Analysis of a new anti-depression mechanism of Chaigui granules based on multi-omics integration: In-depth mining of intestinal microbiota-metabolite interaction network.

Abstract

BACKGROUND: Depression is a common mental disorder that severely affects physical and psychological health of patients. Despite the proven clinical and experimental efficacy of Chaigui granules (CGG), a novel traditional Chinese medicine formulation for depression, its mechanism remains unclear owing to its multi-component nature. METHODS: To establish an optimal depression model, the gut microbiota of humanized and murine donors under healthy and depressed conditions was compared, and subsequent behavioral effects via fecal microbiota transplantation (FMT) in mice was assessed. Based on this, the mechanism of CCG in treating depression was characterized through combining 16S rRNA sequencing, LC-MS metabolomics and integration analysis. RESULTS: The gut microbiota was markedly disrupted in depressed patients and mice. Through FMT, microbiota from depressed donors successfully colonized recipient mice and induced depression-like behaviors. Comparative results demonstrated the superiority of the murine FMT-induced depression model in terms of stability and translational relevance. CGG produced significant improvements in behavioral phenotypes, metabolic profiles, and microbial composition in depressed mice. Specifically, the treatment regulated 17 key metabolites and 7 bacterial strains, primarily involved in 2 major metabolic pathways. Integrated correlation analysis revealed five bacterial strains and seven metabolites that were strongly associated with depression-like behaviors. CONCLUSION: Through integrated approaches, we hypothesize that Chaigui granules alleviate depressive-like behavior in murine FMT-induced depressed mice by modulating Aminoacyl-tRNA biosynthesis and Lysine degradation, inhibiting Bacteroides caccae, Clostridium cocleatum, and Muribaculum intestinale, while promoting Akkermansia muciniphila and Mucispirillum schaedleri, and regulating key metabolites including Glutaric acid, Threonine, Leucine, and Glutamic acid.