Chaihu-shugan-san alleviates depression-like behavior in mice exposed to chronic unpredictable stress by altering the gut microbiota and levels of the bile acids hyocholic acid and 7-ketoDCA

Chong Ma; Dun Yuan; Stephen James Renaud; Ting Zhou; Fan Yang; Yuligh Liou; Xinjian Qiu; Lu Zhou; Ying Guo

doi:10.3389/fphar.2022.1040591

Chaihu-shugan-san alleviates depression-like behavior in mice exposed to chronic unpredictable stress by altering the gut microbiota and levels of the bile acids hyocholic acid and 7-ketoDCA

Front Pharmacol. 2022 Oct 19:13:1040591. doi: 10.3389/fphar.2022.1040591. eCollection 2022.

Authors

Chong Ma^{1

2

2

2

2}, Dun Yuan³, Stephen James Renaud⁴, Ting Zhou^{1

1

1

1}, Fan Yang^{1

1

1

1}, Yuligh Liou⁵, Xinjian Qiu⁶, Lu Zhou⁶, Ying Guo^{1

1

1

1}

Affiliations

¹ Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
² Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.
³ Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
⁴ Department of Anatomy and Cell Biology, The University of Western Ontario, London, ON, Canada.
⁵ China Xiangya Medical Laboratory, Central South University, Changsha, China.
⁶ Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, China.

Abstract

Chaihu-Shugan-San (CSS) is a traditional botanical drug formula often prescribed to treat depression in oriental countries, but its pharmacotherapeutic mechanism remains unknown. It was recently reported that CSS alters the composition of intestinal microflora and related metabolites such as bile acids (BAs). Since the intestinal microflora affects physiological functions of the brain through the gut-microbiota-brain axis, herein we investigated whether CSS altered BA levels, gut microflora, and depression-like symptoms in chronic unpredictable mild stress (CUMS) mice, a well-established mouse model of depression. Furthermore, we determined whether BA manipulation and fecal microbiota transplantation altered CSS antidepressant actions. We found that the BA chelator cholestyramine impaired the antidepressant effects of CSS, which was partially rescued by dietary cholic acid. CSS increased the relative abundance of Parabacteroides distasonis in the colon of CUMS mice, and increased serum levels of various BAs including hyocholic acid (HCA) and 7-ketodeoxycholic acid (7-ketoDCA). Furthermore, gut bacteria transplantation from CSS-treated mice into untreated or cholestyramine-treated CUMS mice restored serum levels of HCA and 7-ketoDCA, alleviating depression-like symptoms. In the hippocampus, CSS-treated mice had decreased expression of genes associated with BA transport (Bsep and Fxr) and increased expression of brain-derived neurotrophic factor and its receptor, TrkB. Overall, CSS increases intestinal P. distasonis abundance, leading to elevated levels of secondary BAs in the circulation and altered expression of hippocampal genes implicated in BA transport and neurotrophic signaling. Our data strongly suggest that the gut microbiota-brain axis contributes to the potent antidepressant action of CSS by modulating BA metabolism.

Keywords: Chaihu-Shugan-San; Parabacteroides distasonis; bile acids; depression; gut microbiota-brain axis.