Are antibiotics responsible for inflammatory bowel diseases? Premium

Irrational antibiotic use damages mucus barrier, leading to intestinal inflammation, as shown in recent Science Advances study.

Besides causing antimicrobial resistant bacteria, irrational use of antibiotics can also act directly on host cells. A recent study published in the journal Science Advances has found that even a short-course treatment of mice with antibiotics twice a day for three days was sufficient to damage the integrity of the mucus barrier, which separates the immune system from microbes present in the intestine. When the thin layer of mucus is damaged, it allows the microbes to come in close contact with host tissues, triggering an immune response and predisposing the mice to intestinal inflammation. Breakdown of the mucus barrier, which separates the intestinal epithelium from the microbiota, is a hallmark of inflammatory bowel diseases (IBDs).

Mice were orally treated with four different antibiotics belonging to different classes of antibiotics — ampicillin, metronidazole, neomycin, and vancomycin. The study found that all four antibiotics were capable of breaking down the mucus barrier leading to encroachment of bacteria upon the colonic epithelium. The study found that vancomycin could impede mucus secretion of goblet cells in the colon, in a microbiota-independent manner.

Mice treated with vancomycin lacked a clear mucus in most areas of the colonic epithelium. Of particular concern was the ability of vancomycin to affect mucus secretion by the goblet cells a few minutes following vancomycin infusion. The study suggests that certain antibiotics induce endoplasmic reticulum (ER) stress in colonic cells, thus diminishing mucus production. Based on this observation, the researchers conclude that antibiotics have a deleterious effect on the mucus barrier by acting directly on the host cells. When the microbiota after antibiotic treatment were transferred to germ-free mice did not lead to transfer of penetration phenotype. This led the researchers to conclude that the effects of vancomycin on the mucus barrier could not be transferred to germ-free mice by transferring the microbiota. Besides antibiotic treatment of germ-free mice, the researchers also used fecal microbiota transplant, RNA sequencing followed by machine learning, ex vivo mucus secretion measurements to confirm that antibiotics directly inhibit mucus secretion in a microbiota-independent manner by inducing ER-stress in goblet cells. This effect was completely independent of the microbiota.

The researchers tested whether they could reverse the mucus secretion defect caused by vancomycin treatment. They had previously found TUDCA (tauroursodeoxycholic acid) treatment could increase mucus secretion rates by reducing endoplasmic reticulum stress in colonic goblet cells. Since vancomycin treatment induces endoplasmic reticulum stress in the colon, they could restore mucus secretion by alleviating the ER stress using the TUDCA treatment. This reconfirmed that vancomycin treatment indeed inhibits secretion from colonic goblet cells by inducing endoplasmic reticulum stress.

“We propose an hypothesis to explain why antibiotic use is a risk factor for development of IBD. We speculate that repetitive antibiotic treatment, perhaps together with predisposing genetic factors, erode the mucus barrier which can, after time, lead to gut inflammation,” Dr. Shai Bel from the Bar-­Ilan University, Safed, Israel and the corresponding author of the paper tweeted.