Microbial metabolite 3-indolepropionic acid alleviated PD pathologies by decreasing enteric glia cell gliosis <i>via</i> suppressing IL-13R<i>α</i>1 related signaling pathways.

Meiyu SHANG; Jingwen NING; Caixia ZANG; Jingwei MA; Yang YANG; Zhirong WAN; Jing ZHAO; Yueqi JIANG; Qiuzhu CHEN; Yirong DONG; Jinrong WANG; Fangfang LI; Xiuqi BAO; Dan ZHANG

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Microbial metabolite 3-indolepropionic acid alleviated PD pathologies by decreasing enteric glia cell gliosis via suppressing IL-13Rα1 related signaling pathways.

Author: Meiyu SHANG ¹ ; Jingwen NING ¹ ; Caixia ZANG ¹ ; Jingwei MA ¹ ; Yang YANG ¹ ; Zhirong WAN ² ; Jing ZHAO ² ; Yueqi JIANG ¹ ; Qiuzhu CHEN ¹ ; Yirong DONG ¹ ; Jinrong WANG ¹ ; Fangfang LI ¹ ; Xiuqi BAO ¹ ; Dan ZHANG ¹
Author Information

1. State Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
2. Department of Neurology, Aerospace Center Hospital, Beijing 100049, China.
Publication Type:Journal Article
Keywords: 16S rRNA; 3-Indolepropionic acid; Enteric glia cells; IL-13Rα1; Inflammation; Microbiota dysbiosis; Parkinson's disease; Pregnane X receptor
From: Acta Pharmaceutica Sinica B 2025;15(4):2024-2038
CountryChina
Language:English
Abstract: Although enteric glial cell (EGC) abnormal activation is reported to be involved in the pathogenesis of Parkinson's disease (PD), and inhibition of EGC gliosis alleviated gut and dopaminergic neuronal dysfunction was verified in our previous study, the potential role of gut microbiota on EGC function in PD still need to be addressed. In the present study, fecal microbiota transplantation revealed that EGC function was regulated by gut microbiota. By employing 16S rRNA and metabolomic analysis, we identified that 3-indolepropionic acid (IPA) was the most affected differential microbial metabolite that regulated EGC gliosis. The protective effects of IPA on PD were validated in rotenone-stimulated EGCs and rotenone (30 mg/kg i.g. for 4 weeks)-induced PD mice, as indicated by decreased inflammation, improved intestinal and brain barrier as well as dopaminergic neuronal function. Mechanistic study showed that IPA targeted pregnane X receptor (PXR) in EGCs, and inhibition of IL-13Rα1 involved cytokine-cytokine receptor interaction pathway, leading to inactivation of downstream JAK1-STAT6 pathway. Our data not only provided evidence that EGC gliosis was critical in spreading intestinal damage to brain, but also highlighted the potential role of microbial metabolite IPA in alleviating PD pathological damages through gut-brain axis.