The gut microbiome from middle-aged women with depression modulates depressive-like behaviors and plasma fatty acid metabolism in female middle-aged mice

Background: Intestinal dysbacteriosis has frequently been involved in the context of depression. Nonetheless, only scant information is available about the features and functional changes of gut microbiota in female middle-aged depression (MAD). Objective: This study aims to explore whether there are characteristic changes in the gut microbes of female MAD and whether these changes are associated with depressive-like behaviors. Meanwhile, this study observed alterations in the lipid metabolism function of gut microbes and further examined changes in plasma medium- and long-chain fatty acids (MLCFAs) in mice that underwent fecal microbiota transplantation (FMT). Methods: Stool samples obtained from 31 MAD, along with 24 healthy individuals (HC) were analyzed by 16 S rRNA gene sequencing. Meanwhile, 14-month-old female C57BL/6J mice received antibiotic cocktails and then oral gavage of the microbiota suspension of MAD or HC for 3 weeks to reconstruct gut microbiota. The subsequent depressive-like behaviors, the composition of gut microbiota, as well as MLCFAs in the plasma were evaluated. Results: A noteworthy disruption in gut microbial composition in MAD individuals compared to HC was observed. Several distinct bacterial taxa, including Dorea, , Butyricicoccus, , and Blautia, , demonstrated associations with the demographic variables. A particular microbial panel encompassing 49 genera effectively differentiated MAD patients from HC (AUC = 0.82). Fecal microbiome transplantation from MAD subjects led to depressive-like behaviors and dysfunction of plasma MLCFAs in mice. Conclusions: These findings suggest that microbial dysbiosis is linked to the pathogenesis of MAD, and its role may be associated with the regulation of MLCFAs metabolism.