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Antibiotics were linked with increased risk for inflammatory bowel disease (IBD), especially among individuals 40 or older, in a population-based study conducted in Denmark.

Of more than 6 million individuals followed for approximately 19 years, antibiotic use was associated with nearly 50% increased incidence of IBD in people ages 40 to 60 (IRR 1.48, 95% CI 1.43-1.54) and older than 60 (IRR 1.47, 95% CI 1.42-1.53) compared with no antibiotic exposure.

A positive dose-response relationship was seen in all age groups, albeit with a smaller excess incidence risk of 28% for 10- to 40-year-olds (IRR 1.28, 95% CI 1.25-1.32), researchers led by Adam Faye, MD, of NYU Langone Health in New York City, reported online in the journal .

Similar results were seen for both ulcerative colitis and Crohn's disease. Notably, 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," Faye and colleagues wrote.

Changes in the intestinal microbial environment as people age can lead to decreased diversity and more susceptibility to disturbances, the researchers explained. Antibiotics can compound these age-related changes, further reducing microbiome diversity and potentially leading to lasting changes in the gut, they said.

"The association between antibiotic exposure and the development of IBD underscores the importance of antibiotic stewardship as a public health measure," Faye and colleagues said, "and suggests the gastrointestinal microbiome as an important factor in the development of IBD, particularly among older adults."

In an email to 木瓜直播, Faye elaborated on these ideas: "One of the main takeaways is not to avoid antibiotics when needed, but in those cases where an illness may be self-limiting (e.g., gastrointestinal or upper respiratory, particularly viral, for instance), empirically prescribing an antibiotic (when not indicated) may have more harm than benefit."

"We hypothesize that antibiotics are contributing to the development of IBD through modulation of the intestinal microbiome, but this needs further exploration and research," Faye explained. "Older adults in particular less often have a positive family history for IBD, suggesting the environment may play an increasing role in pathogenesis of IBD as we age. Determining the factors that contribute to this will also be part of our future research."

Faye's group used national registries, including the Danish National Patient Register and National Prescription Register, to identify a cohort of 6,104,245 individuals ages 10 and older who had not been diagnosed with IBD. Half of the cohort was female.

The researchers followed these individuals from 2000 through 2018. During that time, 91% received at least one course of antibiotics. There were also 52,898 new cases of IBD (36,107 of ulcerative colitis and 16,881 of Crohn's disease). Faye's group used Poisson regression to calculate incidence rate ratios for IBD following antibiotic exposure. They adjusted for age, gender, and other demographic and socioeconomic factors.

"Furthermore, our study is unique in that it adjusts for proton pump inhibitor use, as well as the use of antifungal and antiviral agents, which can all affect the intestinal microbiome," the study authors noted. They also adjusted for prior antibiotic courses, which allowed for a more accurate risk assessment for individual classes of antibiotics, they said.

Two classes commonly used to target gastrointestinal pathogens -- nitroimidazoles and fluoroquinolones -- were linked with the highest IBD risk. In people 60 and older, for example, nitroimidazole exposure was associated with a 61% increased risk (IRR 1.61, 95% CI 1.41-1.83) and fluoroquinolones with a rise in risk of 54% (IRR 1.54, 95% CI 1.41-1.69). The only antibiotic found not to affect IBD risk was nitrofurantoin.

"Moreover, although the risk was attenuated among antibiotics less commonly used to target gastrointestinal pathogens (i.e., narrow-spectrum penicillins), their use was still associated with the development of IBD," the study authors wrote. This finding indicates that many antibiotics, including those not used to treat gastrointestinal pathogens, can affect intestinal microflora, they said.

When the investigators examined the effect of multiple courses of antibiotics, they found a positive dose-response relationship. For patients ages 40 to 60, the risk rose by 15% for each additional antibiotic treatment (IRR 1.15, 95% CI 1.14-1.16). For patients 60 and older who had five or more courses, risk was nearly double that of unexposed individuals (IRR 1.95, 95% CI 1.85-2.04).

The highest IBD risk came 1 to 2 years after antibiotic exposure, and it decreased with each subsequent year. For people ages 40 to 60, for example, the risk was 66% elevated at 1 to 2 years (IRR 1.66, 95% CI 1.59-1.73) but 21% at 4 to 5 years post exposure (IRR 1.21, 95% CI 1.13-1.29).

An important study limitation noted by the authors was that the registries used did not have information on the indication for which antibiotics were prescribed or the pathogens being targeted. Therefore, it is possible the underlying infections themselves could be driving the IBD risk rather than the medications, they said.

"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," they concluded.

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