School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Department of Anorectal Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
J Ethnopharmacol. 2024 Sep 15;331:118256. doi: 10.1016/j.jep.2024.118256. Epub 2024 Apr 25.
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.
We aim to investigate a new gut microbiota-mediated mechanism underlying anti-IBS efficacy of TXYF.
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.
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.
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.
一种传统上用于治疗肠易激综合征（IBS）的草药配方通泄要方（TXYF），现代药理学证据表明，该配方的功效与肠道微生物群的改变有关。然而，肠道微生物群在 TXYF 治疗中的机制作用尚不清楚。我们之前已经阐明，肠道微生物群失调的胆汁酸（BA）代谢导致了 IBS 的发病机制，因此提出了一个假设，即微生物群-BA 代谢轴可能是 TXYF 的一个潜在靶点。
我们旨在研究 TXYF 抗 IBS 疗效的一个新的肠道微生物群介导的机制。
我们建立了一种应激联合的 IBS 大鼠模型，比较了在肠道细菌操作模型中草药的疗效，还通过 16S rRNA 基因测序、靶向代谢组学、qPCR 和多重免疫荧光染色检查了与 BA 代谢相关的微生物群、代谢物、基因和蛋白质。
我们观察到 TXYF 减轻了 IBS 大鼠的内脏痛觉过敏和腹泻，但对肠道细菌耗竭的大鼠没有作用。将来自 TXYF 治疗供体的肠道微生物群转移也降低了 IBS 受体大鼠的内脏敏感性，并略微缓解了腹泻样行为。粪便 16S rRNA 基因测序显示，TXYF 调节了 IBS 大鼠的微生物 β-多样性和分类结构，具有胆汁盐水解酶（BSH）表达的拟杆菌科的相对丰度显著增加。qPCR 和培养数据验证了 TXYF 对拟杆菌属物种的生长和 BSH 活性有促进作用。TXYF 重塑的微生物群上调了肠道 Fgf15 的表达，这是控制肝脏中 BA 合成的反馈信号。结果，TXYF 降低了 IBS 大鼠的 BA 合成和排泄水平，从而减弱了结肠 BA 膜受体 Tgr5 的感应及其介导的降钙素基因相关肽（Cgrp）阳性神经元反应。
本研究提出了 TXYF 的一种新的基于微生物群的治疗作用，强调了从靶向肠道中 BSH 表达细菌的草药配方开发新的抗 IBS 策略的潜力。
