Yang Jin, Wang Qian, Wang Zhuang, Zhang Yuanxing, Liu Qin, Yang Dahai
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China.
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China; Laboratory for Aquatic Animal Diseases of MOA, Shanghai, 201400, China.
Fish Shellfish Immunol. 2025 Aug;163:110425. doi: 10.1016/j.fsi.2025.110425. Epub 2025 May 16.
Enteric pathogens exacerbate intestinal inflammation by disrupting microbiota-host metabolic interactions. While T helper 17 (Th17) cells are critical for maintaining intestinal homeostasis, the mechanisms through which enteric pathogens manipulate the function of Th17 cells to drive inflammation remain poorly understood. In this study, we established an immersion infection model using Edwardsiella piscicida in turbot (Scophthalmus maximus) to investigate the mechanism about enteric pathogen-induced intestinal inflammation, and found that E. piscicida infection significantly impairs the function of intestinal Th17 cells. By analyzing changes in the intestinal microbiota and metabolites, we observed a marked increase in the abundance of Proteobacteria phylum, which positively correlated with elevated levels of tryptophan-kynurenine (Trp-Kyn) pathway metabolites. Further investigation revealed that the enhanced Trp-Kyn pathway inhibits the function of intestinal Th17 cells. Importantly, pharmacological inhibition of the Trp-Kyn pathway could restore the function of Th17 cells and alleviate the infection-induced intestinal inflammation. Taken together, these findings uncover a critical link between microbiota-mediated tryptophan metabolism and Th17 cell's dysregulation during enteric pathogen infection in teleost, which provide novel insights into the metabolic reprogramming of host immunity and to identify potential therapeutic targets for mitigating intestinal inflammation.
肠道病原体通过破坏微生物群与宿主的代谢相互作用来加剧肠道炎症。虽然辅助性T细胞17（Th17细胞）对于维持肠道稳态至关重要，但肠道病原体操纵Th17细胞功能以驱动炎症的机制仍知之甚少。在本研究中，我们利用大菱鲆（Scophthalmus maximus）建立了迟缓爱德华氏菌的浸泡感染模型，以研究肠道病原体诱导肠道炎症的机制，发现迟缓爱德华氏菌感染显著损害肠道Th17细胞的功能。通过分析肠道微生物群和代谢产物的变化，我们观察到变形菌门丰度显著增加，这与色氨酸-犬尿氨酸（Trp-Kyn）途径代谢产物水平升高呈正相关。进一步研究表明，增强的Trp-Kyn途径抑制肠道Th17细胞的功能。重要的是，对Trp-Kyn途径的药理学抑制可恢复Th17细胞的功能，并减轻感染诱导的肠道炎症。综上所述，这些发现揭示了硬骨鱼肠道病原体感染期间微生物群介导的色氨酸代谢与Th17细胞失调之间的关键联系，为宿主免疫的代谢重编程提供了新的见解，并为确定减轻肠道炎症的潜在治疗靶点提供了依据。
