Mucus-degrading Bacteroides link carbapenems to aggravated graft-versus-host disease

Area of Science:

• Microbiome research
• Immunology
• Gastroenterology

Background:

• Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is frequently complicated by graft-versus-host disease (GVHD).
• The intestinal microbiota plays a critical role in modulating GVHD, and broad-spectrum antibiotics like carbapenems are known to increase its risk.
• The precise mechanisms by which antibiotics exacerbate intestinal GVHD remain incompletely understood.

Purpose of the Study:

• To investigate the mechanisms by which meropenem, a carbapenem antibiotic, aggravates colonic GVHD.
• To explore the role of the intestinal microbiota, specifically Bacteroides thetaiotaomicron (BT), in meropenem-induced GVHD.
• To evaluate the potential of nutritional supplementation, such as xylose, to mitigate antibiotic-associated GVHD.

Main Methods:

• Murine model of allo-HSCT to study colonic GVHD.
• Treatment with meropenem and assessment of microbiota composition, focusing on Bacteroides thetaiotaomicron (BT).
• Analysis of mucin glycan degradation, colonic mucus layer thickness, and luminal xylose levels.
• Evaluation of the therapeutic effect of oral xylose supplementation.

Main Results:

• Meropenem treatment led to the expansion of Bacteroides thetaiotaomicron (BT) in allogeneic mice, correlating with aggravated colonic GVHD.
• BT exhibited upregulated expression of mucin-degrading enzymes, resulting in a thinned colonic mucus layer and reduced luminal xylose.
• Oral xylose supplementation effectively prevented the thinning of the colonic mucus layer in meropenem-treated mice.

Conclusions:

• Meropenem exacerbates intestinal GVHD by promoting the growth of Bacteroides thetaiotaomicron, which compromises the colonic mucus barrier.
• The degradation of mucin glycans by BT is a key mechanism underlying antibiotic-induced intestinal injury.
• Nutritional strategies, including xylose supplementation, show promise in counteracting antibiotic-mediated microbiome damage and reducing GVHD risk in allo-HSCT patients.