Does Eradication of Helicobacter Pylori Cause Inflammatory Bowel Disease?

In recent decades, the epidemiology of immune-mediated inflammatory diseases, 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 and Crohn’s disease in regions where these diseases were previously rare or nonexistent.1Ng S.C. Shi H.Y. 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: 1-10Google Scholar For example, the incidence of IBD in Taiwan increased more than 15-fold over a period of 20 years, between 1986 and 2005.2Yang S.K. Yun S. Kim J.H. et al.Epidemiology of inflammatory bowel disease in the Songpa-Kangdong district, Seoul, Korea, 1986-2005: a KASID study.Inflamm Bowel Dis. 2008; 14: 542-549Google Scholar 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.3Burisch 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: 588-597Google Scholar, 4Lophaven S.N. Lynge E. Burisch J. The incidence of inflammatory bowel disease in Denmark 1980-2013: a nationwide cohort study.Aliment Pharmacol Ther. 2017; 45: 961-972Google Scholar Unfortunately, there have been few high-quality, population-based studies carried out in newly industrialized countries and therefore understanding of the changing epidemiology of IBD and other immune-mediated inflammatory diseases in these countries is limited. IBD is thought to be caused by a complex interplay of environmental and genetic factors. Because 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 seem to be uniform,5Ng S.C. Tang W. Ching J.Y. 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: 158-165Google Scholar it makes 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.6Ananthakrishnan A.N. Bernstein C.N. Iliopoulos D. et al.Environmental triggers in IBD: a review of progress and evidence.Nat Rev Gastroenterol Hepatol. 2018; 15: 39-49Google Scholar Although the incidence of IBD has risen in countries undergoing “westernization,” the prevalence of infections with Helicobacter pylori, a pathogen involved in peptic ulcer disease,7Peleteiro 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: 1698-1709Google Scholar 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 before diagnosis of IBD 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 < .01).8Castaño-Rodríguez N. Kaakoush N.O. Lee W.S. et al.Dual role of Helicobacter and Campylobacter species in IBD: a systematic review and meta-analysis.Gut. 2017; 66: 235-249Google Scholar However, there is also accumulating evidence of H pylori possessing anti-inflammatory benefits for the immune system, such as by increasing the expression of regulatory T cells.9Arnold I.C. Hitzler I. Müller A. The immunomodulatory properties of Helicobacter pylori confer protection against allergic and chronic inflammatory disorders.Front Cell Infect Microbiol. 2012; 2: 10Google Scholar This would suggest that eradicating H pylori (eg, as a general strategy in the population) might result in an increased risk of developing T cell–driven immunologic disorders, including IBD. In this issue of Clinical Gastroenterology and Hepatology, Lin et al10Lin K.-D. Chiu G.-F. Waljee A.K. et al.Effects of anti-Helicobacter pylori therapy on incidence of autoimmune diseases, including inflammatory bowel diseases.Clin Gastroenterol Hepatol. 2019; 17: 1991-1999Abstract Full Text Full Text PDF Scopus (33) Google Scholar offer further insights into the possible consequences of H pylori eradication. The authors investigated the effect of H pylori eradication therapy on the risk of developing 1 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 control subjects, and a group of individuals receiving cephalosporins for urinary tract infections, served as control subjects. The authors made several interesting observations. First, when compared with healthy control subjects, patients with peptic ulcer disease who had received H pylori treatment had a significantly increased risk of developing an autoimmune disease (adjusted hazard ratio, 2.36; P < .001), including IBD (adjusted hazard ratio, 2.15; P < .001). However, this increased risk was also observed in patients with ulcers who did not receive H pylori treatment, and 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.11Forbes J.D. Domselaar G Van Bernstein C.N. The gut microbiota in immune-mediated inflammatory diseases.Front Microbiol. 2016; 7: 1081Google Scholar 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, whereas when compared with control subjects there was either no difference or a decreased risk of developing the other autoimmune diseases. The 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 (1) using claims-based data; (2) assuming the patients with peptic ulcer disease and not receiving eradication therapy did not, in fact, have a H pylori infection; (3) comparing subcohorts with marked differences in patient characteristics even after matching; and (4) 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. Effects of Anti–Helicobacter pylori Therapy on Incidence of Autoimmune Diseases, Including Inflammatory Bowel DiseasesClinical Gastroenterology and HepatologyVol. 17Issue 10PreviewHelicobacter pylori induces immune tolerance and is associated with a lower risk for immune-mediated disorders, such as autoimmune and inflammatory bowel diseases (IBD). We aimed to determine the effects of treatment for H pylori infection on the incidence of autoimmune disease and IBD. Full-Text PDF