Antidepressant Effect of Short-Chain Fatty Acids on Chronic Unpredictable Mild Stress in Model Rats And Their Influence on the Oral-Gut Microbiota.

Purpose: To investigate the effects of short-chain fatty acids (SCFAs) on depression-like behaviors and the oral gut microbiota in rats subjected to chronic unpredictable mild stress (CUMS) using behavioral tests and high-throughput sequencing of 16SrRNA. Methods: Sprague-Dawley rats were randomly divided into Control, CUMS, and SCFAs groups. Except for the Control group, all rats underwent CUMS modeling and drug administration for 28 days. Behavioral tests assessed depression-like behaviors, while 16SrRNA sequencing analyzed oral and gut microbiota changes. Histopathological examination of the colon tissues and immunohistochemical analysis of the tight junction protein ZO-1 were performed. Results: Interventions using SCFAs can alleviate symptoms in rats with CUMS-induced depression. Analysis of microbial diversity revealed significant differences in both Alpha and Beta diversities of the gut microbiota among all three groups. The composition of the microbiota showed that, at the phylum level, in the intestinal microbiota, the Firmicutes/Bacteroidetes (F/B) ratio in the SCFAs group was significantly lower than that in the CUMS group. At the genus level, Lactobacillus was the dominant bacterium in the gut. Rothia was predominant among the oral bacteria. Linear discriminant effect size (LEfSe) analysis revealed that, in the gut, the relative abundances of Bifidobacterium, Collinsella, and Sphingobium increased in the SCFAs group. In the oral cavity, the relative abundance of Prevotella increased in the CUMS group but decreased in the SCFAs group. The histopathological examination of the colon revealed that, compared with the CUMS group, in the SCFAs group, the inflammatory cells in the lamina propria decreased, and the tight junction protein ZO-1 in colonic epithelium cells increased. Conclusion: SCFAs intervention ameliorated depression-like behaviors, modulated gut microbiota composition, enhanced ZO-1 expression, reduced gut inflammation, and promoted immune function, thereby restoring oral gut microbiota homeostasis. This study elucidated SCFAs' therapeutic potential of SCFAs in depression and provided a theoretical foundation for their clinical application in antidepressant treatments.