Microbiota-derived IPA alleviates intestinal mucosal inflammation through upregulating Th1/Th17 cell apoptosis in inflammatory bowel disease.

IF 12.2 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut Microbes Pub Date : 2025-12-01 Epub Date: 2025-02-16 DOI:10.1080/19490976.2025.2467235
Han Gao, Mingming Sun, Ai Li, Qiaoyan Gu, Dengfeng Kang, Zhongsheng Feng, Xiaoyu Li, Xuehong Wang, Liang Chen, Hong Yang, Yingzi Cong, Zhanju Liu
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引用次数: 0

Abstract

The gut microbiota-derived metabolite indole-3-propionic acid (IPA) plays an important role in maintaining intestinal mucosal homeostasis, while the molecular mechanisms underlying IPA regulation on mucosal CD4+ T cell functions in inflammatory bowel disease (IBD) remain elusive. Here we investigated the roles of IPA in modulating mucosal CD4+ T cells and its therapeutic potential in treatment of human IBD. Leveraging metabolomics and microbial community analyses, we observed that the levels of IPA-producing microbiota (e.g. Peptostreptococcus, Clostridium, and Fournierella) and IPA were decreased, while the IPA-consuming microbiota (e.g. Parabacteroides, Erysipelatoclostridium, and Lachnoclostridium) were increased in the feces of IBD patients than those in healthy donors. Dextran sulfate sodium (DSS)-induced acute colitis and CD45RBhighCD4+ T cell transfer-induced chronic colitis models were then established in mice and treated orally with IPA to study its role in intestinal mucosal inflammation in vivo. We found that oral administration of IPA attenuated mucosal inflammation in both acute and chronic colitis models in mice, as characterized by increased body weight, and reduced levels of pro-inflammatory cytokines (e.g. TNF-α, IFN-γ, and IL-17A) and histological scores in the colon. We further utilized RNA sequencing, molecular docking simulations, and surface plasmon resonance analyses and identified that IPA exerts its biological effects by interacting with heat shock protein 70 (HSP70), leading to inducing Th1/Th17 cell apoptosis. Consistently, ectopic expression of HSP70 in CD4+ T cells conferred resistance to IPA-induced Th1/Th17 cell apoptosis. Therefore, these findings identify a previously unrecognized pathway by which IPA modulates intestinal inflammation and provide a promising avenue for the treatment of IBD.

微生物源性IPA通过上调炎症性肠病中Th1/Th17细胞凋亡来缓解肠黏膜炎症。
肠道微生物衍生代谢物吲哚-3-丙酸(IPA)在维持肠黏膜稳态中发挥重要作用,但IPA调节炎症性肠病(IBD)中粘膜CD4+ T细胞功能的分子机制尚不清楚。在此,我们研究了IPA在调节粘膜CD4+ T细胞中的作用及其在治疗人IBD中的治疗潜力。利用代谢组学和微生物群落分析,我们观察到IBD患者粪便中产生IPA的微生物群(如胃链球菌、梭状芽胞杆菌和福尼氏菌)和IPA的水平下降,而消耗IPA的微生物群(如副杆菌、Erysipelatoclostridium和Lachnoclostridium)的水平高于健康供者。建立小鼠Dextran sulfate sodium (DSS)诱导的急性结肠炎和CD45RBhighCD4+ T细胞转移诱导的慢性结肠炎模型,并口服IPA,研究其在体内肠道黏膜炎症中的作用。我们发现口服IPA可减轻小鼠急性和慢性结肠炎模型的粘膜炎症,其特征是体重增加,促炎细胞因子(如TNF-α, IFN-γ和IL-17A)水平降低和结肠组织学评分降低。我们进一步利用RNA测序、分子对接模拟和表面等离子体共振分析,发现IPA通过与热休克蛋白70 (HSP70)相互作用,诱导Th1/Th17细胞凋亡,从而发挥其生物学作用。与此一致的是,HSP70在CD4+ T细胞中的异位表达赋予ipa诱导的Th1/Th17细胞凋亡的抗性。因此,这些发现确定了一个以前未被认识的IPA调节肠道炎症的途径,并为IBD的治疗提供了一个有希望的途径。
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来源期刊
Gut Microbes
Gut Microbes Medicine-Microbiology (medical)
CiteScore
18.20
自引率
3.30%
发文量
196
审稿时长
10 weeks
期刊介绍: The intestinal microbiota plays a crucial role in human physiology, influencing various aspects of health and disease such as nutrition, obesity, brain function, allergic responses, immunity, inflammatory bowel disease, irritable bowel syndrome, cancer development, cardiac disease, liver disease, and more. Gut Microbes serves as a platform for showcasing and discussing state-of-the-art research related to the microorganisms present in the intestine. The journal emphasizes mechanistic and cause-and-effect studies. Additionally, it has a counterpart, Gut Microbes Reports, which places a greater focus on emerging topics and comparative and incremental studies.
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