Antibiotics could trigger immune response through gut microbiome metabolites

The microbes inside our bodies not only help break down food but also impact our health. Yet their precise influence is not always understood, especially in the presence of prescription drugs. Now, researchers in ACS Central Science report how one of the most abundant gut bacteria responds to tetracyclines, a class of commonly prescribed antibiotics. Newly characterized signals released by the bacterium could aid the host’s immune response, inhibit pathogens and restructure the gut microbiome.

“We previously showed that exogenous molecules can trigger production of otherwise ‘hidden’ metabolites in marine- and soil-dwelling microbes,” says Mohammad Seyedsayamdost, the corresponding author of the study. “Our goal here was to extend this analysis to human microbiota and examine their responses to FDA-approved drugs.”

Every day, medical professionals across the country prescribe drug treatments for a variety of ailments. Although these drugs may have their desired effect, there is also the possibility that they impact the microbes that keep us healthy. Antibiotics, for example, often inactivate not only offending microbes but also beneficial gut bacteria. Scientists have proposed the idea that consuming pharmaceuticals could also alter microbial metabolism, changing the compounds that bacteria release into the body and impacting human health. To study this, Seyedsayamdost and colleagues exposed separate cultures of the prominent gut microbe Bacteroides dorei to hundreds of U.S. Food and Drug Administration (FDA)-approved drugs — such as antihistamines, hypertension drugs, anticancer agents and antibiotics — and looked for metabolic changes compared to untreated bacterial cultures.

After incubating B. dorei with and without pharmaceuticals, the researchers isolated and identified compounds the bacterium secreted. Among the various drugs tested, low doses of tetracycline antibiotics had the strongest effect on bacterial cultures, inducing the microbes to produce two types of new compounds: doreamides, named in this study, and N-acyladenosines. Further testing showed that both compounds trigger human immune cells to produce proteins called pro-inflammatory cytokines, which can help respond to infections. The doreamides also induced production of host antimicrobial peptides that inhibited the growth of several bacterial strains, including pathogenic ones, but not the growth of B. dorei.

The experiments demonstrated a secondary effect of antibiotic treatment beyond inactivating microbes directly. Low-dose tetracyclines caused B. dorei to produce compounds that stimulate the immune system and induce immune cells to generate antimicrobial peptides, which could alter the microbial balance in the human gut. These findings set the stage for animal studies to explore possible therapeutic properties of the doreamides.

The authors acknowledge funding from the Leona M. and Harry B. Helmsley Charitable Trust, the National Institutes of Health, the MacArthur Foundation, the Simons Foundation, the National Research Foundation of Korea, and the Edward C. Taylor 3rd Year Fellowship in Chemistry.

The paper’s abstract will be available on Dec. 3 at 8 a.m. Eastern time here: http://pubs.acs.org/doi/abs/10.1021/acscentsci.5c00969

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