Causal relationship between oral microbiota and gastrointestinal ulcers: a two-sample Mendelian randomization study_Chinese Journal of Evidence-Based Medicine

Authors：

MAO Ningfeng ^1,2 , HE Jiawei ^1,2 , ZHANG Yang ^1,2 , YU Lin ^1,2 ,  ZHOU Shuhan ^1,2,3 ,  LYU Wenliang ^1,2,3

1. College of Traditional Chinese Medicine Clinical Medicine, Hubei University of Chinese Medicine, Wuhan 430061, P. R. China;
2. Institute of Epidemic Disease, Hubei University of Chinese Medicine, Wuhan 430061, P. R. China;
3. Hubei Shizhen Laboratory, Wuhan 430061, P. R. China;

Corresponding author：

ZHOU Shuhan, Email: 3062@hbucm.edu.cn; LYU Wenliang, Email: lvwenliang66@126.com

Keywords：

Causal effect; Mendelian randomizations; Oral microbiome; Peptic ulcer

DOI：

10.7507/1672-2531.202502067

Video：

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Objective To investigate the potential causal relationship between specific oral microbiota and peptic ulcer disease (PUD) using a Mendelian randomization (MR) approach. Methods The genome-wide association study (GWAS) data from East Asian populations was utilized to perform a two-sample MR analysis to determine the causal relationship between oral microbiota and PUD. The MR analysis was primarily conducted using the inverse-variance weighted (IVW) method, supplemented by MR-Egger and weighted median methods. Heterogeneity and pleiotropy were assessed, and the leave-one-out method was employed to evaluate the stability of the MR results. Results There was a complex association between specific bacterial genera of the oral microbiota and PUD. Prevotella was found to potentially promote duodenal ulcers while exerting a protective effect against gastric ulcers. Campylobacter and Streptococcus demonstrated differing effects on gastric and duodenal ulcers. Furthermore, Fusobacterium and Haemophilus_A were positively associated with peptic ulcers, suggesting an increased risk of gastroduodenal ulcer development. Conclusion This study explores the causal relationship between oral microbiota and PUD, providing new insights into the prevention and treatment of PUD mediated by oral microbiota.

Citation： MAO Ningfeng, HE Jiawei, ZHANG Yang, YU Lin, ZHOU Shuhan, LYU Wenliang. Causal relationship between oral microbiota and gastrointestinal ulcers: a two-sample Mendelian randomization study. Chinese Journal of Evidence-Based Medicine, 2025, 25(7): 796-802. doi: 10.7507/1672-2531.202502067 Copy

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2.	Lanas A, Chan FKL. Peptic ulcer disease. Lancet, 2017, 390(10094): 613-624.
3.	Sung JJ, Kuipers EJ, El-Serag HB. Systematic review: the global incidence and prevalence of peptic ulcer disease. Aliment Pharmacol Ther, 2009, 29(9): 938-946.
4.	Xie X, Ren K, Zhou Z, et al. The global, regional and national burden of peptic ulcer disease from 1990 to 2019: a population-based study. BMC Gastroenterol, 2022, 22(1): 58.
5.	Milosavljevic T, Kostić-Milosavljević M, Jovanović I, et al. Complications of peptic ulcer disease. Dig Dis, 2011, 29(5): 491-493.
6.	Søreide K, Thorsen K, Harrison EM, et al. Perforated peptic ulcer. Lancet, 2015, 386(10000): 1288-1298.
7.	Leow AH, Lim YY, Liew WC, et al. Time trends in upper gastrointestinal diseases and Helicobacter pylori infection in a multiracial Asian population--a 20-year experience over three time periods. Aliment Pharmacol Ther, 2016, 43(7): 831-837.
8.	Savoldi A, Carrara E, Graham DY, et al. Prevalence of antibiotic resistance in Helicobacter pylori: a systematic review and meta-analysis in World Health Organization regions. Gastroenterology, 2018, 155(5): 1372-1382.
9.	Lanas A. We are using too many PPIs, and we need to stop: a European perspective. Am J Gastroenterol, 2016, 111(8): 1085-1086.
10.	Iijima K, Kanno T, Koike T, et al. Helicobacter pylori-negative, non-steroidal anti-inflammatory drug: negative idiopathic ulcers in Asia. World J Gastroenterol, 2014, 20(3): 706-713.
11.	Seneviratne CJ, Balan P, Suriyanarayanan T, et al. Oral microbiome-systemic link studies: perspectives on current limitations and future artificial intelligence-based approaches. Crit Rev Microbiol, 2020, 46(3): 288-299.
12.	李博磊, 程磊, 周学东, 等. 口腔微生物与消化系统疾病关系的研究进展. 华西口腔医学杂志, 2018, 36(3): 331-335.
13.	夏孟蛟, 金钊, 郑川, 等. 基于口腔微生态论结肠炎-癌转化的中医药干预. 中华中医药杂志, 2019, 34(6): 2566-2570.
14.	张志民, 程博群. 口腔微生物与消化系统癌症关系的研究进展. 口腔医学研究, 2020, 36(2): 93-97.
15.	Elghannam MT, Hassanien MH, Ameen YA, et al. Helicobacter pylori and oral-gut microbiome: clinical implications. Infection, 2024, 52(2): 289-300.
16.	Ansari SA, Iqbal MUN, Khan TA, et al. Association of oral Helicobacter pylori with gastric complications. Life Sci, 2018, 205: 125-130.
17.	Belizário JE, Napolitano M. Human microbiomes and their roles in dysbiosis, common diseases, and novel therapeutic approaches. Front Microbiol, 2015, 6: 1050.
18.	Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA, 2017, 318(19): 1925-1926.
19.	Bowden J, Holmes MV. Meta-analysis and Mendelian randomization: a review. Res Synth Methods, 2019, 10(4): 486-496.
20.	Nagai A, Hirata M, Kamatani Y, et al. Overview of the BioBank Japan project: study design and profile. J Epidemiol, 2017, 27: S2-S8.
21.	Hozawa A, Tanno K, Nakaya N, et al. Study profile of the Tohoku Medical Megabank Community-based cohort study. J Epidemiol, 2021, 31(1): 65-76.
22.	The 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature, 2015, 526(7571): 68-74.
23.	Pierce BL, Ahsan H, Vanderweele TJ. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol, 2011, 40(3): 740-752.
24.	Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 2017, 32(5): 377-389.
25.	Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
26.	Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
27.	Hemani G, Zheng J, Elsworth B, et al. The MR-base platform supports systematic causal inference across the human phenome. Elife, 2018, 7: e34408.
28.	Baker JL, Bor B, Agnello M, et al. Ecology of the oral microbiome: beyond bacteria. Trends Microbiol, 2017, 25(5): 362-374.
29.	Tan X, Wang Y, Gong T. The interplay between oral microbiota, gut microbiota and systematic diseases. J Oral Microbiol, 2023, 15(1): 2213112.
30.	Dong Z, Yu K, Xin Y, et al. Association between gut microbiota and peptic ulcer disease, particularly gastric ulcer and duodenal ulcer: a two-sample Mendelian randomization study. Front Microbiol, 2024, 14: 1277300.
31.	Zhao J, Hou Y, Xie T, et al. Genome-wide Mendelian randomization identifies putatively causal gut microbiota for multiple peptic ulcer diseases. Front Immunol, 2023, 14: 1260780.
32.	Zhang J, Hu Y, Wu L, et al. Causal effect of gut microbiota on gastroduodenal ulcer: a two-sample Mendelian randomization study. Front Cell Infect Microbiol, 2023, 13: 1322537.
33.	Kitamoto S, Nagao-Kitamoto H, Hein R, et al. The bacterial connection between the oral cavity and the gut diseases. J Dent Res, 2020, 99(9): 1021-1029.
34.	Horliana AC, Chambrone L, Foz AM, et al. Dissemination of periodontal pathogens in the bloodstream after periodontal procedures: a systematic review. PLoS One, 2014, 9(5): e98271.
35.	Walker MY, Pratap S, Southerland JH, et al. Role of oral and gut microbiome in nitric oxide-mediated colon motility. Nitric Oxide, 2018, 73: 81-88.
36.	Schmidt TS, Hayward MR, Coelho LP, et al. Extensive transmission of microbes along the gastrointestinal tract. Elife, 2019, 8: e42693.
37.	Vich Vila A, Imhann F, Collij V, et al. Gut microbiota composition and functional changes in inflammatory bowel disease and irritable bowel syndrome. Sci Transl Med, 2018, 10(472): eaap8914.
38.	Lim JH, Shin J, Park JS. Effect of a proton pump inhibitor on the duodenum microbiome of gastric ulcer patients. Life (Basel), 2022, 12(10): 1505.
39.	Chen X, Xia C, Li Q, et al. Comparisons between bacterial communities in mucosa in patients with gastric antrum ulcer and a duodenal ulcer. Front Cell Infect Microbiol, 2018, 8: 126.
40.	Fu K, Cheung AHK, Wong CC, et al. Streptococcus anginosus promotes gastric inflammation, atrophy, and tumorigenesis in mice. Cell, 2024, 187(4): 882-896.
41.	Wescombe PA, Heng NC, Burton JP, et al. Streptococcal bacteriocins and the case for Streptococcus salivarius as model oral probiotics. Future Microbiol, 2009, 4(7): 819-835.
42.	Wu L, Wang Z, Sun G, et al. Effects of anti-H. pylori triple therapy and a probiotic complex on intestinal microbiota in duodenal ulcer. Sci Rep, 2019, 9(1): 12874.
43.	Chen L, Xu W, Lee A, et al. The impact of Helicobacter pylori infection, eradication therapy and probiotic supplementation on gut microenvironment homeostasis: an open-label, randomized clinical trial. EBioMedicine, 2018, 35: 87-96.
44.	Torres MDT, Brooks EF, Cesaro A, et al. Mining human microbiomes reveals an untapped source of peptide antibiotics. Cell, 2024, 187(19): 5453-5467.
45.	Larsen JM. The immune response to Prevotella bacteria in chronic inflammatory disease. Immunology, 2017, 151(4): 363-374.
46.	Sharma P, Phatak SM, Warikoo P, et al. Crosstalk between Helicobacter pylori and gastrointestinal microbiota in various gastroduodenal diseases-a systematic review. 3 Biotech, 2023, 13(9): 303.
47.	Viazis N, Argyriou K, Kotzampassi K, et al. A four-probiotics regimen combined with a standard Helicobacter pylori-eradication treatment reduces side effects and increases eradication rates. Nutrients, 2022, 14(3): 632.
48.	Westerik N, Reid G, Sybesma W, et al. The probiotic lactobacillus rhamnosus for alleviation of Helicobacter pylori-associated gastric pathology in East Africa. Front Microbiol, 2018, 9: 1873.
49.	Wu S, Cui W, Zhou Q, et al. Phenyl lactic acid alleviates Helicobacter pylori infection in C57BL/6 mice. Food Funct, 2023, 14(11): 5032-5047.

1. Mertz HR, Walsh JH. Peptic ulcer pathophysiology. Med Clin North Am, 1991, 75(4): 799-814.
2. Lanas A, Chan FKL. Peptic ulcer disease. Lancet, 2017, 390(10094): 613-624.
3. Sung JJ, Kuipers EJ, El-Serag HB. Systematic review: the global incidence and prevalence of peptic ulcer disease. Aliment Pharmacol Ther, 2009, 29(9): 938-946.
4. Xie X, Ren K, Zhou Z, et al. The global, regional and national burden of peptic ulcer disease from 1990 to 2019: a population-based study. BMC Gastroenterol, 2022, 22(1): 58.
5. Milosavljevic T, Kostić-Milosavljević M, Jovanović I, et al. Complications of peptic ulcer disease. Dig Dis, 2011, 29(5): 491-493.
6. Søreide K, Thorsen K, Harrison EM, et al. Perforated peptic ulcer. Lancet, 2015, 386(10000): 1288-1298.
7. Leow AH, Lim YY, Liew WC, et al. Time trends in upper gastrointestinal diseases and Helicobacter pylori infection in a multiracial Asian population--a 20-year experience over three time periods. Aliment Pharmacol Ther, 2016, 43(7): 831-837.
8. Savoldi A, Carrara E, Graham DY, et al. Prevalence of antibiotic resistance in Helicobacter pylori: a systematic review and meta-analysis in World Health Organization regions. Gastroenterology, 2018, 155(5): 1372-1382.
9. Lanas A. We are using too many PPIs, and we need to stop: a European perspective. Am J Gastroenterol, 2016, 111(8): 1085-1086.
10. Iijima K, Kanno T, Koike T, et al. Helicobacter pylori-negative, non-steroidal anti-inflammatory drug: negative idiopathic ulcers in Asia. World J Gastroenterol, 2014, 20(3): 706-713.
11. Seneviratne CJ, Balan P, Suriyanarayanan T, et al. Oral microbiome-systemic link studies: perspectives on current limitations and future artificial intelligence-based approaches. Crit Rev Microbiol, 2020, 46(3): 288-299.
12. 李博磊, 程磊, 周学东, 等. 口腔微生物与消化系统疾病关系的研究进展. 华西口腔医学杂志, 2018, 36(3): 331-335.
13. 夏孟蛟, 金钊, 郑川, 等. 基于口腔微生态论结肠炎-癌转化的中医药干预. 中华中医药杂志, 2019, 34(6): 2566-2570.
14. 张志民, 程博群. 口腔微生物与消化系统癌症关系的研究进展. 口腔医学研究, 2020, 36(2): 93-97.
15. Elghannam MT, Hassanien MH, Ameen YA, et al. Helicobacter pylori and oral-gut microbiome: clinical implications. Infection, 2024, 52(2): 289-300.
16. Ansari SA, Iqbal MUN, Khan TA, et al. Association of oral Helicobacter pylori with gastric complications. Life Sci, 2018, 205: 125-130.
17. Belizário JE, Napolitano M. Human microbiomes and their roles in dysbiosis, common diseases, and novel therapeutic approaches. Front Microbiol, 2015, 6: 1050.
18. Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA, 2017, 318(19): 1925-1926.
19. Bowden J, Holmes MV. Meta-analysis and Mendelian randomization: a review. Res Synth Methods, 2019, 10(4): 486-496.
20. Nagai A, Hirata M, Kamatani Y, et al. Overview of the BioBank Japan project: study design and profile. J Epidemiol, 2017, 27: S2-S8.
21. Hozawa A, Tanno K, Nakaya N, et al. Study profile of the Tohoku Medical Megabank Community-based cohort study. J Epidemiol, 2021, 31(1): 65-76.
22. The 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature, 2015, 526(7571): 68-74.
23. Pierce BL, Ahsan H, Vanderweele TJ. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol, 2011, 40(3): 740-752.
24. Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 2017, 32(5): 377-389.
25. Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
26. Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
27. Hemani G, Zheng J, Elsworth B, et al. The MR-base platform supports systematic causal inference across the human phenome. Elife, 2018, 7: e34408.
28. Baker JL, Bor B, Agnello M, et al. Ecology of the oral microbiome: beyond bacteria. Trends Microbiol, 2017, 25(5): 362-374.
29. Tan X, Wang Y, Gong T. The interplay between oral microbiota, gut microbiota and systematic diseases. J Oral Microbiol, 2023, 15(1): 2213112.
30. Dong Z, Yu K, Xin Y, et al. Association between gut microbiota and peptic ulcer disease, particularly gastric ulcer and duodenal ulcer: a two-sample Mendelian randomization study. Front Microbiol, 2024, 14: 1277300.
31. Zhao J, Hou Y, Xie T, et al. Genome-wide Mendelian randomization identifies putatively causal gut microbiota for multiple peptic ulcer diseases. Front Immunol, 2023, 14: 1260780.
32. Zhang J, Hu Y, Wu L, et al. Causal effect of gut microbiota on gastroduodenal ulcer: a two-sample Mendelian randomization study. Front Cell Infect Microbiol, 2023, 13: 1322537.
33. Kitamoto S, Nagao-Kitamoto H, Hein R, et al. The bacterial connection between the oral cavity and the gut diseases. J Dent Res, 2020, 99(9): 1021-1029.
34. Horliana AC, Chambrone L, Foz AM, et al. Dissemination of periodontal pathogens in the bloodstream after periodontal procedures: a systematic review. PLoS One, 2014, 9(5): e98271.
35. Walker MY, Pratap S, Southerland JH, et al. Role of oral and gut microbiome in nitric oxide-mediated colon motility. Nitric Oxide, 2018, 73: 81-88.
36. Schmidt TS, Hayward MR, Coelho LP, et al. Extensive transmission of microbes along the gastrointestinal tract. Elife, 2019, 8: e42693.
37. Vich Vila A, Imhann F, Collij V, et al. Gut microbiota composition and functional changes in inflammatory bowel disease and irritable bowel syndrome. Sci Transl Med, 2018, 10(472): eaap8914.
38. Lim JH, Shin J, Park JS. Effect of a proton pump inhibitor on the duodenum microbiome of gastric ulcer patients. Life (Basel), 2022, 12(10): 1505.
39. Chen X, Xia C, Li Q, et al. Comparisons between bacterial communities in mucosa in patients with gastric antrum ulcer and a duodenal ulcer. Front Cell Infect Microbiol, 2018, 8: 126.
40. Fu K, Cheung AHK, Wong CC, et al. Streptococcus anginosus promotes gastric inflammation, atrophy, and tumorigenesis in mice. Cell, 2024, 187(4): 882-896.
41. Wescombe PA, Heng NC, Burton JP, et al. Streptococcal bacteriocins and the case for Streptococcus salivarius as model oral probiotics. Future Microbiol, 2009, 4(7): 819-835.
42. Wu L, Wang Z, Sun G, et al. Effects of anti-H. pylori triple therapy and a probiotic complex on intestinal microbiota in duodenal ulcer. Sci Rep, 2019, 9(1): 12874.
43. Chen L, Xu W, Lee A, et al. The impact of Helicobacter pylori infection, eradication therapy and probiotic supplementation on gut microenvironment homeostasis: an open-label, randomized clinical trial. EBioMedicine, 2018, 35: 87-96.
44. Torres MDT, Brooks EF, Cesaro A, et al. Mining human microbiomes reveals an untapped source of peptide antibiotics. Cell, 2024, 187(19): 5453-5467.
45. Larsen JM. The immune response to Prevotella bacteria in chronic inflammatory disease. Immunology, 2017, 151(4): 363-374.
46. Sharma P, Phatak SM, Warikoo P, et al. Crosstalk between Helicobacter pylori and gastrointestinal microbiota in various gastroduodenal diseases-a systematic review. 3 Biotech, 2023, 13(9): 303.
47. Viazis N, Argyriou K, Kotzampassi K, et al. A four-probiotics regimen combined with a standard Helicobacter pylori-eradication treatment reduces side effects and increases eradication rates. Nutrients, 2022, 14(3): 632.
48. Westerik N, Reid G, Sybesma W, et al. The probiotic lactobacillus rhamnosus for alleviation of Helicobacter pylori-associated gastric pathology in East Africa. Front Microbiol, 2018, 9: 1873.
49. Wu S, Cui W, Zhou Q, et al. Phenyl lactic acid alleviates Helicobacter pylori infection in C57BL/6 mice. Food Funct, 2023, 14(11): 5032-5047.

Chinese Journal of Evidence-Based Medicine

Causal relationship between oral microbiota and gastrointestinal ulcers: a two-sample Mendelian randomization study

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