Low-Molecular-Weight Peptides from Musca domestica Larvae Alleviate Diarrhea-Predominant Irritable Bowel Syndrome Comorbid with Depression via Regulating Gut Microbiota, Short-Chain Fatty Acids and Serum Metabolism

Diarrhea-predominant irritable bowel syndrome (IBS-D) frequently occurs alongside depression, greatly impairing patients’ life quality, with limited targeted treatments. Low-molecular-weight peptides (LMWPs) from Musca domestica larvae exert gut-protective bioactivities, but their efficacy and molecular mechanisms for comorbid IBS-D and depression remain unelucidated. A chronic–acute combined stress (CACS)-induced rat model of IBS-D complicated with depression was established and treated with LMWPs. The study evaluated intestinal and depressive behavioral phenotypes, and integrated 16S rRNA sequencing, untargeted serum metabolomics and quantitative detection of fecal SCFAs for multi-omics correlation analysis. 1. CACS triggered typical comorbid symptoms, which LMWPs alleviated with effects similar to trimebutine maleate. 2. LMWP treatment was associated with reshaped gut microbiota, restored metabolic pathways, altered levels of 27 disease-associated serum metabolites, and increased fecal SCFA levels. 3. Multi-omics correlation analyses suggested that the therapeutic benefits may involve crosstalk among gut microbiota, SCFAs, and tryptophan metabolites. Larva-derived LMWP relieves IBS-D combined with depression by modulating gut microecology, SCFA generation and serum metabolic balance through the gut–brain axis, which can serve as a novel promising therapeutic candidate.