Disordered gut microbiota and changes in short-chain fatty acids and inflammatory processes in stress-vulnerable mice

Long-term exposure to chronic stress increases the incidence of depression. However, chronic stress is an associated risk factor in only a subset of individuals. Inflammation has been identified as a putative mechanism promoting stress vulnerability. Because of the gut microbiota's potential role as a source of inflammatory substances, short-chain fatty acids (SCFAs) may exert their influence on inflammation, emotional states, and cognition via the gut-brain axis. In this study, Classic behavioral tests were used to categorize C57BL/6 J mice into a CUMS-vulnerable and a CUMS-resilient group after they were exposed to chronic unpredictable mild stress (CUMS). We compared the 16S ribosomal RNA (rRNA) gene sequences retrieved from fecal samples between control, CUMS-vulnerable, and CUMS-resilient mice. SCFAs in fecal samples were detected by liquid chromatography and gas chromatography-mass spectrometry. Hippocampal cytokine production and TLR4/MYD88/NF-κB inflammatory pathway activation were evaluated using enzyme-linked immunosorbent assays (ELISAs) and western blotting. Then, we supplemented SCFAs in CUMS mice. we observed depression-like behavior and the expression of TLR4/MYD88/NF-κB inflammatory pathway in hippocampus of SCFAs supplementation mice. Susceptible mice to CUMS showed more severe symptoms of depression and anxiety, α diversity was significantly different, as well as higher expression of interleukin (IL)-1β and TLR4/MYD88/NF-κB inflammatory pathway components in the hippocampus. SCFA levels in the feces were significantly higher in CUMS-resilient mice than in control mice. Depressive behavior was reversed in CUMS-SCFAs group, and the protein level of TLR4/MYD88/NF-κB in hippocampus was decreased. Overall, these results provide new light on the possible involvement of the microbiome in the gut-brain axis development in depressive disorder and provide a theoretical basis for identifying novel therapeutic targets.