has an effect of reduction of gut microbiome diversity already after 24 hours of administration.\u003csup\u003e67\u003c/sup\u003e Decreased diversity of Shanon and Chao indices was observed in methadone-treated subjects. \u003csup\u003e68\u003c/sup\u003e Also, essential oils may be considered as a factor that influences the gut microbiome. Notably, a component of these oils, geraniol, has proven to increase butyrate-producer bacteria and improve intestinal dysbiosis.\u003csup\u003e69\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e[Here Table 4]\u003c/p\u003e\n\u003cp\u003eDiet, chemicals, environment, and/or habits interaction\u003c/p\u003e\n\u003cp\u003eSumming up, diet, chemicals, environment, and habits have been described as influencing the digestive microbiota. These factors are typically considered individually without considering the interactions between them. Diet, sleep quality, medications, supplements, physical activity, and psychological status are considered possible causes of dysbiosis. \u003csup\u003e70, 71, 72\u003c/sup\u003e However, it is also very important to study the interactions between factors on the microbiota quality.\u0026nbsp;Boisseau et al.\u0026nbsp;(2022) found that the microbiota of athletes is different from the rest of the population. Diets and treatments could be the origin of these differences. However, it is also known that exercise improves microbiota in sedentary people, but excessive practice does not improve microbiota and even worsens health. Nevertheless, there are no studies on humans that search for the interaction between diet and physical activity.\u0026nbsp;\u003csup\u003e6\u003c/sup\u003e Also, a positive interaction was found between diet, physical exercise, and HPD. Natural plant extracts with polyphenols, prebiotics, probiotics, and regular physical exercise improved gut microbiota, reducing dysbiosis produced by HPD\u0026nbsp;\u003csup\u003e36\u003c/sup\u003e.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eOf the 73 articles that meet the inclusion criteria, the majority described the influence of diet, habits, chemicals, or environment independently affecting the gut microbiota. All the factors reviewed act together in people\u0026acute;s daily lives. Therefore, the existence of an interaction between them is something that should be considered. In fact, in almost all the studies analyzed, the questionnaires given to the participants contain questions about all or some of these factors in order to exclude their influence from the results.\u003c/p\u003e \u003cp\u003eIn the group of 19 papers about diet influence (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) data were collected about diet (16/19), habits (12/19), environment (3/19), and chemicals (7/19)\u003c/p\u003e \u003cp\u003eIn addition to checking the consumption of foods whose influence on the diet is proven, such as fermented foods, \u003csup\u003e17, 18, 19\u003c/sup\u003e it would be interesting to investigate more about whether there is a difference between homemade and commercial fermentation meals since there are already many elaborate fermentation products on the market whose microorganism content is probably different from the homemade ones. Information in this regard can be collected in the questionnaire (homemade or commercial). The positive effects of some types of diet rich in vegetables have been proven. \u003csup\u003e30, 31, 32, 33\u003c/sup\u003e Therefore, it is also necessary to ask about the frequency of consumption since we can eat vegetables, but not in an appropriate frequency to notice positive effects.\u003csup\u003e34\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIt would be also interesting to investigate about the consumption of diets high in proteins or protein supplements and their duration, given that, in some cases, it can negatively influence the digestive microbiota.\u003csup\u003e35\u003c/sup\u003e UP foods should also be checked since high consumption has been seen to affect the diversity of the digestive microbiota. \u003csup\u003e37\u003c/sup\u003e Treatments with vitamin D are becoming more common in the population. Since this also influences the digestive microbiota, \u003csup\u003e40\u003c/sup\u003e should be considered.\u003c/p\u003e \u003cp\u003eFurthermore, the influence of some nutritional habits, such as snacking, intermittent fasting, and the number of daily intakes were not included in any of the questionnaires. Herein, we suggest including snacking as another factor to be considered. Snacking behavior is a practice that can be done with different types of foods and therefore can contribute to improving diet but also to worsening it.\u003csup\u003e72\u003c/sup\u003e Other factors that may be suitable to include were intermittent fasting and the number of daily intakes. These are habits that may influence the function of the digestive tract at different rhythms and frequencies, and this may affect the environment of microbiota.\u003c/p\u003e \u003cp\u003eThe 6 papers that analyze habits influence (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) data were retrieved about diet (5/6), habits (5/6), environment (1/6), and chemicals (2/6). Furthermore, these questionnaires do not consider the type of sport practiced. This is important to consider since team sports and sports in contact with water must be possible sources of different microbiota. Furthermore, none of these questionnaires considers body and hair hygiene, analyzing both frequency and time spent washing it. This may affect skin microbiota and, consequently, the digestive microbiota too.\u003c/p\u003e \u003cp\u003eIn the 7 papers addressing the environmental factors (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), data were recorded about diet (7/7), habits (7/7), environment (3/7), and chemicals (1/7). However, there were not retrieved other circumstances related to the environment. Living with pets may influence the human microbiota due to the interaction with their own specific microbiota. Domestic dogs share the house with the owners. Its microbiota has a taxonomic similarity with humans, much larger than mice or pig.\u003csup\u003e73, 74\u003c/sup\u003e Living or working with another type of animals may influence the human microbiota, too, due to their different specific microbiota. The microbiome of teleost fish, broiler chicken, and clam (Agropecten ventricosus) is different from the microbiome of mammals.\u003csup\u003e10, 75, 76\u003c/sup\u003e Cows that consume more pastures have a higher amount of \u003cem\u003eFirmicutes\u003c/em\u003e and \u003cem\u003eBacteroidetes\u003c/em\u003e, while cows that consume more concentrated food have the inverse proportion.\u003csup\u003e11\u003c/sup\u003e Not only microorganisms from pets but also parasites may alter gut conditions and contribute to intestinal dysbiosis. \u003csup\u003e77, 78\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThere are many professions developed in contact with animals and or with people with different microbiota composition, such as livestock, veterinary, fishing, agriculture, slaughterhouse, medicine, nursing, physiotherapy, nursing homes, public transport driver, police, prisons, schools, nurseries, masseuse, aesthetic centers (manicures, pedicures, tattoo artists, hairdressers), research laboratories with animal or biological material, zoos. We have not found any research about the influence of these kinds of environments on digestive microbiota, but they probably have some role in its variation. Moreover, the type of transportation daily used (individual, public) may also be an important source of variation of the microbiota taken from the environment.\u003c/p\u003e \u003cp\u003ePlace of work may also be an influencing factor since different environments can harbor different microbiota: home, office, industry, field, ship, plane, educational center, and transports such as trucks and taxis. Home cleaning is a daily action that can also modify the home microbiome, and coexistence with domestic animals or working with them are also important data to collect in a questionnaire for microbiota research.\u003c/p\u003e \u003cp\u003ePesticides also modify the microbiota of the animals. It has been described that long-term (lifelong) exposure to a low dose of a glyphosate herbicide (GBH-RUp) in drinking water led to significant changes in the intestinal microbiome composition in mice.\u003csup\u003e79\u003c/sup\u003e Daily contact with pesticides may be important for people working in aquaculture, poultry farming, and livestock farming.\u003c/p\u003e \u003cp\u003eAnother possible source of variation in the human microbiota environment may be home cleaning habits. Cleaning of chicken sponges significantly affected its microbiome structure. The authors of this study visualize the role of kitchen sponges as microbial hot spot in building the environment with the capability to collect and spread bacteria. \u003csup\u003e80\u003c/sup\u003e The environment has a high microbial diversity. Sites like home, offices, industry, and transport have very different physicochemical conditions. The role of the ambient microbiome in the skin and digestive microbiota is evident but not well understood nowadays. \u003csup\u003e81\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe 8 papers regarding the chemical factors (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) collected data about diet (5/8), habits (2/8), environment (1/8), and chemicals (7/8). Noteworthy, none of these questionnaires consider some type of therapy that could also affect the digestive microbiome, such as radiotherapy.\u003csup\u003e82\u003c/sup\u003e There are also other treatments widely used as opioids,\u003csup\u003e83\u003c/sup\u003e immune suppressants, corticosteroids, and anovulatory that should be considered.\u003c/p\u003e \u003cp\u003eAlmost all the studies included in this review investigated one of these factors and have provided evidence about their impact on our inner microbiota. However, further studies are necessary to obtain more data about the interaction between these aforementioned factors to shed light on their implications for the quality of the digestive microbiota.\u003c/p\u003e \u003cp\u003eOf all the articles reviewed, only one considers studying the interaction between factors. Boisseau et al. (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) reviewed the relationship between diet and physical activity. In humans, short-term changes in diet affect microbiota but in a transient way. A high fat content causes a decrease in \u003cem\u003eBifidobacteria\u003c/em\u003e, while protein increase \u003cem\u003ebifidobacteria\u003c/em\u003e and \u003cem\u003elactobacillus\u003c/em\u003e, and carbohydrates increase \u003cem\u003eBifidobacteria\u003c/em\u003e and reduce \u003cem\u003eBacteroides\u003c/em\u003e. On the other hand, the microbiota of athletes is different of the rest of the population. Diets and treatments could be the origin of these differences. However, it is also known that exercise improves microbiota in sedentary people, but an excessive practice does not improve microbiota and even worsen health. Nevertheless, there are no studies on humans that search about the interaction between diet and physical activity. This can be extensive to the other factors. For example, it is possible that different changes in the microbiota of different individuals due to probiotic consumption could be due to differences in some other factor studied in this review.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eSumming up, diet, chemicals, environment, and habits have been described to influence in the digestive microbiota. These factors are typically considered individually without considering the interactions between them. Furthermore, as shown in this review some cases that could influence human digestive microbiota are not yet studied. However, further studies are necessary to obtain more data about the influence on digestive microbiota of these aforementioned factors and about the interaction between all of them to shed light on their implications for the quality of the digestive microbiota. There is a great variety of questionnaires used in research about human digestive microbiota. It would be helpful to use a standardized tool that help to collect data about these factors.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe financial support for the publication of this paper is made by Universidad Internacional de La Rioja. The role of the sponsor of this review\u0026nbsp;was restricted to providing economic support, and it were not involved in the study process, manuscript preparation, or submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors´contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBPLL: Conceptualization, data curation, formal analysis, investigation, methodology, writing original draft and edition.\u003c/p\u003e\n\u003cp\u003eCMR: \u0026nbsp;Data curation, formal analysis, investigation, methodology, writing review and edition, validation.\u003c/p\u003e\n\u003cp\u003eEGF: Formal analysis, methodology, supervision, validation, writing review.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMcBurney MI, Davis C, Fraser CM, et al. 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HIV, opioid use, and alterations to the gut microbiome: elucidating independent and synergistic effects. \u003cem\u003eFront Immunol\u003c/em\u003e. 2023;14. doi:10.3389/fimmu.2023.1156862\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"gut microbiota dysbiosis, diet, lifestyle, environment, chemicals","lastPublishedDoi":"10.21203/rs.3.rs-4663650/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4663650/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground / objectives\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHuman digestive microbiota is affected by a wide variety of different factors. The objective of this study was to perform a scoping review that gathers and updates the information available about factors that affect human digestive microbiota in healthy adults. It is also reviewed if other factors are considered and if some type of interaction between them is studied. We searched in MEDLINE, Web of Science, Scielo, PROSPERO, and Cochrane databases. Two authors independently reviewed study eligibility and data extraction. Articles were classified based on the main factor studied upon one of the following categories: diet, habits, environment, or chemical exposure.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe literature search provided a total of 73 studies that met the inclusion criteria. The presence of data about the influence of diet, habits, environment, and exposition to chemicals on digestive microbiota were registered. Analysis of the studies indicates that the assessment of risk factors is often focused on a specific aspect (diet, habits, environment, and chemicals) and the study of the interaction between factors is up to now not sufficiently investigated. In addition, there are some situations probably relevant to the human digestive microbiota that are not being assessed (snacking, intermittent fasting, type of sport practiced, living with pets or working with animals, type of transportation daily used, home cleaning habits, treatments with radiotherapy, immune suppressants, corticosteroids).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLittle is known about the impact of the combined interaction of possible risk factors (diet, habits, environment, and chemical exposure) of dysbiosis in human digestive microbiota. Further studies are encouraged to evaluate more broadly the interactions between the risk factors that may influence the diversity of the human digestive microbiota. All of them are factors that act together every day on our health.\u003c/p\u003e","manuscriptTitle":"The diversity of factors influencing human digestive microbiota in healthy adults and their interaction: A scoping review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-25 07:38:23","doi":"10.21203/rs.3.rs-4663650/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":"d7fa8f78-a830-4a5e-bd77-72280688a605","owner":[],"postedDate":"July 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-04-24T15:30:58+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-25 07:38:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4663650","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4663650","identity":"rs-4663650","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}