Antibiotic Use May Promote IBD Development by Disrupting Gut Immune Cells, Mouse Study Suggests

Antibiotic Use May Promote IBD Development by Disrupting Gut Immune Cells, Mouse Study Suggests

Antibiotics can disrupt immune cells residing in the gut, triggering the rise of pro-inflammatory cells and reducing healthy bacteria — two steps key in the development of inflammatory bowel disease (IBD), a study in mice shows.

The study, “Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis,” was published in the journal Science Translational Medicine.

Antibiotics are routinely administered to both children and adults as a strategy to fight bacterial infections, but they are increasingly recognized as also having other effects.

In fact, epidemiological data links antibiotic use early in life with disruption of the gut microbiota — the collection of trillions of healthy microbes, primarily bacteria, that reside in our gut — and IBD.

“Epidemiological evidence already links antibiotics given to babies and young children, when the immune system is still developing, to inflammatory bowel disease, asthma, psoriasis and other inflammatory diseases later in life,” Elizabeth Mann, PhD, a researcher at the Lydia Becker Institute of Immunology and Inflammation at the University of Manchester in the U.K. and the study’s lead author, said in a press release.

However, the way in which antibiotic use may foster the development of IBD was still unclear.

“Until now it has been hard to determine cause and effect, especially with the time lag between taking the antibiotics and the development of disease later in life,” Mann said.

To understand the impact of antibiotic use and disruption of the microbiome on intestine immunity, researchers gave broad-spectrum antibiotics to mice, diluted in their drinking water, for one week.

They then introduced a normal microbiome into the animals’ gut after antibiotic treatment. While antibiotics per se had no impact on the number of resident gut-immune cells, after re-exposure to a microbiome, there was an infiltration of inflammatory immune cells.

Specifically, researchers saw an increase in the so-called Th1-CD4 T-cells, a group that secretes inflammatory signaling molecules (cytokines), such as interferon (IFN)-gamma and tumor necrosis factor (TNF).

This response, they found, was mediated by a group of resident immune cells in the intestine called macrophages.

Researchers performed additional experiments to further understand how antibiotic effects on intestinal immunity are associated with alterations in the microbiome.

They profiled the genetic makeup of the microbiome and found that a weeklong of antibiotics induced a sustained disruption of the intestinal microbiome that persisted for a minimum of two months compared with control mice.

The analysis revealed that antibiotic treatment induced an increase in bacteria belonging to the Bacteroidetes phylum — similar to what has been detected in humans with IBD — and a decrease in bacteria of the Firmicutes phylum, namely bacteria called Allobaculum.

“Although little is known about the interactions between Allobaculum bacteria and the immune system, these bacteria have regulatory properties that are beneficial during inflammatory disease and are potent generators of SCFAs [short-chain fatty acids], which have a variety of immunoregulatory effects in the intestine,” the researchers wrote.

Short-chain fatty acids, or SCFAs, are known for their beneficial properties for the gut — for example, butyrate is a key component for colon health, with anti-carcinogenic and anti-inflammatory properties. Moreover, SCFAs foster healing and regeneration of the intestinal epithelium, reduce the colon’s pH, and stimulate the growth of beneficial microflora while preventing the development of colon pathogens.

Researchers then studied whether supplementation with SCFAs during antibiotic treatment could reduce the immune dysfunction seen after they repopulated the mice gut with a microbiome.

They administered three different SCFAs — acetate, propionate, and butyrate — orally to the mice while they were being treated with antibiotics. Only butyrate was capable of reducing the production of inflammatory cytokines.

In addition, giving butyrate to the mice during antibiotic treatment prevented an increase of Th1-CD4 T-cells in the gut 20 days after the animals received a microbiome.

These findings show that antibiotics can perturb the intestinal immunity and increase the chances of a person developing IBD, but, researchers caution, this doesn’t mean that antibiotic use should be stopped.

“It’s very important that patients continue their antibiotics as these drugs are critical in clearing bacterial infections that can persist and cause serious health problems if left untreated,” Mann said.

Instead, the team argues that these results support the careful use of antibiotics only under prescription.

“What we’re saying is that antibiotics must only prescribed when absolutely needed for bacterial infections,” Mann said. “Antibiotics, for example, are useless against viral infections such as those that cause the common cold, flu and many chest infections.”