Accepted Manuscript. Does eradication of Helicobacter pylori cause inflammatory bowel disease? Johan Burisch, Tine Jess

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1 Accepted Manuscript Does eradication of Helicobacter pylori cause inflammatory bowel disease? Johan Burisch, Tine Jess PII: S (19) DOI: Reference: YJCGH To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 5 February 2019 Please cite this article as: Burisch J, Jess T, Does eradication of Helicobacter pylori cause inflammatory bowel disease?, Clinical Gastroenterology and Hepatology (2019), doi: j.cgh This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Title: Does eradication of Helicobacter pylori cause inflammatory bowel disease? Johan Burisch 1,2, Tine Jess 2 1 Abdominal Center K, Bispebjerg and Frederiksberg Hospital, Bispebjerg, Denmark 2 Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, Denmark Correspondence Johan Burisch, MD, PhD Center for Clinical Research and Prevention Bispebjerg and Frederiksberg Hospital, University of Copenhagen Nordre Fasanvej 57, 2000 Frederiksberg, Denmark johan.burisch@regionh.dk Grant Support: None Conflicts of interest: JB: grants and personal fees from AbbVie, personal fees from Janssen-Cilag, personal fees from Celgene, personal fees from MSD, personal fees from Pfizer, grants and personal fees from Takeda, and personal fees from Samsung Bioepis (none related to the paper submitted). TJ: none. 1

3 In recent decades, the epidemiology of immune-mediated inflammatory diseases (IMID), and specifically inflammatory bowel disease (IBD), has changed dramatically in much of the newly-industrialized and developing world. Cohort studies from Asia and South America have consistently shown rapid increases in the incidence of both ulcerative colitis (UC) and Crohn s disease (CD) in regions where these diseases were previously rare or nonexistent 1. For example, the incidence of IBD in Taiwan increased more than 15-fold over a period of twenty years, between 1986 and In contrast, incidence rates of IBD in Europe, North America and Australia have either plateaued or increased at much lower rates during the same period 3,4. Unfortunately, there have been few high-quality, population-based studies carried out in newly-industrialized countries and therefore our understanding of the changing epidemiology of IBD and other IMIDs in these countries is limited. IBD is thought to be caused by a complex interplay of environmental and genetic factors. As the rising incidence is occurring in parallel with the transition from developing to industrialized economies, and because the rate of increase in IBD does not appear to be uniform 5, it would make sense to look for changes in environmental factors that might have a significant role in disease onset. Several environmental factors associated with the westernization of societies have been proposed as important in the emergence of IBD, such as improved hygiene, increased use of antibiotics, higher prevalence of cigarette smoking, and dietary changes including the increased use of processed foods containing chemical food additives 6. While the incidence of IBD has risen in countries undergoing westernization, the prevalence of infections with Helicobacter pylori (H. pylori), a pathogen involved in peptic ulcer disease 7, has instead fallen. H. pylori infection is associated with larger family size and poor sanitary conditions, both of which are usually inversely associated with developing IBD. The inverse association between H. pylori infection and IBD could merely be a proxy marker of the hygiene hypothesis, including more frequent antibiotic use prior to diagnosis of IBD 2

4 and more sanitary living conditions. A recent meta-analysis found a negative association between H. pylori infection and IBD, with a pooled odds ratio of 0.4 (p<0.01) 8. However, there is also accumulating evidence of H. pylori possessing anti-inflammatory benefits for the immune system, for example by increasing the expression of regulatory T cells 9. This would suggest that eradicating H. pylori say, as a general strategy in the population might result in an increased risk of developing T cell-driven immunological disorders, including IBD. In this issue of Clinical Gastroenterology and Hepatology, Lin and colleagues offer further insights into the possible consequences of H. Pylori eradication 10. The authors investigated the effect of H. pylori eradication therapy on the risk of developing one of several common autoimmune diseases, including IBD, in a nationwide cohort from Taiwan. The prevalence of H. pylori in the general population in Taiwan is currently approaching 80%. Within the National Health Insurance Research Database of Taiwan, the authors identified adults with peptic ulcer disease and compared those that had received eradication therapy for H. pylori with those that had not. A group of healthy controls, as well as a group of individuals receiving cephalosporins for urinary tract infections, served as controls. The authors made several interesting observations. First, when compared to healthy controls, patients with peptic ulcer disease who had received H. pylori treatment had a significantly increased risk of developing an autoimmune disease (adjusted hazard ratio (ahr): 2.36, p<0.001), including IBD (ahr: 2.15, p<0.001). However, this increased risk was also observed in patients with ulcers who did not receive H. pylori treatment, as well as in individuals receiving antibiotics for a urinary tract infection. The results therefore support a previous finding that treatment with antibiotics alone increases the risk of developing an autoimmune disease 11. Second, in a subsequent competing risk model analysis some aspects of these observations did not hold true. The increased risk of IBD was only seen in patients receiving H. pylori treatment, while when compared to controls there was either no difference or a decreased risk of developing the other autoimmune diseases. The 3

5 substantially different estimates from applying a competing risk model may bring into question the robustness of these findings. Furthermore, the authors rightfully acknowledge the potential limitations of (i) using claims-based data, (ii) assuming the patients with peptic ulcer disease and not receiving eradication therapy did not, in fact, have a H. pylori infection, (iii) comparing sub-cohorts with marked differences in patient characteristics even after matching, and (iv) assuming that eradication therapy was in fact successful in all treated cases. Nonetheless, their results merit reassessment in an unselected population-based cohort of patients from a background population with a prevalence of H. pylori of less than 80% and with detailed accompanying information about eradication treatment and exposure to other antibiotics. In conclusion, although increases in the incidence of IBD may parallel frequencies of eradication of H. pylori in westernized countries, it remains uncertain whether a direct causal relationship exists. The Taiwanese study suggests an association between eradication of H. pylori and the risk of autoimmune diseases, including IBD. However, the question remains as to whether it is the treatment per se, or the absence of the pathogen resulting from the treatment, that has a pathogenetic influence on the development of IBD. 4

6 References 1. Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: A systematic review of population-based studies. Lancet 2017;6736: Yang SK, Yun S, Kim JH, et al. Epidemiology of inflammatory bowel disease in the Songpa-Kangdong district, Seoul, Korea, : A KASID study. Inflamm Bowel Dis 2008;14: Burisch J, Pedersen N, Čuković-Čavka S, et al. East-West gradient in the incidence of inflammatory bowel disease in Europe: the ECCO-EpiCom inception cohort. Gut 2014;63: Lophaven SN, Lynge E, Burisch J. The incidence of inflammatory bowel disease in Denmark : a nationwide cohort study. Aliment Pharmacol Ther 2017;45: Ng SC, Tang W, Ching JY, et al. Incidence and phenotype of inflammatory bowel disease based on results from the Asia-Pacific Crohn s and colitis epidemiology study. Gastroenterology 2013;145: Ananthakrishnan AN, Bernstein CN, Iliopoulos D, et al. Environmental triggers in IBD: a review of progress and evidence. Nat Rev Gastroenterol Hepatol 2018;15: Peleteiro B, Bastos A, Ferro A, et al. Prevalence of Helicobacter pylori infection worldwide: a systematic review of studies with national coverage. Dig Dis Sci 2014;59: Castaño-Rodríguez N, Kaakoush NO, Lee WS, et al. Dual role of Helicobacter and Campylobacter species in IBD: a systematic review and meta-analysis. Gut 2017;66: Arnold IC, Hitzler I, Müller A. The immunomodulatory properties of Helicobacter pylori confer protection against allergic and chronic inflammatory disorders. Front Cell Infect Microbiol 2012;2: Lin K-D, Chiu G-F, Waljee AK, et al. Effects of Anti-Helicobacter pylori Therapy on 5

7 Incidence of Autoimmune Diseases, Including Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol Forbes JD, Domselaar G Van, Bernstein CN. The Gut Microbiota in Immune-Mediated Inflammatory Diseases. Front Microbiol 2016;7: