Tong-Xie-Yao-Fang strengthens intestinal feedback control of bile acid synthesis to ameliorate irritable bowel syndrome by enhancing bile salt hydrolase-expressing microbiota

Fengjing Jia; Liqing Du; Jinchao He; Zhaozhou Zhang; Xinxin Hou; Qinjun Dong; Zhaoxiang Bian; Ling Zhao

doi:10.1016/j.jep.2024.118256

Tong-Xie-Yao-Fang strengthens intestinal feedback control of bile acid synthesis to ameliorate irritable bowel syndrome by enhancing bile salt hydrolase-expressing microbiota

J Ethnopharmacol. 2024 Apr 25:331:118256. doi: 10.1016/j.jep.2024.118256. Online ahead of print.

Authors

Fengjing Jia¹, Liqing Du¹, Jinchao He², Zhaozhou Zhang¹, Xinxin Hou¹, Qinjun Dong², Zhaoxiang Bian³, Ling Zhao⁴

Affiliations

¹ School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
² Department of Anorectal Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
³ Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong SAR, China. Electronic address: bianzxiang@gmail.com.
⁴ School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: lzhao@shutcm.edu.cn.

PMID: 38677571
DOI: 10.1016/j.jep.2024.118256

Abstract

Ethnopharmacological relevance: A herbal formula Tong-Xie-Yao-Fang (TXYF) is traditionally used to treat irritable bowel syndrome (IBS), modern pharmacological evidence supports that the formula efficacy is associated with altered gut microbiota. Yet, the mechanistic role of gut microbiota in the therapy of TXYF remains unclear. We previously clarified that gut microbiota-dysregulated bile acid (BA) metabolism contribute to the pathogenesis of IBS, deriving a hypothesis that microbiota-BA metabolic axis might be a potential target of TXYF.

Aim of the study: We aim to investigate a new gut microbiota-mediated mechanism underlying anti-IBS efficacy of TXYF.

Materials and methods: We established an IBS rat model with a combination of stressors, compared the herbal efficacy in models undergone gut bacterial manipulations, also examined BA metabolism-related microbiota, metabolites, genes and proteins by 16S rRNA gene sequencing, targeted metabolomics, qPCR and multiplex immunofluorescence staining.

Results: We observed that TXYF attenuated visceral hyperalgesia and diarrhea in IBS rats but not in those underwent gut bacteria depletion. Transferring gut microbiota from TXYF-treated donors also decreased visceral sensitivity and slightly relief diarrhea-like behaviors in IBS recipient rats. Fecal 16S rRNA gene sequencing revealed that TXYF modulated microbial β-diversity and taxonomic structure of IBS rats, with a significant increase in relative abundance of bile salt hydrolase (BSH)-expressing Bacteroidaceae. qPCR and culturing data validated that TXYF had a promotive effect on the growth and BSH activity of Bacteroides species. TXYF-reshaped microbiota upregulated the expression of intestinal Fgf15, a feedback signal to control BA synthesis in the liver. As a result, the BA synthetic and excretory levels in IBS rats were decreased by TXYF, so as that colonic BA membrane receptor Tgr5 sensing and its mediated Calcitonin gene-related peptide (Cgrp)-positive neuronal response were attenuated.

Conclusion: This study poses a new microbiota-driven therapeutic action for TXYF, highlighting the potential of developing new anti-IBS strategies from the herbal formula targeting BSH-expressing gut bacteria.

Keywords: Bile acids; Chronic stress; Gut microbiota; Herbal formula; Irritable bowel syndrome; Visceral hyperalgesia.