Gut Microbiome-Linked Metabolites in the Pathobiology of Major Depression With or Without Anxiety-A Role for Bile Acids

Background: The gut microbiome may play a role in the pathogenesis of neuropsychiatric diseases including major depressive disorder (MDD). Bile acids (BAs) are steroid acids that are synthesized in the liver from cholesterol and further processed by gut-bacterial enzymes, thus requiring both human and gut microbiome enzymatic processes in their metabolism. BAs participate in a range of important host functions such as lipid transport and metabolism, cellular signaling and regulation of energy homeostasis. BAs have recently been implicated in the pathophysiology of Alzheimer's and several other neuropsychiatric diseases, but the biochemical underpinnings of these gut microbiome-linked metabolites in the pathophysiology of depression and anxiety remains largely unknown. Method: Using targeted metabolomics, we profiled primary and secondary BAs in the baseline serum samples of 208 untreated outpatients with MDD. We assessed the relationship of BA concentrations and the severity of depressive and anxiety symptoms as defined by the 17-item Hamilton Depression Rating Scale (HRSD17) and the 14-item Hamilton Anxiety Rating Scale (HRSA-Total), respectively. We also evaluated whether the baseline metabolic profile of BA informs about treatment outcomes. Results: The concentration of the primary BA chenodeoxycholic acid (CDCA) was significantly lower at baseline in both severely depressed (log(2) fold difference (LFD) = -0.48; p = 0.021) and highly anxious (LFD = -0.43; p = 0.021) participants compared to participants with less severe symptoms. The gut bacteria-derived secondary BAs produced from CDCA such as lithocholic acid (LCA) and several of its metabolites, and their ratios to primary BAs, were significantly higher in the more anxious participants (LFD's range = [0.23, 1.36]; p's range = [6.85E-6, 1.86E-2]). The interaction analysis of HRSD17 and HRSA-Total suggested that the BA concentration differences were more strongly correlated to the symptoms of anxiety than depression. Significant differences in baseline CDCA (LFD = -0.87, p = 0.0009), isoLCA (LFD = -1.08, p = 0.016) and several BA ratios (LFD's range [0.46, 1.66], p's range [0.0003, 0.049]) differentiated treatment failures from remitters. Conclusion: In patients with MDD, BA profiles representing changes in gut microbiome compositions are associated with higher levels of anxiety and increased probability of first-line treatment failure. If confirmed, these findings suggest the possibility of developing gut microbiome-directed therapies for MDD characterized by gut dysbiosis.