Inflammatory Bowel Disease

Subject Category: Inflammatory Bowel Disease

Am J Gastroenterol 2011; 106:2143–2145; doi:10.1038/ajg.2011.308

Editorial: Bugs and Drugs: Insights into the Pathogenesis of Inflammatory Bowel Disease

Geoffrey C Nguyen MD, PhD, FRCPC1,2

  1. 1Mount Sinai Hospital Centre for Inflammatory Bowel Disease, University of Toronto, Toronto, Ontario, Canada
  2. 2Division of Gastroenterology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

Correspondence: Geoffrey C. Nguyen, MD, PhD, FRCPC, Mount Sinai Hospital, Centre for Inflammatory Bowel Disease, University of Toronto, 600 University Avenue, Suite 437, Toronto, Ontario, Canada M5G 1X5. E-mail: geoff.nguyen@utoronto.ca

Received 7 June 2011; Accepted 1 August 2011

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Abstract

The dysbiosis hypothesis posits that perturbations in the gut microbiome may contribute to the development of inflammatory bowel disease (IBD). A recent Canadian population-based study has shown an association between new-onset IBD and antibiotic use in the 2–5 years preceding diagnosis. Though these findings do not establish a causal relationship, it supports the role of dysbiosis in the pathogenesis of IBD. Furthermore, the study reinforces the importance of the judicious use of antibiotics.

The inflammatory bowel diseases (IBDs), comprising Crohn's disease (CD) and ulcerative colitis (UC), are idiopathic conditions that affect over 1.2 million Americans (1). Though a myriad of recent advances have contributed toward understanding the genetic underpinnings of IBD, we are only beginning to uncover the multitude of environmental factors that may also have a role in the development of IBD (2). Among these new frontiers is the contribution of the gut microbiome and host–microbial interactions to the pathogenesis of IBD.

There is an accumulating evidence that dysbiosis, or imbalance of the gut microbiome, may predispose to IBD. Studies have shown that IBD patients, compared with healthy controls, have a greater abundance of mucosa-associated bacteria, especially Escherichia coli (3). IBD patients may also have greater prevalence of mucolytic bacteria that penetrate the intestinal mucosa (4,5). Other metagenomic studies have shown that IBD patients exhibit a lesser diversity of commensal bacteria (6,7). More specifically, bacterial ribosomal RNA sequencing of intestinal tissue samples from CD and UC patients have shown depletion of Bacteroidetes and Firmicutes compared with samples from non-IBD controls. Bacteroides fragilis and Faecalibacterium prausnitzii are members of these phyla and have been shown to have anti-inflammatory properties (8). Their reduced numbers among IBD patients may thus contribute to mucosal inflammation. Despite these observations, we have yet to definitively distinguish whether an altered gut microbial profile contributes to the development of IBD or is a consequence of the underlying disease.

Because the gut microbiome likely has a role in IBD pathogenesis, manipulation of the intestinal microflora through the use of antibiotics, probiotics, and prebiotics may prove to be effective modes of treatment. A recent meta-analysis suggests that antibiotics may be effective in the primary treatment of both CD and UC (9). One of the more promising antimicrobials, rifaximin, has been shown to increase the concentration of Bifidobacterium and Faecalibacterium prausnitzi and concurrently alter the metabolic profile of CD patients (10). However, if antibiotics can alter the intestinal flora to favor an anti-inflammatory state, could they also, under certain circumstances, precipitate IBD?

In this issue of the American Journal of Gastroenterology, Shaw et al. (11) report an association between the development of IBD and the use of antibiotics 2–5 years before diagnosis. The investigators conducted a nested case–control using a population-based inception cohort of 2,234 IBD cases and 22,346 non-IBD controls. In their main analysis, they found that IBD patients had 1.5-fold higher odds of having received at least three dispensed prescriptions for antibiotics 2 years before their diagnosis than controls. Interestingly, they showed a dose-dependent relationship in which the adjusted odds ratio for developing IBD increased with higher number of antibiotic prescriptions. The apparent relationship between IBD and antibiotics extended back at least 5 years before diagnosis and were consistent over different time periods.

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This study was the first population-based analysis to demonstrate antibiotic use as a potential risk factor for UC as well as CD. The nested case–control design and selection of controls from the same population-based cohort as IBD cases effectively reduces selection bias—a limitation of many case–control studies. The use of administrative prescription data also mitigates issues with recall bias. Importantly, the study investigators have reasonably addressed the potential issue of reverse causality, wherein it may be symptoms of undiagnosed IBD that directly or indirectly precipitate antibiotic use. First, they have implemented at least a 2-year lag period between antibiotic use and onset of IBD, establishing a clear temporal sequence. Prior adult and pediatric studies have shown that the time interval between IBD diagnosis and preceding symptoms are well under a year (12,13). Second, the regression analyses adjusted for both number of non-antibiotic prescriptions and number of gastroenterologist visits, indicators for individual prescription patterns and health utilization for gastrointestinal symptoms.

The findings by Shaw et al. are consistent with those from a European population-based case–control study of only CD patients. Card et al. (14) previously used the General Practitioner Research Database to demonstrate an association between CD and antibiotic use 2–5 years before diagnosis (adjusted odds ratio, 1.3; 95% CI: 1.05–1.65). Other studies have also reported an association between early life exposure to antibiotics and CD (15,16). These studies, however, used questionnaires to assess antibiotic exposure and were, therefore, prone to recall bias. Shaw et al. have recently published a study in the pediatric population, which demonstrated an association between antibiotic use during the first year of life and a nearly threefold higher odds of developing IBD (17). Paradoxically, in this current study, the investigators found no association between development between IBD and antibiotic exposure 2–5 years before disease onset in the pediatric subgroup (age at diagnosis ≤18 years). It is unclear why, in pediatric cases, antibiotic prescriptions during the first year of life may contribute to the onset of IBD, but similar exposure in the 2–5 years preceding diagnosis would not. One might hypothesize that the gut's microbiome is particularly susceptible to antibiotics during the first few years of life when it is being established and has greatest plasticity, but may be more resilient to antibiotic therapy thereafter (18).

The crucial question remains whether the relationship between antibiotic use and IBD is causal. The consistency of the findings over different calendar periods and different study cohorts certainly substantiates the generalizability of findings. The dose–response relationship observed with greater number of antibiotic prescriptions is also another criterion that supports causality. Importantly, these findings are biologically plausible and fit cohesively with the dysbiosis hypothesis, whereby an antibiotic-induced perturbation of the gut microbiome has a role in the development of IBD. Disconcertingly, antibiotics appear to have a long-lasting effect implied by the association of IBD with exposure up to 5 years before diagnosis. There is evidence that antibiotics may impact the diversity of certain bacterial groups for at least 2 years (19).

An alternative explanation for the above findings may be that dysregulation of innate and adaptive immunity may lead to both IBD and certain infections that require antibiotics—without the former being etiologically related to the latter. In animal models, deficiency in NOD2, which predisposes to CD, also increases susceptibility to certain pathogens such as Listeria monocytogenes, Salmonella typhimurium, and Helicobacter hepaticus (20). In humans, NOD2 mutations been shown to predispose to bacteremia and sepsis in the critical care setting (21). The relationship between isotretinoin and UC is another example where underlying immune dysregulation may have confounded the observed association between a putative exposure and IBD. A recent case–control study by Crockett et al. (22) showed a greater than fourfold association between prior isotretinoin and UC; a dose–response relationship was also observed. However, other drugs that treat acne, such as the tetracycline family of antimicrobials, have also been reported to be linked with the development of IBD (23). The association of IBD with two separate and very distinct classes of acne medications raises the issue whether it is dysregulation in a common immune pathway that links acne to IBD. Though isotretinoin and tetracyclines may have a causal effect on IBD, one could alternatively hypothesize that an aberration in the immune system may predispose to hyperactive immune responses to bacteria in both the skin (leading to severe acne) and in the intestinal mucosa (leading to IBD) in the same individual.

Given the potential public reaction, the causative role of antibiotics in IBD must be interpreted with caution and requires a considerable burden of evidence. The findings by Shaw and colleagues provide further epidemiological support for an etiological role of antibiotics and indirectly corroborate the dysbiosis hypothesis. However, future studies need to identify and characterize perturbations in the gut microbiome and metabolic profile before and after IBD diagnosis among individuals receiving and not receiving antibiotics before their diagnosis. These studies could be potentially conducted within high-risk cohorts such as the one being established by the Genetics, Environmental, and Microbial project in Canada. Even if we were to assume a causative role of antibiotics, it should be emphasized just less than half of IBD cases in this study were exposed to antibiotics before diagnosis. Furthermore, there are by far more prescriptions for antibiotics each year than new diagnoses of IBD. Thus, even though antibiotic use may be a risk factor for the development of IBD, it is neither sufficient nor necessary. The cardinal message is that physicians should not avoid prescribing antibiotics when clinically indicated even if it bears out that IBD may be a long-term consequence. What should be reinforced, however, is the importance of the judicious use of antibiotics and, when possible, the selection of narrow spectrum antimicrobials that appropriately target a given infection.

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Conflict of interest

Geoffrey C. Nguyen has recently collaborated in an unrelated Manitoba-based study with Souradet Shaw and Charles Bernstein. Dr Nguyen has also served as a consultant for Merck and Abbott Laboratories in a capacity, which was unrelated to this study.

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