Microbiota-dependent citrulline metabolism alleviates sepsis by activating the aryl hydrocarbon receptor/IL-22 pathway to restore intestinal homeostasis.

CECAL ligation and puncture sepsis in mice showed that citrulline fermentation products increased short-chain fatty acids and indole derivatives, activating AhR/IL-22 signaling to restore intestinal homeostasis.

• Why it matters: Sepsis often injures the gut and amplifies inflammation, but it remains unclear how a specific nutrient reshapes microbiota metabolites to regulate immune balance and barrier integrity.
• What they did: The authors used an in vitro co-culture system and CLP mice, then tested whether AhR or STAT3 inhibition blocked citrulline fermentation–driven changes in IL-22 secretion, STAT3 phosphorylation, Treg/Th17 balance, and barrier markers.
• The result: In vivo, citrulline improved sepsis severity scores, reduced intestinal neutrophil infiltration and mucosal injury, increased goblet cells, and shifted cytokines toward IL-10; antibiotic treatment or AhR inhibition diminished these effects.

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