When doctors prescribe antibiotics, they’re usually only thinking about the bacteria that need to be killed — not whether the antibiotics will also cause harm. Yet, recent epidemiological studies have found a dose-dependent link between antibiotics and inflammatory bowel disease (IBD) (1).
Shai Bel, an immunologist at Bar-Ilan University, wanted to find out how antibiotic usage could lead to IBD with the ultimate goal of developing a cure. “We have treatments to subdue the immune response … But we're not treating the source because we don't know what the source is,” he said.
We're not treating the source because we don't know what the source is.”
– Shai Bel, Bar-Ilan University
In a recent study, Bel’s group found that in mice, a variety of antibiotics from four different classes given orally damaged the mucus layer in the gut, which separates the epithelial cells lining the intestine from the microbes that live in the open space of the lumen (2). “From the first experiment, it was very clear that once you give antibiotics to the mouse, the mucus layer just disappears,” he said. That was a problem because without the mucus layer, microbes attached themselves to cells in the epithelium and activated immune responses that led to damaging inflammation. “As long as the barrier is there, we can live in peace with our microbiota. We can be in symbiosis, where we help them and they help us.” Bel hypothesized that in humans, once the mucus barrier is gone, the body’s immune system goes into overdrive sensing the bacteria constantly, which could contribute to the development of IBD.
To find out what caused the mucus layer to disappear, Bel’s team administered vancomycin and neomycin systemically in mice. They found that these two antibiotics activated genes that are involved in the endoplasmic reticulum (ER) stress response, which decreases the amount of mucus production by gut epithelial cells. By giving the mice a molecule that reduces ER stress, the researchers restored mucus secretions from the cells.
Bel explained that they are now doing further studies in mice to see whether inducing mucus secretions could help relieve inflammation in IBD mouse models. “We hope that if that works, we can move on to human studies,” he said. Bel added that a treatment like the one they’re testing would not leave patients immunocompromised, unlike current options. “The way we're looking at it is we want to give the immune system a chance to take a break. We want to rebuild the barrier, get the bacteria further away, and then the immune system will [by] itself heal.”
Bel also emphasized that their results mean that physicians need to be more cautious when prescribing antibiotics. “There's kind of an unwritten rule that antibiotics are not supposed to harm us; they're supposed to harm microbes. That's why they're so prolific, and physicians barely give a second thought about prescribing them,” he said. “We can't just keep on giving them out like they're candy.”
References
- Faye, A.S. et al. Antibiotic use as a risk factor for inflammatory bowel disease across the ages: a population-based cohort study. Gut 72, 663–670 (2023).
- Sawaed, J. et al. Antibiotics damage the colonic mucus barrier in a microbiota-independent manner. Sci Adv 10, eadp4119 (2024).
