Antibiotics and IBD
Link Between Antibiotics and IBD Remains Circumstantial
Effect stronger in children, and underscores need for antibiotic stewardship in prescribing for pediatric infections
Since inflammatory bowel disease (IBD) is linked to disruption of the intestinal microbiome, antibiotics have come under increasing scrutiny as possible environmental catalysts in IBD – especially if taken in early childhood.
So far, the association has been largely circumstantial. For example, a 2004 study by Timothy Card, PhD, of the University of Nottingham, and colleagues reported that persons diagnosed with IBD in a large U.K. cohort were significantly more likely than controls to have received antibiotic prescriptions 2 to 5 years before diagnosis.
The IBD-antibacterial correlation has emerged as more pronounced in children, whose immature immune systems are still in development. The first year of life appears to be critical, and infective events in that window could cause permanent changes in some people that may promote the onset of IBD in later childhood, the teens, or early 20s.
Souradet Shaw et al reported in 2010 that children with IBD were almost three times more likely to have had an antibiotic in the first year of life, while in a 2014 meta-analysis, Ryan Ungaro et al reported that antibiotic exposure increased the odds of being newly diagnosed with Crohn’s disease but not ulcerative colitis, with the effect most notable in children.
In another study, Anders Hviid and co-authors observed a strong IBD-antibiotic association in Danish children, but warned against possible confounding by indication, since children who already had undiagnosed Crohn’s disease (CD) may have received antibiotics for intestinal symptoms caused by their unrecognized disease.
“In theory, the idea would be that if you alter the microbiome at an early stage of life, you may predispose people to develop IBD,” Alan C. Moss, MD, of Beth Israel Deaconess Medical Center in Boston, told MedPage Today. “There are a few studies linking that exposure to antibiotics before age 6 and future risk of CD, and one that showed a moderately higher risk of IBD in teens given tetracycline for acne. But it’s unknown whether the antibiotic is the risk per se or whether people who develop acne are more likely to develop IBD because they have an underlying liability of the acne as a surrogate marker.”
In children, the use of drugs in the penicillin family in particular has been associated with risk, but that may be because penicillin antibiotics are so frequently commonly used for pediatric ear infections — “So it may not be the specific drug per se but rather, its common use,” Moss said.
In a 2013 Q&A overview on antibiotics and IBD, Charles N. Bernstein, MD, head of the Section of Gastroenterology and director of the IBD Clinical & Research Centre of the University of Manitoba in Canada, reported that IBD patients in a Canadian provincial healthcare database were significantly more likely than matched controls to have been diagnosed with otitis media by age 5, and in most cases were presumably given antibiotics. However, otitis media is unlikely to be an extra-intestinal manifestation of IBD as immune diseases in other organ systems can be, Bernstein explained.
Nor is IBD likely to develop in most children who receive antibiotics, he said: “Risk is more relevant in the child who has an older sibling with IBD, suggesting a genetic predisposition. Attention should be given, and care should be exercised regarding antibiotic use and the gut microbiome in such a child.”
As for other antimicrobials, a paper by Thomas Lee et al concluded that use of doxycycline is a risk factor for developing irritable bowel syndrome and possibly IBD when deployed to developing and developed countries, respectively. Doxycycline as a risk factor for chronic gastrointestinal illness warrants a prospective large-scale study, the researchers said.
Regarding the potential impact on the offspring of mothers who have been treated with antibiotics for infections during pregnancy, a reassuring study this year by Bernstein and colleagues found comparable infection rates and presumably similar antibiotic usage in the mothers of children who developed IBD and the mothers of controls; there were also no differences in the mothers’ infection rates during pregnancy between offspring diagnosed with IBD and siblings without IBD.
As for using probiotics after antibacterial drugs to hasten the repopulation of the microbiome, Moss said there is not much indication that this is useful: “There’s some evidence that the yeast Saccharomyces boulardii can help after antibiotics for Clostridium difficile infection,” he said.
Then what kind of study could upgrade these observational associations to more definite correlations? One that is unlikely to be done, according to Peter D.R. Higgins, MD, PhD, director of the IBD program at the University of Michigan in Ann Arbor. “That would mean a roughly 25-year study in which you randomize children to receive or never receive antibiotics between birth and age 25, and measure the incidence of IBD in the two groups. Hard to do,” he told MedPage Today.
A more do-able alternative, he explained, would be a retrospective study in a national healthcare system such as Denmark’s comparing antibiotic users and nonusers, adjusted for propensity to receive antibiotics — “But I don’t know of any studies being planned, as the researchers would likely be retired before the outcomes were achieved!”
According to Moss, the observed associations are not sufficient to deter the use of antibiotics. But while the disruption to the commensal gut flora are usually transient, he added, the best policy is not to prescribe antibiotics unless they are truly required: “In most cases the microbiome will revert to normal within a few months, but people need to know there can be knock-on effects that you don’t want,” he said.
Medical training may need to place more focus on the gastrointestinal downside of antibiotics, adding possible IBD risk to other negatives such as the promotion of antibiotic-resistant microbial strains. “That possible effect is mentioned in training, but it’s not emphasized,” Higgins said.
The abiding take-home message is that gastroenterologists, as all physicians, need to be forward-thinking about prescribing antibiotics, especially in young children — a message pediatricians have been sending for decades.