Microbiota-derived isovalerate ameliorates sex-specific gut barrier dysfunction in malnutrition

Area of Science:

• Microbiology
• Nutrition Science
• Gastroenterology

Background:

• Malnutrition exacerbates intestinal permeability and sepsis risk.
• Mechanisms of malnutrition-induced gut barrier dysfunction are not well understood.
• The role of the gut microbiome and its metabolites in this process requires further investigation.

Purpose of the Study:

• To investigate how gut microbiota and their metabolites affect intestinal barrier function in malnutrition.
• To identify specific microbial metabolites that influence gut barrier integrity.
• To explore potential therapeutic interventions targeting gut barrier dysfunction in malnutrition.

Main Methods:

• Induction of malnutrition in specific pathogen-free (SPF) and germ-free (GF) mice using a low-protein, low-fat diet.
• Quantification of colonic permeability and bacterial translocation.
• Targeted metabolomics to identify depleted microbial metabolites.
• In vitro screening of candidate metabolites using human colonoid monolayers.
• In vivo administration of metabolites and precursors to malnourished mice.

Main Results:

• Malnutrition increased gut permeability and bacterial translocation in male SPF mice, but not in GF mice.
• Branched-chain fatty acids (BCFAs), including isovalerate, were depleted in malnourished SPF mice.
• BCFAs, particularly isovalerate, enhanced epithelial barrier function in human colonoids.
• Isovalerate and leucine administration restored colonic barrier integrity and claudin-8 localization in malnourished male mice.

Conclusions:

• BCFAs are critical microbiota-derived metabolites regulating intestinal barrier integrity.
• Leucine, a precursor to BCFAs, represents a potential microbiota-directed therapy for malnutrition-induced gut barrier dysfunction.