Gut Microbiota-Mediated Elevated Production of Secondary Bile Acids in Chronic Unpredictable Mild Stress

Abstract

A growing body of evidence suggests that gut microbiota could participate in the progression of depression via the microbiota–gut–brain axis. However, the detailed microbial metabolic profile changes in the progression of depression is still not fully elucidated. In this study, a liquid chromatography coupled to mass spectrometry-based untargeted serum high-throughput metabolomics method was first performed to screen for potential biomarkers in a depressive-like state in a chronic unpredictable mild stress (CUMS)-induced mouse model. Our results identified that the bile acid and energy metabolism pathways were significantly affected in CUMS progression. The detailed bile acid profiles were subsequently quantified in the serum, liver, and feces. The results showed that CUMS significantly promoted the deconjugation of conjugated bile acid and secondary bile acid biosynthesis. Furthermore, 16S rRNA gene sequencing revealed that the increased secondary bile acid levels in the feces positively correlated with Ruminococcaceae_UCG-010, Ruminococcus, and Clostridia_UCG-014 abundance. Taken together, our study suggested that changes in family Ruminococcaceae abundance following chronic stress increased biosynthesis of deoxycholic acid (DCA), a unconjugated secondary bile acid in the intestine. Aberrant activation of secondary bile acid biosynthesis pathway thereby increased the hydrophobicity of the bile acid pool, which might, in turn, promoted metabolic disturbances and disease progression in CUMS mice.

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

“…The mutual regulation between the gut microbiome and BA synthesis and function complicates the role of BAs in general physiology. Gut microbiota is known to modify host-derived BA into secondary BAs that exhibit alterations in patients with neuropsychiatric disorders ( Aizawa et al, 2019 ; Liu et al, 2021 ; Zhang et al, 2022 ), while the BA composition can be affected by environmental stressors ( Silvennoinen et al, 2015 ; Qu et al, 2022 ). The relative abundance of intestinal microbiota at the phylum level is modifiable by BA present within the system ( Islam et al, 2011 ) through the direct antimicrobial effect of BA or BA effects on alternate antimicrobial molecules ( Begley et al, 2005 ; Inagaki et al, 2006 ).…”

“…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.…”

Ameliorative effect of Aconite aqueous extract on diarrhea is associated with modulation of the gut microbiota and bile acid metabolism

“…However, unclassified_f_Ruminococcaceae inhibited the formation of 12-keto-LCA, dehydro-LCA, and β -UDCA. Previous studies have shown that norank_f_Muribaculaceae ( Shao et al, 2021 ; Lei et al, 2022 ; Yang C. et al, 2022 ), Parasutterella ( Ju et al, 2019 ; Li et al, 2019 ), Ruminococcus ( Fiorucci et al, 2018 ; Jia et al, 2018 ), Escherichia ( Fiorucci and Distrutti, 2015 ; Jia et al, 2018 ; Xie et al, 2022 ), Prevotellaceae_UCG-001 ( Huang et al, 2019 ), and norank_f_norank_o_Clostridia_UCG-014 (belonging to the Clostridia_UCG-014 order) ( Qu et al, 2022 ) are involved in BA metabolism. Overall, our results further suggested that AA can regulate the gut microbiota while gradually restoring disrupted BA metabolism.…”

Effects of earthworm hydrolysate in production performance, serum biochemical parameters, antioxidant capacity and intestinal function of Muscovy ducks

“…Eubacterium coprostanoligenes could turn cholesterol into coprostanol ( Freier et al, 1994 ). Ruminococcaceae transforms primary bile acids into major microorganisms of secondary bile acids ( Qu et al, 2022 ). Prevotellaceae-Ga6A1-group are capable of breaking down proteins and carbohydrates ( Guo et al, 2019 ).…”