The role of serum trimethylamine n-oxide and lipopolysaccharide levels in the pathogenesis of chronic gastritis infected with Helicobacter pylori

The role of serum trimethylamine n-oxide and lipopolysaccharide levels in the pathogenesis of chronic gastritis infected with Helicobacter pylori | 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 role of serum trimethylamine n-oxide and lipopolysaccharide levels in the pathogenesis of chronic gastritis infected with Helicobacter pylori Erhan Onalan, Ugur Kaplankaya, Burkay Yakar, Senanur Onalan Yıldırım, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6879633/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 Aim Helicobacter pylori (HP) infection can cause chronic, intense inflammation of the gastric mucosa, which can lead to stomach cancer. Trimethylamine N-oxide (TMAO) is a dietary metabolite that increases HP virulence and inflammatory process. In this study, we aimed to find out how serum TMAO, lipopolysaccharide (LPS) and pepsinogen levels are affected in patients with HP-induced chronic gastritis. Material and methods Forty-five age- and sex-matched patients diagnosed with chronic gastritis caused by H. Pylori and 45 healthy controls were included in this cross-sectional study. The diagnosis of H. Pylori-associated chronic gastritis was confirmed by endoscopy and biopsy. Serum TMAO, LPS, pepsinogen 1 and pepsinogen 2 levels were studied by the ELISA method. Results Serum TMAO level of patients with HP gastritis was 48.61 (2.29-120.66) and that of the control group was 7.89 (1.22–76.40). Serum TMAO levels were statistically significantly higher in patients with HP-related chronic gastritis than in the control group (p < 0.001). Serum LPS levels were statistically significantly higher in patients with HP-related chronic gastritis than in the control group (p = 0.008). Serum pepsinogen 1 levels were statistically significantly higher in patients with HP-related chronic gastritis than in the control group (p = 0.001). Conclusion The present study found elevated serum TMAO, LPS and pepsinogen 1 levels in patients with H. Pylori gastritis. These serum markers can be used as a non-invasive method in the evaluation of chronic gastritis infected with H. pylori. Helicobacter pylori Trımethylamıne n-oxıde lipopolysaccharide chronic gastritis Summary at a glance This study aimed to investigate the serum TMAO and LPS levels in patients with H. pylori-induced chronic gastritis. The present study found elevated serum TMAO, LPS and pepsinogen 1 levels in patients with H. Pylori gastritis. These serum markers can be used as a non-invasive method in the evaluation of chronic gastritis infected with H. pylori. Introduction Helicobacter pylori (H. pylori) is a Gram-negative, microaerophilic bacterium that predominantly resides in the gastric mucosa of humans. It represents one of the most prevalent chronic bacterial infections globally, with an estimated colonization rate affecting approximately half of the global population ( 1 ). In Turkey, H. pylori prevalence has been reported at much higher rates of 82.5% ( 2 ). H. Pylori colonizes the stomach and the resulting gastric inflammatory response is a major risk factor for chronic gastritis and gastric malignancies. H. pylori infection not only directly damages the gastric epithelial cell but also enhances the inflammatory response by increasing the production of inflammatory cytokines. It causes epithelial cell proliferation and apoptosis disorders due to the inflammation it causes. Persistent inflammation induced by Helicobacter pylori infection plays a central role in the pathogenesis of gastric carcinoma( 3 ). Trimethylamine N-oxide (TMAO) is derived from metabolites by the action of the intestinal microbiota and also comes in part from diets such as meat, eggs, dairy products and fish. TMAO levels are associated with systemic inflammation and at the same time increase systemic inflammation ( 4 ). Previous studies have shown a striking association between TMAO levels and the risk of atherosclerosis and cardiovascular disease in chronic inflammatory diseases. TMAO has been shown to trigger cytokine-mediated gene expression of the immunoinflammatory response via the NF-k B signaling pathway and increase vascular inflammation ( 5 ). The association between TMAO and H. Pylori may contribute to chronic inflammation. A previous study has shown that TMAO increases the survival and virulence of H. pylori in vitro and facilitates the production of inflammatory factors induced by H. pylori ( 6 ). LPS increases the resistance of bacteria to environmental stresses and can also be recognized by the immune system and generate strong immune responses. The lipopolysaccharide (LPS) of H. pylori shows a high degree of phase variation, which helps it escape the immune system ( 7 ). Endotoxinemia, which occurs in the event of systemic or excessive exposure to LPS, can lead to serious pathophysiological consequences such as tissue damage, inflammatory reactions, and organ failure. A previous study has shown that LPS exposure does not induce apoptosis-associated barrier dysfunction and increases TNFα secretion from activated macrophages ( 8 ). Chronic gastritis caused by H. pylori is a significant risk factor for systemic inflammatory response and malignancy. TMAO and LPS may have a negative contribution to this inflammatory process. TMAO and LPS levels in patients with H. pylori-induced chronic gastritis may help us predict the severity of the disease and inflammation. The objective of this research was to evaluate circulating levels of trimethylamine N-oxide (TMAO) and lipopolysaccharide (LPS) in individuals diagnosed with chronic gastritis associated with Helicobacter pylori infection. Methods Study population This observational case-control study was carried out between December 2023 and October 2024. All participants provided written informed consent, and the study protocol received ethical approval from the Non-Interventional Ethics Committee of Fırat University (Approval Date: July 27, 2023; Reference Number: 2023/10 − 04). The study population was randomly selected from patients aged 18 years and over who applied to the gastroenterology clinic for outpatient examination and treatment. The study population consisted of two groups: patients diagnosed with H. pylori chronic gastritis and healthy controls. Subjects with chronic gastritis caused by H. Pylori infection were recruited from outpatients of the Gastroenterology and Hepatology Department based on the diagnosis of upper gastrointestinal endoscopy. Exclusion criteria were as follows: ( 1 ) Subjects were identified as having metabolic or other chronic diseases other than gastritis; ( 2 ) subjects who had taken H 2 receptor antagonists, proton pump inhibitors, antibiotics or other medications to treat digestive diseases within the past 30 days; ( 3 ) pregnant or lactating women; ( 4 ) subjects with a diagnosis of malignancy; and ( 5 ) subjects with a history of previous gastrointestinal surgery. The healthy control group was selected from volunteers who applied to the gastroenterology clinic and did not have any complaints of gastritis and whose urea breath test and H. Pylori antigen in stool were negative. Exclusion criteria in the health control group were as follows; ( 1 ) known history of gastritis; ( 2 ) previous treatment for gastritis; ( 3 ) Individuals who had used antibiotics, proton pump inhibitors, or any medications related to gastrointestinal treatment within the preceding 30 days were excluded ; ( 4 ) pregnant or lactating women; ( 5 ) subjects with a diagnosis of malignancy; ( 6 ) subjects with a history of previous gastrointestinal surgery. A 10 mL venous blood sample was taken from all participants on an empty stomach in the morning. Blood samples taken into biochemistry tubes with aprotinin were centrifuged at 5000 rpm for 5 minutes within half an hour, serum was separated and stored at -80 0C until studied. Biochemical analysis Biochemical parameters, including glucose, lipid profile (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], and low-density lipoprotein cholesterol [LDL-C]), as well as AST, ALT, ALP, GGT, LDH, total protein, albumin, urea, creatinine, uric acid, and creatine kinase (CK), were retrieved from hospital laboratory records. These measurements were performed using the Advia 2400 Clinical Chemistry System (Siemens, Tarrytown, NY, USA) with reagents provided by the manufacturer. Levels of TMAO, LPS, Pepsinogen-1, and Pepsinogen-2 were measured using enzyme-linked immunosorbent assay (ELISA) in accordance with the protocols provided by the manufacturer. Analytical sensitivity and dynamic range were considered for each of these biomarkers. Plate washing procedures were carried out with a Bio-Tek ELX50 automated washer (BioTek Instruments, USA), and optical densities were recorded at 450 nm using a ChroMate Microplate Reader P4300 (Awareness Technology Instruments, USA). The ELISA kits utilized in the analysis demonstrated intra-assay coefficients of variation (CV) below 10%, and inter-assay CVs were under 12%. Statistical analysis The research data were analyzed using the Statistical Package for the Social Sciences (SPSS) version 22.0 statistical package program. Error checks, analyses and tables of the data were made in the same program. Descriptive statistics were presented as number (n) and percentage (%) for categorical data and as mean ± standard deviation or median (minimum-maximum) for continuous variables. Comparisons between categorical data were made with Pearson Chi-Square test. The distribution of continuous variables was evaluated with the Kolmogorov Smirnov test. In the analysis of continuous variables that did not meet the normal distribution conditions, the Mann Whitney U test was used to compare two independent groups. The Spearman correlation test was used for correlation analysis between continuous variables. p < 0.05 was considered statistically significant. Results The study cohort comprised 45 individuals diagnosed with H. pylori-associated gastritis and 45 healthy controls matched by age and sex. The median age of the gastritis group was 40.00 years (range: 19.0–61.0), while that of the control group was 41.00 years (range: 19.0–62.0), showing no statistically significant difference. Smoking prevalence differed significantly between groups: 57.8% (n = 26) of the control group reported smoking, compared to 33.3% (n = 15) in the patient group (p = 0.034). Detailed sociodemographic data of the participants are summarized in Table 1 . (Table 1 ) Table 1 Sociodemographic characteristics of the participants Variables H. pylori positive (n = 45) Control (n = 45) p Age (year) 40.00 (19.00–61.00) 41.00 (19.00–62.00) 0.818 BMI (kg/m 2 ) 23.50 (19.50–38.90) 22.85 (18.50–33.50) 0.244 Gender n(%) Female 30 (66.7) 28 (62.2) 0.826 Male 15 (33.3) 17 (37.8) Smoke n(%) Yes 15 (33.3) 26 (57.8) 0.034 No 30 (66.7) 19 (42.2) Alcohol n(%) Yes 1 (2.0) 2 (5.3) No 49 (98.0) 36 (94.7) Comparisons of baseline biochemical parameters in blood samples of all study participants are presented in Table 2 . No statistically significant difference was found between the biochemical parameters of the patient and control groups (p > 0.05). (Table 2 ) Table 2 Comparison of biochemical parameters of the participants Parameters H. pylori Pozitif Sağlıklı p Değeri Glucose 85.00 (59.0-160.0) 88.00 (66.0-184.0) 0.692 Cholesterol 183.64 ± 33.83 178.40 ± 38.95 0.497 LDL 116.71 ± 27.25 108.07 ± 37.13 0.211 HDL 46.39 ± 12.21 50.78 ± 15.46 0.138 AST 19.00 (6.0-175.0) 18.00 (8.0–56.0) 0.710 ALT 19.00 (12.0–37.0) 21.00 (12.0-107.0) 0.495 ALP 74.00 (42.0-136.0) 68.00 (29.0-129.0) 0.364 GGT 16.00 (6.0-202.0) 18.00 (4.0–87.0) 0.389 LDH 212.00 (153.0-338.0) 192.50 (122.0-289.0) 0.130 T.Protein 7.19 ± 0.55 7.14 ± 0.39 0.627 Albumin 4.60 ± 0.31 4.61 ± 0.25 0.841 T.Bilirubin 0.50 (0.15–1.50) 0.57 (0.20–1.20) 0.544 Ure 27.00 (15.0–77.0) 28.00 (15.0–43.0) 0.910 Creatinin 0.69 (0.44–1.12) 0.74 (0.54–1.18) 0.051 Uric Acid 4.70 (1.50–8.20) 4.80 (2.40–7.10) 0.482 CK 80.00 (24.0-255.0) 77.00 (32.0-229.0) 0.726 The median TMAO value of the patient group was 48.61 (2.29-120.66) and 7.89 (1.22–76.40) in the control group. The median TMAO value of the patient group was statistically higher than the control group (p < 0.001). The LPS median value of the patient group was 3.93 (0.00-55.50) and the LPS median value of the control group was 1.98 (0.07–9.59). The LPS median value of the patient group was statistically higher than the control group (p = 0.008). The pepsinogen 1 median value of the patient group was statistically higher than the control group (p = 0.001). There was no statistically significant difference between the pepsinogen 2 values of the patient and control groups (p = 0.151). (Table 3 ) Table 3 Comparison of TMAO, LPS, pepsinogen 1 and 2 levels of participants Parameters H. pylori positive Control p TMAO 48.61 (2.29-120.66) 7.89 (1.22–76.40) < 0.001 LPS 3.93 (0.00-55.50) 1.98 (0.07–9.59) 0.008 Pepsinojen 1 136.29 (15.59-414.65) 75.46 (19.17-251.74) 0.001 Pepsinojen 2 7.46 (0.63-164.77) 5.95 (0.43–33.09) 0.151 There was a statistically significant positive correlation between serum TMAO levels and LPS levels (r:0.259; p = 0.032). There was a significant positive correlation between serum TMAO levels and pepsinogen 1 (r:0.210; p = 0.047) and pepsinogen 2 (r:0.217; p = 0.040). There was a positive significant correlation between LPS levels and pepsinogen 1 (r:0.393; p < 0.001) (Table 4 ). Table 4 Spearman’s correlation analysis between TMAO, LPS, pepsinojen 1 ve 2 levels Parameters TMAO LPS pepsinojen 1 pepsinojen 2 TMAO r 1.000 0.259 * 0.210 * 0.217 * p -. 0.032 0.047 0.040 LPS r 0.259 * 1.000 0.393 ** 0.056 p 0.032 . < 0.001 0.600 Pepsinojen 1 r 0.210 * 0.393 ** 1.000 0.068 p 0.047 < 0.001 . 0.525 Pepsinojen 2 r 0.217 * 0.056 0.068 1.000 p 0.040 0.600 0.525 . Discussion In this study, patients with H. pylori-induced chronic gastritis exhibited elevated serum levels of TMAO, LPS, and Pepsinogen-1 when compared to healthy controls. Chronic gastritis associated with H. pylori is influenced by continuous interactions among bacterial components, host responses, and environmental conditions. As a result, a significant proportion of individuals infected with H. pylori remain asymptomatic ( 9 ). Prior research has demonstrated that TMAO can enhance H. pylori’s urease activity and stimulate the expression of its virulence determinants ( 10 ). Wu et al. reported that TMAO administration in rats led to increased expression of CagA, a major virulence protein of H. pylori ( 6 ). Virulence elements such as CagA not only contribute to bacterial colonization and pathogenicity but also modulate host inflammatory responses and gastric acid secretion ( 11 ). Furthermore, studies indicate that H. pylori exhibits augmented urease activity in the presence of TMAO. Thus, high TMAO not only increases inflammation and virulence but also increases the acid resistance of the bacteria ( 12 ). All this information may explain our finding of high TMAO levels in patients with chronic gastritis due to H. pylori. H. pylori infection may increase TMAO production by causing imbalances in the gut microbiota. Wang et al. reported that intestinal microbiota changed in a direction favoring TMAO production in patients with H. pylori infection ( 13 ). The present study showed that serum TMAO levels were high in patients with chronic gastritis due to H. Pylori. The present finding supported the previous literature data. We believe that the effect of dietary metabolites such as TMAO on the development of H.pylori-induced chronic gastritis may be a pioneer for further studies. The present study found that lipopolysaccharide (LPS) levels were higher in patients with chronic gastritis compared to the control group. LPS is a macromolecule found in the cell wall of gram-negative bacteria. LPS triggers a strong inflammatory response by the immune system ( 14 ). Lipopolysaccharide (LPS) is a critical virulence factor of H. pylori bacteria and causes persistent inflammation and gastric carcinogenesis. Elevated LPS levels are expected in patients with H. pylori gastritis. In addition, a positive correlation was found between TMAO and LPS levels. Previous studies have found positive lipopolysaccharide (LPS) levels in approximately 73.5% of gastric biopsy specimens obtained from H. pylori positive chronic gastritis patients ( 15 ). The present study showed that both serum TMAO and LPS levels increased in H.pylori gastritis. Pepsinogens have an important place as biomarkers assessing the functional integrity of the gastric mucosa. Pepsinogen 1 and Pepsinogen 2 may be indicators of structural changes in the gastric mucosa and gastric atrophy. In previous studies, it was reported that Pepsinogen 1 and 2 levels showed the damage occurring in the gastric mucosa as a result of H. pylori infection ( 16 ). In our study, Pepsinogen 1 and Pepsinogen 2 levels were found to be significantly higher in H. pylori positive individuals. In addition, we found a positive significant correlation between LPS and Pepsinogen 1 levels. Kitamura et al. reported that chronic gastritis infected with H. pylori can be diagnosed by using pepsinogen, a serum marker ( 17 ). The present study supported the previous literature information. The findings of the present study showed that serum TMAO, LPS, pepsinogen 1 and pepsinogen 2 levels increased in patients with chronic gastritis due to H. pylori. The use of these serologic tests may be a practical approach in the diagnosis of gastritis and evaluation of eradication. This study has some limitations. Although the diagnosis of H. Pylori-induced gastritis was confirmed endoscopically, endoscopy was not performed in the control group. The control group was selected from individuals who did not have gastritis complaints and did not have antihen in the stool. Another limitation is that, although we accepted H. Pylori eradication treatment as an exclusion criterion, the use of broad-spectrum antibiotics was ignored. Unfortunately, Turkey is a country where inappropriate antibiotic use is common. This situation may have affected both H. Pylori and microbiota and may have affected serum marker levels. Another limitation is that the microbiota of the participants was not evaluated. Both TMAO and LPS levels may be affected by microbiota. Differences in the microbiota of the participants may also affect the levels of these markers. Conclusion The present study found elevated serum TMAO, LPS and pepsinogen levels in patients with H. pylori gastritis. These serum markers can be used as a non-invasive method for the evaluation of H. pylori-infected chronic gastritis. We suggest that future studies should focus on the role of serum markers in the diagnosis, severity, prognosis and response to treatment of H. pylori-infected chronic gastritis. Declarations Data availability statement: The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions Funding statement: The current study was financially supported by Fırat University Scientific Research Project Unit. (project number: TF:24.03) Conflict of interest disclosure: The authors declare that they have no conflicts of interest, financial or otherwise. Ethics of approval statement: This cross-sectinal study was approved by the Noninvasive Ethics Committee of the Firat University. (Ethics committee approval date: 27.07.2023 number: 2023/10-04). Patient consent statement: Written consent was obtained from all participants. Permission to reproduce material from other sources : None Clinical trial registration : None Author contributions: EO, BY, UK: Data collection, design, Led and conceived the project, and authored the manuscript. SYO, ED, TK: Data collection, compiling, and discussion, BY, ED, MFG: Contributed to collecting and analysis data, discussion . ED, MFG, SYO: Supervision, writing, review and editing. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Please address all correspondence concerning this manuscript to me at [email protected] Erhan Onalan (Assoc. Prof): 0000-0001-5395-0390 email: [email protected] Ugur Kaplankaya(MD): 0009-0001-8529-9501 email: [email protected] Burkay Yakar(Assoc. Prof): 0000-0003-2745-6561 email: [email protected] Senanur Onalan Yıldırım(MD): 0009-0003-2537-8894 email: [email protected] Mehmet Ferit Gursu(PhD): 0000-0003-3552-7315 email: [email protected] Emir Donder(MD): 0000-0003-2537-6023 email: [email protected] Tuğçe Kaymaz (PhD): 0000-0002-1359-7358 email: [email protected] References FitzGerald R, Smith SM. An Overview of Helicobacter pylori Infection. Methods Mol Biol. 2021;2283:1-14. doi: 10.1007/978-1-0716-1302-3_1. Kocazeybek B, Tokman HB. Prevalence of Primary Antimicrobial Resistance of H. pylori in Turkey: A Systematic Review. Helicobacter 2016;21:251-260. https://doi.org/10.1111/hel.12272 Lim NR, Chung WC. 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Epub 2016 Apr 12. Chochi K, Ichikura T, Kinoshita M, Majima T, Shinomiya N, Tsujimoto H, Kawabata T, Sugasawa H, Ono S, Seki S, Mochizuki H. Helicobacter pylori augments growth of gastric cancers via the lipopolysaccharide-toll-like receptor 4 pathway whereas its lipopolysaccharide attenuates antitumor activities of human mononuclear cells. Clin Cancer Res. 2008 May 15;14(10):2909-17. doi: 10.1158/1078-0432.CCR-07-4467. Kiyohira K, Yoshihara M, Ito M, Haruma K, Tanaka S, Chayama K. Serum pepsinogen concentration as a marker of Helicobacter pyloriinfection and the histologic grade of gastritis; evaluation of gastric mucosa by serum pepsinogen levels. J Gastroenterol. 2003;38(4):332-8. doi: 10.1007/s005350300060. Kitamura Y, Yoshihara M, Ito M, Boda T, Matsuo T, Kotachi T, Tanaka S, Chayama K. Diagnosis of Helicobacter pylori-induced gastritis by serum pepsinogen levels. J Gastroenterol Hepatol. 2015 Oct;30(10):1473-7. doi: 10.1111/jgh.12987. 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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-6879633","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":473259961,"identity":"65a09cd5-b60c-4c41-b999-e0b189aaaf5e","order_by":0,"name":"Erhan Onalan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4ElEQVRIie3RsQrCMBCA4ZODdql0jYP6CpVA6SD6KimCLnV3cFAEXWJnfQvfwEigLsW5g4MiOBcEcVKjbg6xo0N+CNzycQcBMJn+tQNAzZ585tKoEGEA1JFqEG+CxUjIRVHi2vNNzob7HrfLx0sOzepKuEmuIxW+6xCWnPscbUoEdOlKIC50xMsijzBL9tdogSIyfBHtYe0sojd2lz0HLbwJePwmHol8Ek4lU8RSW8RvQtLUD8JYNrgiQep16FIi1RJ3xmmWX2XdcRPMBoNWNd6OT1ryfad6RX7SZDKZTPqeOOJG85SmkZ4AAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-5395-0390","institution":"Firat University School of Medicine: Firat Universitesi Tip Fakultesi","correspondingAuthor":true,"prefix":"","firstName":"Erhan","middleName":"","lastName":"Onalan","suffix":""},{"id":473259962,"identity":"e4241234-2bb2-459e-be77-29ff6535144b","order_by":1,"name":"Ugur Kaplankaya","email":"","orcid":"","institution":"Firat University School of Medicine: Firat Universitesi Tip Fakultesi","correspondingAuthor":false,"prefix":"","firstName":"Ugur","middleName":"","lastName":"Kaplankaya","suffix":""},{"id":473259963,"identity":"1bc144fa-4e86-437c-ab58-4cd31d04db95","order_by":2,"name":"Burkay Yakar","email":"","orcid":"","institution":"Firat University School of Medicine: Firat Universitesi Tip Fakultesi","correspondingAuthor":false,"prefix":"","firstName":"Burkay","middleName":"","lastName":"Yakar","suffix":""},{"id":473259964,"identity":"d91b3811-8f25-4988-81ec-e7b863230ed4","order_by":3,"name":"Senanur Onalan Yıldırım","email":"","orcid":"","institution":"Medical College Hospital","correspondingAuthor":false,"prefix":"","firstName":"Senanur","middleName":"Onalan","lastName":"Yıldırım","suffix":""},{"id":473259965,"identity":"f80f3667-4a20-48d0-b5b2-9bd3ab5874ca","order_by":4,"name":"Mehmet Ferit Gursu","email":"","orcid":"","institution":"Firat University School of Medicine: Firat Universitesi Tip Fakultesi","correspondingAuthor":false,"prefix":"","firstName":"Mehmet","middleName":"Ferit","lastName":"Gursu","suffix":""},{"id":473259966,"identity":"eec10b20-a46e-46f1-9333-931faf292b0e","order_by":5,"name":"Tugce Kaymaz","email":"","orcid":"","institution":"Nevşehir Hacı Bektaş Veli Üniversitesi: Nevsehir Haci Bektas Veli Universitesi","correspondingAuthor":false,"prefix":"","firstName":"Tugce","middleName":"","lastName":"Kaymaz","suffix":""},{"id":473259967,"identity":"f1287316-ec4c-47f2-9a15-1d3913ed2de3","order_by":6,"name":"Emir Donder","email":"","orcid":"","institution":"Firat University School of Medicine: Firat Universitesi Tip Fakultesi","correspondingAuthor":false,"prefix":"","firstName":"Emir","middleName":"","lastName":"Donder","suffix":""}],"badges":[],"createdAt":"2025-06-12 11:06:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6879633/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6879633/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85799323,"identity":"09acacb0-5d2a-4e3b-a087-3d469ffacec2","added_by":"auto","created_at":"2025-07-01 21:39:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":800820,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6879633/v1/cca3ebd5-098d-4e67-91dd-8a7c876ccde5.pdf"}],"financialInterests":"","formattedTitle":"The role of serum trimethylamine n-oxide and lipopolysaccharide levels in the pathogenesis of chronic gastritis infected with Helicobacter pylori","fulltext":[{"header":"Summary at a glance","content":"\u003cp\u003eThis study aimed to investigate the serum TMAO and LPS levels in patients with H. pylori-induced chronic gastritis. The present study found elevated serum TMAO, LPS and pepsinogen 1 levels in patients with H. Pylori gastritis. These serum markers can be used as a non-invasive method in the evaluation of chronic gastritis infected with H. pylori.\u003c/p\u003e\n"},{"header":"Introduction","content":"\u003cp\u003eHelicobacter pylori (H. pylori) is a Gram-negative, microaerophilic bacterium that predominantly resides in the gastric mucosa of humans. It represents one of the most prevalent chronic bacterial infections globally, with an estimated colonization rate affecting approximately half of the global population (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). In Turkey, H. pylori prevalence has been reported at much higher rates of 82.5% (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). H. Pylori colonizes the stomach and the resulting gastric inflammatory response is a major risk factor for chronic gastritis and gastric malignancies. H. pylori infection not only directly damages the gastric epithelial cell but also enhances the inflammatory response by increasing the production of inflammatory cytokines. It causes epithelial cell proliferation and apoptosis disorders due to the inflammation it causes. Persistent inflammation induced by Helicobacter pylori infection plays a central role in the pathogenesis of gastric carcinoma(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Trimethylamine N-oxide (TMAO) is derived from metabolites by the action of the intestinal microbiota and also comes in part from diets such as meat, eggs, dairy products and fish. TMAO levels are associated with systemic inflammation and at the same time increase systemic inflammation (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Previous studies have shown a striking association between TMAO levels and the risk of atherosclerosis and cardiovascular disease in chronic inflammatory diseases. TMAO has been shown to trigger cytokine-mediated gene expression of the immunoinflammatory response via the NF-k B signaling pathway and increase vascular inflammation (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). The association between TMAO and H. Pylori may contribute to chronic inflammation. A previous study has shown that TMAO increases the survival and virulence of H. pylori in vitro and facilitates the production of inflammatory factors induced by H. pylori (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). LPS increases the resistance of bacteria to environmental stresses and can also be recognized by the immune system and generate strong immune responses. The lipopolysaccharide (LPS) of H. pylori shows a high degree of phase variation, which helps it escape the immune system (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Endotoxinemia, which occurs in the event of systemic or excessive exposure to LPS, can lead to serious pathophysiological consequences such as tissue damage, inflammatory reactions, and organ failure. A previous study has shown that LPS exposure does not induce apoptosis-associated barrier dysfunction and increases TNFα secretion from activated macrophages (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Chronic gastritis caused by H. pylori is a significant risk factor for systemic inflammatory response and malignancy. TMAO and LPS may have a negative contribution to this inflammatory process. TMAO and LPS levels in patients with H. pylori-induced chronic gastritis may help us predict the severity of the disease and inflammation. The objective of this research was to evaluate circulating levels of trimethylamine N-oxide (TMAO) and lipopolysaccharide (LPS) in individuals diagnosed with chronic gastritis associated with Helicobacter pylori infection.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eThis observational case-control study was carried out between December 2023 and October 2024. All participants provided written informed consent, and the study protocol received ethical approval from the Non-Interventional Ethics Committee of Fırat University (Approval Date: July 27, 2023; Reference Number: 2023/10\u0026thinsp;\u0026minus;\u0026thinsp;04).\u003c/p\u003e \u003cp\u003eThe study population was randomly selected from patients aged 18 years and over who applied to the gastroenterology clinic for outpatient examination and treatment. The study population consisted of two groups: patients diagnosed with H. pylori chronic gastritis and healthy controls. Subjects with chronic gastritis caused by H. Pylori infection were recruited from outpatients of the Gastroenterology and Hepatology Department based on the diagnosis of upper gastrointestinal endoscopy. Exclusion criteria were as follows: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Subjects were identified as having metabolic or other chronic diseases other than gastritis; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) subjects who had taken H\u003csub\u003e2\u003c/sub\u003e receptor antagonists, proton pump inhibitors, antibiotics or other medications to treat digestive diseases within the past 30 days; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) pregnant or lactating women; (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) subjects with a diagnosis of malignancy; and (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) subjects with a history of previous gastrointestinal surgery. The healthy control group was selected from volunteers who applied to the gastroenterology clinic and did not have any complaints of gastritis and whose urea breath test and H. Pylori antigen in stool were negative. Exclusion criteria in the health control group were as follows; (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) known history of gastritis; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) previous treatment for gastritis; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Individuals who had used antibiotics, proton pump inhibitors, or any medications related to gastrointestinal treatment within the preceding 30 days were excluded ; (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) pregnant or lactating women; (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) subjects with a diagnosis of malignancy; (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) subjects with a history of previous gastrointestinal surgery. A 10 mL venous blood sample was taken from all participants on an empty stomach in the morning. Blood samples taken into biochemistry tubes with aprotinin were centrifuged at 5000 rpm for 5 minutes within half an hour, serum was separated and stored at -80 0C until studied.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eBiochemical analysis\u003c/h3\u003e\n\u003cp\u003eBiochemical parameters, including glucose, lipid profile (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], and low-density lipoprotein cholesterol [LDL-C]), as well as AST, ALT, ALP, GGT, LDH, total protein, albumin, urea, creatinine, uric acid, and creatine kinase (CK), were retrieved from hospital laboratory records. These measurements were performed using the Advia 2400 Clinical Chemistry System (Siemens, Tarrytown, NY, USA) with reagents provided by the manufacturer.\u003c/p\u003e \u003cp\u003eLevels of TMAO, LPS, Pepsinogen-1, and Pepsinogen-2 were measured using enzyme-linked immunosorbent assay (ELISA) in accordance with the protocols provided by the manufacturer. Analytical sensitivity and dynamic range were considered for each of these biomarkers. Plate washing procedures were carried out with a Bio-Tek ELX50 automated washer (BioTek Instruments, USA), and optical densities were recorded at 450 nm using a ChroMate Microplate Reader P4300 (Awareness Technology Instruments, USA). The ELISA kits utilized in the analysis demonstrated intra-assay coefficients of variation (CV) below 10%, and inter-assay CVs were under 12%.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe research data were analyzed using the Statistical Package for the Social Sciences (SPSS) version 22.0 statistical package program. Error checks, analyses and tables of the data were made in the same program. Descriptive statistics were presented as number (n) and percentage (%) for categorical data and as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median (minimum-maximum) for continuous variables. Comparisons between categorical data were made with Pearson Chi-Square test. The distribution of continuous variables was evaluated with the Kolmogorov Smirnov test. In the analysis of continuous variables that did not meet the normal distribution conditions, the Mann Whitney U test was used to compare two independent groups. The Spearman correlation test was used for correlation analysis between continuous variables. p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe study cohort comprised 45 individuals diagnosed with H. pylori-associated gastritis and 45 healthy controls matched by age and sex. The median age of the gastritis group was 40.00 years (range: 19.0\u0026ndash;61.0), while that of the control group was 41.00 years (range: 19.0\u0026ndash;62.0), showing no statistically significant difference. Smoking prevalence differed significantly between groups: 57.8% (n\u0026thinsp;=\u0026thinsp;26) of the control group reported smoking, compared to 33.3% (n\u0026thinsp;=\u0026thinsp;15) in the patient group (p\u0026thinsp;=\u0026thinsp;0.034). Detailed sociodemographic data of the participants are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSociodemographic characteristics of the participants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eH. pylori positive\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;45)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;45)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (year)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e40.00 (19.00\u0026ndash;61.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e41.00 (19.00\u0026ndash;62.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.818\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBMI (kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23.50 (19.50\u0026ndash;38.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22.85 (18.50\u0026ndash;33.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.244\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28 (62.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.826\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17 (37.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmoke n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26 (57.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19 (42.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAlcohol n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (5.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e49 (98.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36 (94.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eComparisons of baseline biochemical parameters in blood samples of all study participants are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. No statistically significant difference was found between the biochemical parameters of the patient and control groups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of biochemical parameters of the participants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eH. pylori Pozitif\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSağlıklı\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep Değeri\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGlucose\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e85.00 (59.0-160.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88.00 (66.0-184.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.692\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCholesterol\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e183.64\u0026thinsp;\u0026plusmn;\u0026thinsp;33.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e178.40\u0026thinsp;\u0026plusmn;\u0026thinsp;38.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.497\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLDL\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e116.71\u0026thinsp;\u0026plusmn;\u0026thinsp;27.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e108.07\u0026thinsp;\u0026plusmn;\u0026thinsp;37.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.211\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHDL\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46.39\u0026thinsp;\u0026plusmn;\u0026thinsp;12.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50.78\u0026thinsp;\u0026plusmn;\u0026thinsp;15.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.138\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAST\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19.00 (6.0-175.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.00 (8.0\u0026ndash;56.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.710\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eALT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19.00 (12.0\u0026ndash;37.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.00 (12.0-107.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.495\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eALP\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74.00 (42.0-136.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68.00 (29.0-129.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.364\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGGT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.00 (6.0-202.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.00 (4.0\u0026ndash;87.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.389\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLDH\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e212.00 (153.0-338.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e192.50 (122.0-289.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.130\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eT.Protein\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.19\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.627\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAlbumin\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.60\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.61\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.841\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eT.Bilirubin\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.50 (0.15\u0026ndash;1.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.57 (0.20\u0026ndash;1.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.544\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUre\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.00 (15.0\u0026ndash;77.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.00 (15.0\u0026ndash;43.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.910\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCreatinin\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.69 (0.44\u0026ndash;1.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.74 (0.54\u0026ndash;1.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.051\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUric Acid\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.70 (1.50\u0026ndash;8.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.80 (2.40\u0026ndash;7.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.482\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCK\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80.00 (24.0-255.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e77.00 (32.0-229.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.726\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe median TMAO value of the patient group was 48.61 (2.29-120.66) and 7.89 (1.22\u0026ndash;76.40) in the control group. The median TMAO value of the patient group was statistically higher than the control group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The LPS median value of the patient group was 3.93 (0.00-55.50) and the LPS median value of the control group was 1.98 (0.07\u0026ndash;9.59). The LPS median value of the patient group was statistically higher than the control group (p\u0026thinsp;=\u0026thinsp;0.008). The pepsinogen 1 median value of the patient group was statistically higher than the control group (p\u0026thinsp;=\u0026thinsp;0.001). There was no statistically significant difference between the pepsinogen 2 values of the patient and control groups (p\u0026thinsp;=\u0026thinsp;0.151). (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of TMAO, LPS, pepsinogen 1 and 2 levels of participants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026minus;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eH. pylori positive\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTMAO\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c2\"\u003e \u003cp\u003e48.61 (2.29-120.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.89 (1.22\u0026ndash;76.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLPS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c2\"\u003e \u003cp\u003e3.93 (0.00-55.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.98 (0.07\u0026ndash;9.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.008\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePepsinojen 1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c2\"\u003e \u003cp\u003e136.29 (15.59-414.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e75.46 (19.17-251.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePepsinojen 2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c2\"\u003e \u003cp\u003e7.46 (0.63-164.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.95 (0.43\u0026ndash;33.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.151\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThere was a statistically significant positive correlation between serum TMAO levels and LPS levels (r:0.259; p\u0026thinsp;=\u0026thinsp;0.032). There was a significant positive correlation between serum TMAO levels and pepsinogen 1 (r:0.210; p\u0026thinsp;=\u0026thinsp;0.047) and pepsinogen 2 (r:0.217; p\u0026thinsp;=\u0026thinsp;0.040). There was a positive significant correlation between LPS levels and pepsinogen 1 (r:0.393; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSpearman\u0026rsquo;s correlation analysis between TMAO, LPS, pepsinojen 1 ve 2 levels\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTMAO\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLPS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003epepsinojen 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003epepsinojen 2\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eTMAO\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.259\u003c/b\u003e\u003csup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.210\u003c/b\u003e\u003csup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.217\u003c/b\u003e\u003csup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.032\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.047\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.040\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eLPS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.259\u003c/b\u003e\u003csup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.393\u003c/b\u003e\u003csup\u003e\u003cb\u003e**\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.056\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.032\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.600\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003ePepsinojen 1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.210\u003c/b\u003e\u003csup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.393\u003c/b\u003e\u003csup\u003e\u003cb\u003e**\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.068\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.047\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.525\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003ePepsinojen 2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.217\u003c/b\u003e\u003csup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.068\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.040\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.600\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.525\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, patients with H. pylori-induced chronic gastritis exhibited elevated serum levels of TMAO, LPS, and Pepsinogen-1 when compared to healthy controls. Chronic gastritis associated with H. pylori is influenced by continuous interactions among bacterial components, host responses, and environmental conditions. As a result, a significant proportion of individuals infected with H. pylori remain asymptomatic (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Prior research has demonstrated that TMAO can enhance H. pylori\u0026rsquo;s urease activity and stimulate the expression of its virulence determinants (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Wu et al. reported that TMAO administration in rats led to increased expression of CagA, a major virulence protein of H. pylori (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Virulence elements such as CagA not only contribute to bacterial colonization and pathogenicity but also modulate host inflammatory responses and gastric acid secretion (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Furthermore, studies indicate that H. pylori exhibits augmented urease activity in the presence of TMAO. Thus, high TMAO not only increases inflammation and virulence but also increases the acid resistance of the bacteria (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). All this information may explain our finding of high TMAO levels in patients with chronic gastritis due to H. pylori. H. pylori infection may increase TMAO production by causing imbalances in the gut microbiota. Wang et al. reported that intestinal microbiota changed in a direction favoring TMAO production in patients with H. pylori infection (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). The present study showed that serum TMAO levels were high in patients with chronic gastritis due to H. Pylori. The present finding supported the previous literature data. We believe that the effect of dietary metabolites such as TMAO on the development of H.pylori-induced chronic gastritis may be a pioneer for further studies. The present study found that lipopolysaccharide (LPS) levels were higher in patients with chronic gastritis compared to the control group. LPS is a macromolecule found in the cell wall of gram-negative bacteria. LPS triggers a strong inflammatory response by the immune system (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Lipopolysaccharide (LPS) is a critical virulence factor of H. pylori bacteria and causes persistent inflammation and gastric carcinogenesis. Elevated LPS levels are expected in patients with H. pylori gastritis. In addition, a positive correlation was found between TMAO and LPS levels. Previous studies have found positive lipopolysaccharide (LPS) levels in approximately 73.5% of gastric biopsy specimens obtained from H. pylori positive chronic gastritis patients (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The present study showed that both serum TMAO and LPS levels increased in H.pylori gastritis.\u003c/p\u003e \u003cp\u003ePepsinogens have an important place as biomarkers assessing the functional integrity of the gastric mucosa. Pepsinogen 1 and Pepsinogen 2 may be indicators of structural changes in the gastric mucosa and gastric atrophy. In previous studies, it was reported that Pepsinogen 1 and 2 levels showed the damage occurring in the gastric mucosa as a result of H. pylori infection (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). In our study, Pepsinogen 1 and Pepsinogen 2 levels were found to be significantly higher in H. pylori positive individuals. In addition, we found a positive significant correlation between LPS and Pepsinogen 1 levels. Kitamura et al. reported that chronic gastritis infected with H. pylori can be diagnosed by using pepsinogen, a serum marker (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). The present study supported the previous literature information. The findings of the present study showed that serum TMAO, LPS, pepsinogen 1 and pepsinogen 2 levels increased in patients with chronic gastritis due to H. pylori. The use of these serologic tests may be a practical approach in the diagnosis of gastritis and evaluation of eradication.\u003c/p\u003e \u003cp\u003eThis study has some limitations. Although the diagnosis of H. Pylori-induced gastritis was confirmed endoscopically, endoscopy was not performed in the control group. The control group was selected from individuals who did not have gastritis complaints and did not have antihen in the stool. Another limitation is that, although we accepted H. Pylori eradication treatment as an exclusion criterion, the use of broad-spectrum antibiotics was ignored. Unfortunately, Turkey is a country where inappropriate antibiotic use is common. This situation may have affected both H. Pylori and microbiota and may have affected serum marker levels. Another limitation is that the microbiota of the participants was not evaluated. Both TMAO and LPS levels may be affected by microbiota. Differences in the microbiota of the participants may also affect the levels of these markers.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe present study found elevated serum TMAO, LPS and pepsinogen levels in patients with H. pylori gastritis. These serum markers can be used as a non-invasive method for the evaluation of H. pylori-infected chronic gastritis. We suggest that future studies should focus on the role of serum markers in the diagnosis, severity, prognosis and response to treatment of H. pylori-infected chronic gastritis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability statement: \u003c/strong\u003eThe data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement: \u003c/strong\u003eThe current study was financially supported by Fırat University Scientific Research Project Unit. (project number: TF:24.03)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest disclosure: \u003c/strong\u003eThe authors declare that they have no conflicts of interest, financial or otherwise.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics of approval statement: \u003c/strong\u003eThis cross-sectinal study was approved by the Noninvasive Ethics Committee of the Firat University. (Ethics committee approval date: 27.07.2023 number: 2023/10-04). \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient consent statement: \u003c/strong\u003eWritten consent was obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e Permission to reproduce material from other sources\u003c/strong\u003e: None\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial registration\u003c/strong\u003e: None\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEO, BY, UK:\u003c/strong\u003e Data collection, design, Led and conceived the project, and authored the manuscript. \u003cstrong\u003eSYO, ED, TK:\u003c/strong\u003e Data collection, compiling, and discussion, \u003cstrong\u003eBY, ED, MFG: \u003c/strong\u003eContributed to collecting and analysis data, discussion\u003cstrong\u003e. ED, MFG, SYO: \u003c/strong\u003eSupervision, writing, review and editing.\u003c/p\u003e\n\u003cp\u003eAll authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003ePlease address all correspondence concerning this manuscript to me at \u003cstrong\[email protected]\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eErhan Onalan (Assoc. Prof): 0000-0001-5395-0390 email: [email protected]\u003c/p\u003e\n\u003cp\u003eUgur Kaplankaya(MD): 0009-0001-8529-9501 email: [email protected]\u003c/p\u003e\n\u003cp\u003eBurkay Yakar(Assoc. Prof): 0000-0003-2745-6561 email: [email protected]\u003c/p\u003e\n\u003cp\u003eSenanur Onalan Yıldırım(MD): 0009-0003-2537-8894 email: [email protected]\u003c/p\u003e\n\u003cp\u003eMehmet Ferit Gursu(PhD): 0000-0003-3552-7315 email: [email protected]\u003c/p\u003e\n\u003cp\u003eEmir Donder(MD): 0000-0003-2537-6023 email: [email protected]\u003c/p\u003e\n\u003cp\u003eTuğ\u0026ccedil;e Kaymaz (PhD): 0000-0002-1359-7358 email: [email protected]\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFitzGerald R, Smith SM. An Overview of Helicobacter pylori Infection. Methods Mol Biol. 2021;2283:1-14. doi: 10.1007/978-1-0716-1302-3_1.\u003c/li\u003e\n\u003cli\u003eKocazeybek B, Tokman HB. Prevalence of Primary Antimicrobial Resistance of H. pylori in Turkey: A Systematic Review. Helicobacter 2016;21:251-260. https://doi.org/10.1111/hel.12272\u003c/li\u003e\n\u003cli\u003eLim NR, Chung WC. 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Adv Anat Pathol. 2020 May;27(3):193-205. doi: 10.1097/PAP.0000000000000214.\u003c/li\u003e\n\u003cli\u003eWu D, Cao M, Peng J, Li N, Yi S, Song L, Wang X, Zhang M, Zhao J. The effect of trimethylamine N-oxide on Helicobacter pylori-induced changes of immunoinflammatory genes expression in gastric epithelial cells. Int Immunopharmacol. 2017 Feb;43:172-178. doi: 10.1016/j.intimp.2016.11.032.\u003c/li\u003e\n\u003cli\u003eKusters JG, Van V, Arnoud HM, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clinical microbiology reviews, 2006, 19.3: 449-490.\u003c/li\u003e\n\u003cli\u003eGhalehnoei H, Ahmadzadeh A, Farzi N, Alebouyeh M, Aghdaei HA, Azimzadeh P, Molaei M, Zali MR. Relationship between ureB Sequence Diversity, Urease Activity and Genotypic Variations of Different Helicobacter pylori Strains in Patients with Gastric Disorders. Pol J Microbiol. 2016;65(2):153-9.\u003c/li\u003e\n\u003cli\u003eHolz C, Busjahn A, Mehling H, Arya S, Boettner M, Habibi H, Lang C. Significant Reduction in Helicobacter pylori Load in Humans with Non-viable Lactobacillus reuteri DSM17648: A Pilot Study. Probiotics Antimicrob Proteins. 2015 Jun;7(2):91-100. doi: 10.1007/s12602-014-9181-3.\u003c/li\u003e\n\u003cli\u003eMaldonado RF, S\u0026aacute;-Correia I, Valvano MA. Lipopolysaccharide modification in Gram-negative bacteria during chronic infection. FEMS Microbiol Rev. 2016 Jul;40(4):480-93. doi: 10.1093/femsre/fuw007. Epub 2016 Apr 12.\u003c/li\u003e\n\u003cli\u003eChochi K, Ichikura T, Kinoshita M, Majima T, Shinomiya N, Tsujimoto H, Kawabata T, Sugasawa H, Ono S, Seki S, Mochizuki H. Helicobacter pylori augments growth of gastric cancers via the lipopolysaccharide-toll-like receptor 4 pathway whereas its lipopolysaccharide attenuates antitumor activities of human mononuclear cells. Clin Cancer Res. 2008 May 15;14(10):2909-17. doi: 10.1158/1078-0432.CCR-07-4467.\u003c/li\u003e\n\u003cli\u003eKiyohira K, Yoshihara M, Ito M, Haruma K, Tanaka S, Chayama K. Serum pepsinogen concentration as a marker of Helicobacter pyloriinfection and the histologic grade of gastritis; evaluation of gastric mucosa by serum pepsinogen levels. J Gastroenterol. 2003;38(4):332-8. doi: 10.1007/s005350300060.\u003c/li\u003e\n\u003cli\u003eKitamura Y, Yoshihara M, Ito M, Boda T, Matsuo T, Kotachi T, Tanaka S, Chayama K. Diagnosis of Helicobacter pylori-induced gastritis by serum pepsinogen levels. J Gastroenterol Hepatol. 2015 Oct;30(10):1473-7. doi: 10.1111/jgh.12987.\u003c/li\u003e\n\u003c/ol\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":"Helicobacter pylori, Trımethylamıne n-oxıde, lipopolysaccharide, chronic gastritis","lastPublishedDoi":"10.21203/rs.3.rs-6879633/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6879633/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eAim\u003c/h2\u003e \u003cp\u003eHelicobacter pylori (HP) infection can cause chronic, intense inflammation of the gastric mucosa, which can lead to stomach cancer. Trimethylamine N-oxide (TMAO) is a dietary metabolite that increases HP virulence and inflammatory process. In this study, we aimed to find out how serum TMAO, lipopolysaccharide (LPS) and pepsinogen levels are affected in patients with HP-induced chronic gastritis.\u003c/p\u003e\u003ch2\u003eMaterial and methods\u003c/h2\u003e \u003cp\u003eForty-five age- and sex-matched patients diagnosed with chronic gastritis caused by H. Pylori and 45 healthy controls were included in this cross-sectional study. The diagnosis of H. Pylori-associated chronic gastritis was confirmed by endoscopy and biopsy. Serum TMAO, LPS, pepsinogen 1 and pepsinogen 2 levels were studied by the ELISA method.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eSerum TMAO level of patients with HP gastritis was 48.61 (2.29-120.66) and that of the control group was 7.89 (1.22\u0026ndash;76.40). Serum TMAO levels were statistically significantly higher in patients with HP-related chronic gastritis than in the control group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Serum LPS levels were statistically significantly higher in patients with HP-related chronic gastritis than in the control group (p\u0026thinsp;=\u0026thinsp;0.008). Serum pepsinogen 1 levels were statistically significantly higher in patients with HP-related chronic gastritis than in the control group (p\u0026thinsp;=\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe present study found elevated serum TMAO, LPS and pepsinogen 1 levels in patients with H. Pylori gastritis. These serum markers can be used as a non-invasive method in the evaluation of chronic gastritis infected with H. pylori.\u003c/p\u003e","manuscriptTitle":"The role of serum trimethylamine n-oxide and lipopolysaccharide levels in the pathogenesis of chronic gastritis infected with Helicobacter pylori","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-20 11:06:58","doi":"10.21203/rs.3.rs-6879633/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":"52076298-c862-46c1-99ef-d7aff3e06fb8","owner":[],"postedDate":"June 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-30T14:08:15+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-20 11:06:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6879633","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6879633","identity":"rs-6879633","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}