Antibiotics Linked to inflammatory bowel disease
Authors: Adam S Faye, Kristine Højgaard Allin, Aske T Iversen, Manasi Agrawal, Jeremiah Faith, Jean-Frederic Colombel, Tine Jesse
Media Release: RACGP – Antibiotics linked to inflammatory bowel disease
WHAT IS ALREADY KNOWN ON THIS TOPIC
- Environmental factors are thought to play a pivotal role in the development of inflammatory bowel disease (IBD).
- Antibiotics have been implicated in the development of IBD among younger individuals; however, limited data are available assessing this among adults.
WHAT THIS STUDY ADDS
- Antibiotic exposure increased the risk of IBD in all individuals aged ≥10 years, but was highest among those aged 40–60 years and ≥60 years.
- A positive dose–response was observed, with highest risk seen in the 1–2 years following exposure, and with antibiotics targeting gastrointestinal pathogens.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
- The association between antibiotic exposure and the development of IBD underscores the importance of antibiotic stewardship as a public health measure, and suggests the gastrointestinal microbiome as an important factor in the development of IBD, particularly among older adults.
Abstract
Background There is an increasing incidence of inflammatory bowel disease (IBD) for which environmental factors are suspected. Antibiotics have been associated with development of IBD in earlier generations, but their influence on IBD risk in adults is uncertain.
Objective To assess the impact of antibiotic exposure, including dose–response, timing and antibiotic class, on the risk of IBD in all individuals aged ≥10 years.
Design Using Denmark nationwide registries, a population-based cohort of residents aged ≥10 years was established between 2000 and 2018. Incidence rate ratios (IRRs) for IBD following antibiotic exposure were calculated using Poisson regression.
Results There were a total of 6 104 245 individuals, resulting in 87 112 328 person-years of follow-up, and 52 898 new cases of IBD. Antibiotic exposure was associated with an increased risk of IBD as compared with no antibiotic exposure for all age groups, although was greatest among individuals aged 40–60 years and ≥60 years (age 10–40 years, IRR 1.28, 95% CI 1.25 to 1.32; age 40–60 years, IRR 1.48, 95% CI 1.43 to 1.54; age ≥60 years, IRR 1.47, 95% CI 1.42 to 1.53). For all age groups a positive dose–response was observed, with similar results seen for both ulcerative colitis and Crohn’s disease. The highest risk of developing IBD was seen 1–2 years after antibiotic exposure, and after use of antibiotic classes often prescribed to treat gastrointestinal pathogens.
Conclusion Antibiotic exposure is associated with an increased risk of IBD, and was highest among individuals aged 40 years and older. This risk increased with cumulative antibiotic exposure, with antibiotics targeting gastrointestinal pathogens and within 1–2 years after antibiotic exposure.
Discussion
In this Danish nationwide population-based study of more than six million individuals, antibiotic use was associated with an increased risk of incident IBD, and was observed for both UC and CD. The risk of IBD was greatest among individuals aged 40 years and older, increased with each subsequent antibiotic course, and was highest following exposure to antibiotic groups commonly prescribed to treat gastrointestinal pathogens.
As individuals age, the changing microbial environment can lead to decreased diversity and an increased susceptibility to perturbations. In one recent study comparing the microbiome of healthy older and younger adults, older adults were found to have decreased abundance of Bifidobacterium, which is a signature that has also been seen in patients with IBD. These aging-related changes can be compounded by antibiotic use, which further deprives the gut microbiome of diversity, and has the potential to lead to longstanding microbial changes. In another recent study, antibiotic perturbations led to recovery of the intestinal microbiome within 20 days in younger mice, whereas microbiome alterations were still present at 6 months among older mice, further emphasising the impact of age on microbiome shifts. In our study, we see possible evidence of this, as antibiotic use was associated with a higher risk of developing IBD among older adults as compared with younger individuals. Analogous results were seen in the case–control study by Nguyen et al, further supporting the notion that antibiotic use, perhaps through intestinal microbial shifts, may play an increasingly important role in the development of IBD as individuals age.
Furthermore, with repeated courses of antibiotics, these shifts can become more pronounced, ultimately limiting recovery of the intestinal microbiota. This, in part, further supports our finding that an increasing number of antibiotic courses was associated with a higher risk for developing IBD. On subgroup analysis, we also observed an increased risk of both UC and CD after antibiotic use. Prior studies, however, have found less consistent results, with some finding antibiotic use to be associated with the development of CD but not UC. This is probably influenced by the younger age of inclusion in these prior studies, as the association between UC and antibiotic use was lowest in the 10–40-year-old age group in our study. The higher risk for developing both UC and CD observed among older adults, further emphasises the strong role of environmental factors in the development of IBD later in life, and implicates microbiome alterations as a risk factor for both the development of UC and CD.
When evaluating the timing of antibiotic use, including a 1-year lag time to minimise the risk for reverse causality, we found that the highest risk for all individuals was 1–2 years after antibiotic exposure. This held true for both UC and CD and suggests the importance of antibiotic use as a potential trigger for the development of IBD. Additionally, on sensitivity analysis, when including a 2-year lag time for our exposure, analogous results were seen. This further supports our findings, particularly as the diagnostic delay in UC is assumed to be limited since the presence of haematochezia often prompts immediate evaluation. Although attenuated, we also observed an increased risk for developing IBD 4–5 years after exposure. In conjunction with prior data, this may be the result of persisting changes in the microbial environment as a result of antibiotic use, which ultimately contribute to the development of IBD.
When evaluating specific antibiotic classes, we found that those affecting the gut microbiota increased the risk of developing IBD. As such, this risk was highest when using nitroimidazole or fluoroquinolones, which particularly target bacterial pathogens in the gastrointestinal tract, and persisted when evaluating UC and CD separately. This has been shown in children and younger adults, but has not been previously assessed among older individuals. Moreover, although the risk was attenuated among antibiotics less commonly used to target gastrointestinal pathogens (ie, narrow-spectrum penicillins), their use was still associated with the development of IBD. This further supports the notion that alterations in the gut microbial environment may play a significant role in the development of IBD, and highlights the important point that many antibiotics, including those not used to treat gastrointestinal pathogens, can affect the intestinal microflora.
We also observed that nitrofurantoin, a drug that has less of an impact on the gastrointestinal flora, was not associated with the risk of developing IBD across all age groups. This finding is in accordance with prior data from Nguyen et al, showing that antibiotic classes targeting gastrointestinal specific pathogens carry the highest risk for developing IBD. In this prior study, however, it should be noted that all antibiotic classes assessed were found to be associated with the development of IBD. This specific difference probably stems from the fact that the prior study did not assess nitrofurantoin as its own class, did not assess antibiotic classes by age, did not adjust for PPIs, antifungal or antiviral use, or an individual’s use of multiple antibiotic classes over time, as was performed in this analysis.
Strengths of this study include the design and size, prospectively following up an unselected population of over six million adults across Denmark for 19 years, with almost no loss to follow-up. This ensures adequate power and a high generalisability of our findings. Additionally, the national register data available in Denmark allow for all individuals and prescriptions to be tracked carefully and prospectively over time, hence eliminating the risk of recall or selection bias. Furthermore, our study is unique in that it adjusts for PPI use, as well as the use of antifungal and antiviral agents, which can all affect the intestinal microbiome. Lastly, adjusting for prior antibiotic courses allows for a more accurate assessment of risk estimates for individual classes.
Despite these strengths, there are still several limitations which warrant discussion. Although we included both a 1- and 2-year lag time from antibiotic exposure, the possibility of reverse causality still exists. As noted above, however, we feel this is less likely due to the persistence of findings among individuals who have (1) shorter diagnostic delays (new-onset UC), (2) disease onset 4–5 years after antibiotic exposure and (3) used antibiotics not traditionally prescribed to treat gastrointestinal infections (ie, narrow-spectrum penicillin). Second, although antibiotic classes were obtained, specific indications relating to antibiotic use, as well as the potential pathogen, are not publicly available within the data registries. Thus, although we see an association between antibiotic use and the development of IBD, it is plausible that the underlying infection itself might be the main driver for these results. This, however, may be less likely, as antimicrobial therapy in the setting of an infection has been shown to contribute additional risk for developing IBD. Third, although complete data regarding outpatient antibiotic prescriptions can be obtained, inpatient antibiotic use and medication adherence cannot be confirmed. Last, although we adjusted for age, sex, time period, degree of urbanisation, socioeconomic index, PPI use, antiviral and antifungal use, as well as prior antibiotic courses, the possibility of additional confounders still exist.
In conclusion, this is the first national cohort study providing critical insights into the role that antibiotics play in the development of IBD across the ages. Our results demonstrate a positive dose–response, highlighting the strong association between antibiotic exposure and the development IBD, particularly among adults aged 40 years and older. Furthermore, this risk was highest in the years immediately following antibiotic use, persisted across antibiotic classes affecting the gastrointestinal microbiome and was associated with the development of both UC and CD. Thus, as a public health measure, antibiotic stewardship may be important to limit the development of multidrug-resistant organisms, and also to reduce the risk of IBD. In order to further our understanding of the underlying pathophysiology, future research should build on this work, investigating changes in the intestinal microbiome as a result of antibiotic use that are associated with the development of IBD.