International researchers have found that a short-term oral antibiotic treatment is enough to impair the separation between host and microbiota in the colon.
This phenomenon was true for all antibiotics tested.
According to Dr Shai Bel, principal investigator at the Azreili Faculty of Medicine at Bar-Ilan University in Israel and lead author of the study, the extensive use of antibiotics in medicine assumed that other than toxicity issues when used in large doses, antibiotics only disrupted biological processes in microbes and not the host.
“Yet, recent research in germ-free animals is beginning to uncover the overlooked effects that antibiotics have on the host,” he said.
“The growing exposure to antibiotics in the past centuries has been linked to multiple diseases that are now common in industrialized countries. For example, an interaction between diet and antibiotic induced alteration to the gut microbiota is associated with obesity and diabetes.”
The team decided to specifically examine antibiotic use and its potential impact on IBD risk because recent epidemiological studies have identified strong links between antibiotic use and risk of developing IBD – in a dose-dependent manner.
The colonic mucus layer separates the host from the trillions of microbes that inhabit the gut lumen and if this mucus barrier is breached, bacteria can encroach on the host intestinal epithelium and trigger a proinflammatory response – one of the hallmarks of IBDs.
“Antibiotic treatment in mice leads to translocation and uptake of bacteria to gut-draining lymph nodes while predisposing to development of intestinal inflammation, yet whether antibiotics directly damage the mucus barrier is not clear,” Dr Bel said.
“However, unlike many other environmental factors, this was one that could be tested in the lab in a well-controlled fashion. We found that all four antibiotics tested led to breakdown of the mucus barrier and encroachment of bacteria upon the colonic epithelium.
“Spatial fluorescent intensity imaging also revealed bacterial signals originating in the colonic epithelium, demonstrating that short-term oral antibiotic treatment leads to disruption of the mucus barrier.”
The study found that two antibiotics – neomycin and vancomycin – impaired the mucus barrier via a direct effect on the host, producing the same barrier-dysfunction phenotype and affecting the same transcriptional pathways.
The genes that were similarly affected by both neomycin and vancomycin were involved in the ER stress response and the unfolded-protein response pathways, revealing that these genes were activated in response to bacterial invasion to epithelial cells and processing of proteins in the ER: systemic treatment with neomycin or vancomycin induced an ER stress response in the colon.
“ER stress is an intracellular switch that limits mucus secretion by goblet cells and we found that all issues treated with vancomycin showed impaired mucus secretion rates,” Dr Bel said.
“As the vancomycin was infused only on the basolateral side of the colonic tissue, and for only 45 min, this result demonstrates that the deleterious effect of vancomycin on mucus secretion was microbiota independent.
“Our study answers one question (does antibiotic treatment impair the mucus barrier?) but raises two more questions. The first is: Does antibiotic treatment play a causative role in development of IBD? The second question is: How do antibiotics impair mucus production?
“We found it unexpected that two distinct antibiotics from different classes, neomycin and vancomycin, both induced an ER stress response in the colon. As both drugs have distinct antimicrobial mechanisms, it is not clear why both would induce ER stress in host cells.”