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

Abstract

BackgroundThe 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.MethodUsing 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.ResultsThe concentration of the primary BA chenodeoxycholic acid (CDCA) was significantly lower at baseline in both severely depressed (log2 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.ConclusionIn 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.

Monoamine Neurotransmitters Control Basic Emotions and Affect Major Depressive Disorders

“…The intestine, also known as the second brain, has a close connection with the brain [ 55 ]. Tremendous progress has been made in studying the bidirectional interactions between the gastrointestinal tract and the central nervous system [ 56 ], and understanding the interaction between the digestive system with the brain may provide novel approaches for prevention and treatment of MDD [ 57 , 58 ].…”

“…Recently, it has been found that patients with MDD had a significantly higher prevalence and incidence of chronic liver disease than the general population [ 74 ]; thus, the integrative activity of liver and brain might play a role in depression [ 59 , 60 ]. Part of the reason might be due to the metabolites, such as the bile acids [ 55 ]. Bile acids are steroid acids which are synthesized in the liver and further processed in the gut by digestive enzymes.…”

Liver’s influence on the brain through the action of bile acids

“…Bile acids (BA) can independently modulate the function and effects of the brain ( Nunes et al, 2012 ; Bazzari et al, 2019 ), gut ( Zhou et al, 2020 ), and gut microbiome ( van Best et al, 2020 ), while each of these layers of the brain-gut-microbiome axis may contribute to the overall outcome in the brain ( Garcia et al, 2022 ; Lirong et al, 2022 ; MahmoudianDehkordi et al, 2022 ; Qu et al, 2022 ). Hence, there is a large spectrum and significant complexity in how BA and the intestinal flora affect brain function.…”

Acupuncture treatment for post-stroke depression: Intestinal microbiota and its role

“…According to researchers' speculation, acupuncture restored gut flora balance primarily by regulating glycerophospholipid metabolism and primary bile acid biosynthesis. Several studies have shown that intestinal microflora is involved in the pathogenesis of depression 10.3389/fnins.2023.1146946 through glycerophospholipid metabolism and primary bile acid biosynthesis (Gong et al, 2021;MahmoudianDehkordi et al, 2022). Accordingly, it can be speculated that electroacupuncture might be useful in treating depression by regulating intestinal flora's production of glycerophospholipids and bile acids.…”