Traditional Chinese medicine formulation Chang-Kang-Fang restores gut-brain homeostasis in IBS-D via the Lactobacillus johnsonii-indole-3-lactic acid-aryl hydrocarbon receptor/interleukin-22 axis.

BACKGROUND: Gut dysbiosis contributes to irritable bowel syndrome (IBS) by disrupting intestinal barrier functions and promoting inflammation. Chang‑kang‑fang (CKF), a Chinese herbal formula proven effective for diarrhea‑predominant IBS (IBS‑D) in a phase III trial, is thought to modulate the gut microbiota, yet the underlying mechanism remains unclear. PURPOSE: To elucidate how CKF ameliorates IBS‑D by modulating the gut microbiota. METHODS: IBS‑D was induced by restraint stress, tail pinch, and senna gavage. Intestinal function, inflammation, and behavior were evaluated. Gut microbiota and metabolites were profiled via 16S rRNA sequencing and metabolomics. FMT confirmed the causal involvement of the microbiota. The key microbe and metabolite were validated in vivo. Mechanistic analyses evaluated intestinal barrier integrity, systemic inflammation, hippocampal blood‑brain barrier (BBB) function, neuroinflammation, and synaptic plasticity. RESULTS: CKF alleviated diarrhea, visceral hypersensitivity, inflammation, barrier dysfunction, and anxiety‑ and depression‑like behaviors. These benefits were associated with gut microbiota remodeling, featuring enrichment of Lactobacillus johnsonii and enhanced tryptophan metabolism. FMT confirmed that this microbial remodeling mediates the therapeutic effects of CKF. Supplementation with L. johnsonii or its metabolite indole‑3‑lactic acid (ILA) largely recapitulated these gut-brain benefits via AhR/IL‑22 activation. Mechanistically, CKF‑induced L. johnsonii enrichment activated the ILA-AhR-IL‑22 pathway, which enhanced intestinal and BBB integrity, thereby attenuating systemic and neuroinflammation, and restoring hippocampal synaptic plasticity. CONCLUSION: This study positions CKF as a microbiota‑modulating therapy for IBS‑D that restores gut‑brain homeostasis via the L. johnsonii-ILA-AhR-IL‑22 axis, highlighting L. johnsonii and ILA as potential therapeutics for IBS and its comorbidities.