Gut microbiota-mediated ursodeoxycholic acids regulate the inflammation of microglia through TGR5 signaling after MCAO

Feng Zhang; Yiting Deng; Huidi Wang; Jingxiang Fu; Guangyan Wu; Zhuo Duan; Xiru Zhang; Yijia Cai; Hongwei Zhou; Jia Yin; Yan He

doi:10.1016/j.bbi.2023.11.021

Gut microbiota-mediated ursodeoxycholic acids regulate the inflammation of microglia through TGR5 signaling after MCAO

Brain Behav Immun. 2024 Jan:115:667-679. doi: 10.1016/j.bbi.2023.11.021. Epub 2023 Nov 19.

Authors

Feng Zhang¹, Yiting Deng², Huidi Wang³, Jingxiang Fu³, Guangyan Wu³, Zhuo Duan³, Xiru Zhang³, Yijia Cai³, Hongwei Zhou⁴, Jia Yin⁵, Yan He⁶

Affiliations

¹ Microbiome Medicine Centre, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, PR China; Department of Neurosurgery, Huzhou Central Hospital, Zhejiang University School of Medicine, Huzhou, PR China.
² Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China.
³ Microbiome Medicine Centre, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, PR China.
⁴ Microbiome Medicine Centre, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, PR China; Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, Guangdong 510033, PR China; State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, Guangdong 510515, PR China.
⁵ Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China. Electronic address: yinj@smu.edu.cn.
⁶ Microbiome Medicine Centre, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, PR China; Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, Guangdong 510033, PR China; State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, Guangdong 510515, PR China; Key Laboratory of Mental Health of the Ministry of Education, Guangzhou, Guangdong 510515, PR China. Electronic address: yanhe@i.smu.edu.cn.

PMID: 37989444
DOI: 10.1016/j.bbi.2023.11.021

Abstract

Ischemic stroke has been demonstrated to cause an imbalance of gut microbiota. However, the change in gut microbiota-mediated bile acids (BAs) metabolites remains unclear. Here, we observed a decrease in gut microbiota-mediated BAs, especially ursodeoxycholic acid (UDCA), in the serum of stroke patients as well as in the intestine, serum and brain of stroke mice. Restoration of UDCA could decrease the area of infarction and improve the neurological function and cognitive function in mice in association with inhibition of NLRP3-related pro-inflammatory cytokines through TGR5/PKA pathway. Furthermore, knocking out TGR5 and inhibiting PKA activity reduce the protective effect of UDCA. Taken together, our results suggest that microbiota-mediated UDCA plays an important role in alleviating inflammatory responses and might be a promising therapeutic target in ischemic stroke.

Keywords: Ischemic stroke; NLRP3 inflammasome; Neuroinflammation; TGR5; Ursodeoxycholic acid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bile Acids and Salts
Gastrointestinal Microbiome*
Humans
Inflammation
Ischemic Stroke*
Mice
Microglia / metabolism
Stroke*
Ursodeoxycholic Acid / metabolism

Substances

Bile Acids and Salts
Ursodeoxycholic Acid
GPBAR1 protein, human
Gpbar1 protein, mouse