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

Yuchen Qu,Jie Pan,Liuxing Tang,Yunli Yu,Yueyuan Wang,Zheng Xiang,Delai Xu,Aiming Shi,Cunjin Su,Fenglun Zhao,Qinhong Zhao,Yang Wang

doi:10.3389/fphar.2022.837543

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.

Highlights

According to the World Health Organization, an estimated 3.8% of the global population has been affected by depression and the number is still increasing worldwide (World Health Organization, 2021)
Significant chronic unpredictable mild stress (CUMS) effects were present in the case of the sucrose consumption in sucrose preference test (SPT), immobility time in both forced swim test (FST) and TST compared with the control group
The results demonstrated that a CUMS mouse model was successfully created

Summary

Introduction

According to the World Health Organization, an estimated 3.8% of the global population has been affected by depression and the number is still increasing worldwide (World Health Organization, 2021). Modern psychology- and biology-related concepts revealed that depression is a common psychological disorder, and a physical disease complex involving the imbalance of neurotransmitters, injury of neurogenesis, decline of neuroplasticity, and abnormality of neuronal circuitry (Chaudhury et al, 2015; Liu et al, 2017). An important function of the gut microbiota is participating in bile acid metabolism. Bile acids are the major constituents of the human bile synthesized from cholesterol by perivenous hepatocytes, Bile Acids Metabolism in CUMS playing an important role in dietary fat digestion and absorption (Hofmann., 1999). Most bile acids undergo enterohepatic circulation and microbial biotransformation in the intestinal tract (Chiang and Ferrell, 2018). Bile acids are secreted into the gastrointestinal tract, where they are subsequently deconjugated, dehydroxylated, and oxidized in the intestinal lumen by gut microbes to generate hydrophobic secondary bile acids: deoxycholic and lithocholic acid (Ridlon et al, 2014)

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Discussion

Conclusion