Is Antibiotic Use a Cause of IBD Worldwide?

There is increasing concern that dysbiosis of the gut microbiome is an important component of the pathogenesis of inflammatory bowel disease (IBD) and even other chronic immune diseases.1 Although dysbiosis has been repeatedly reported in persons with established IBD,2 it has not been established whether the dysbiosis is cause or effect. However, finding dysbiosis in other chronic immune diseases where the gut is not inflamed lends support to the notion that the dysbiosis leads to immune dysregulation.1 It is unknown what specifically causes the dysbiosis in IBD. There are, however, some leading candidates. It is known that changing one’s diet can alter one’s gut microbiome,3 but to date there has been little research reporting on specific diets or dietary components that lead to the dysbiosis typically seen in IBD.4 However, diet therapy can be effective,5 so it is likely that further research will emerge exploring the impact of different nutrients either administered or withdrawn at specific times in life before the onset of IBD. Whatever dietary component(s) prove to be important will need to be relevant worldwide, as IBD is now a universal disease.6 Food additives are a fascinating consideration as they are ubiquitous worldwide, and the increase of food additives has paralleled the rise in chronic immune diseases universally.7 It is unknown, however, exactly how various food additives impact the gut microbiome. It is known that antibiotic ingestion does alter the gut microbiome, and changes can persist for several months after antibiotic cessation.8, 9 After antibiotic ingestion, the overgrowth of toxin-producing Clostridioides difficile leads to colitis, so there is certainly precedent for antibiotics causing significant gut inflammation. There is also considerable epidemiological evidence that antibiotic use some years before IBD diagnosis is significantly greater in persons with IBD compared with matched controls.10 Data from Manitoba and the United Kingdom have shown that antibiotic use in the first year of life was more common in children with IBD than in controls.11, 12 In a recent study, the Manitoba group reported that infections that would trigger antibiotic use in the first year of life were significantly associated with later development of IBD.13 The association was strongest in persons who developed IBD in childhood and strongest for infections in the first year of life, as opposed to infections in the first 3 years of life. That antibiotics in the first year of life may be linked to IBD development, especially pediatric IBD development, underscores the importance of the vulnerability of an infant’s microbiome. It is through the first year of life that it is developing into its ultimate lifelong microbiome; hence altering it at that vulnerable time with either antibiotics or diet may be critical. Although diets may vary worldwide, the use of antibiotics is a worldwide phenomenon. In fact, consumption of antibiotics assessed in 71 countries increased 36% from 2000 to 2010.14 Unfortunately, antibiotics can often be prescribed indiscriminately and are prescribed quite commonly.15 In this issue of Inflammatory Bowel Diseases, Troelsen and Jick used the United Kingdom Clinical Practice Research Datalink in a case–control study exploring the association of antibiotic use before IBD diagnosis in 1144 cases and 4576 controls.16 The authors reported no association between ever use of antibiotics and the risk of ulcerative colitis (odds ratio [OR], 1.02; 95% confidence interval [CI], 0.72–1.44) or Crohn’s disease (OR, 1.01; 95% CI, 0.73–1.39) compared with never use. Their overall conclusion was that there was no association between IBD and prior use of antibiotics. Yet a number of their findings mirror previously reported associations of antibiotics and IBD diagnosis. There was an increased risk of Crohn’s disease among ever users of quinolones (OR, 1.76; 95% CI, 1.00–3.11) and metronidazole (OR, 1.43; 95% CI, 0.87–2.34) compared with never users. In the Ungaro meta-analysis, the antibiotics with the strongest association with later development of IBD were metronidazole (OR, 5.01; 95% CI, 1.65–15.25) or fluoroquinolones (OR, 1.79; 95% CI, 1.03–3.12).10 It is interesting to consider that in the absence of an evidence base of randomized controlled trials, these 2 classes of drugs have become favorites of gastroenterologists in treating pouchitis or fistulizing disease. Gastroenterologists should consider whether this approach might actually be causing harm. In the report by Troelsen and Jick, when analyses were restricted to persons registered before 3 months of age, ever users compared with never users were at increased risk of Crohn’s disease (OR, 2.20; 95% CI, 0.75–6.43). Antibiotic use within the first year of life has been previously reported to be associated with later development of IBD,11, 12 especially pediatric IBD, including in a UK study.12 An advantage of this study was the ability to control for other potential confounding factors that might affect the risk for IBD or the gut microbiome, such as smoking, oral contraceptive use, nonsteroid anti-inflammatory drug use, or proton pump inhibitor use,17, 18 some of which could not be identified in other administrative database studies. Further, prior diagnosis of asthma or appendectomy were covariates, both of which have been associated with risk for IBD.17, 19 Hence, this study’s mixed results in the context of the rest of the literature support the notion that risk factors for IBD are best considered in the context of the timing and specific types of exposures and also the timing of disease onset, as opposed to considering risk factors from a binary perspective. Although there is evidence that breastfeeding may protect against development of IBD,20 more information will be required to determine the duration of and impact of exclusivity of breastfeeding, as opposed to any breastfeeding. It may be that specific types of antibiotics with specific antibacterial spectra administered at specific times in a person’s life have differential risks for IBD development. Also, it may be that what triggers IBD in children is different than what triggers IBD later in life. However, whatever aspects of antibiotic use pose a risk for IBD, it is plausible that they are causing some of the IBD that is increasingly diagnosed worldwide. Supported by: Dr. Bernstein is supported in part by the Bingham Chair in Gastroenterology. Conflicts of interest: Charles Bernstein has been on advisory boards for Abbvie Canada, Ferring Canada, Janssen Canada, Shire Canada, Takeda Canada, and Pfizer Canada and consulted for Mylan Pharmaceuticals. He has received educational grants from Abbvie Canada, Pfizer Canada, Shire Canada, Takeda Canada, and Janssen Canada and has been on speakers’ panels for Ferring Canada, Medtronic Canada, Takeda Canada, and Shire Canada.

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