Gut microbiota-derived tryptophan metabolite attenuates calcium oxalate nephropathy by suppressing renal tubular cell apoptosis through the AhR-SOCS3-STAT1 axis.

IF 5.4 2区医学 Q1 ONCOLOGY

The Journal of Pathology Pub Date : 2026-10-09 DOI:10.1002/path.70135

Ya Li, Jiawei Chen, Lede Lin, Zhongyu Jian, Linhu Liu, Menghua Wang, Jingwen Wei, Xiaoting Chen, Mengzhu Yang, Tianyue Li, Liyuan Xiang, Banghua Liao, Xi Jin, Kunjie Wang

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引用次数: 0

Abstract

Calcium oxalate (CaOx) nephropathy is a highly prevalent urological disease worldwide. Gut microbiota dysbiosis and host metabolic dysregulation are recognized as pivotal drivers in disease pathogenesis, yet the underlying mechanisms remain incompletely understood. In this study, by integrating metagenomics and metabolomics, we identified dysregulation of tryptophan metabolites in patients with CaOx nephrolithiasis, with microbiota-derived indole-3-propionic acid (IPA) as the most discriminatory differential metabolite. Oral IPA supplementation markedly reduced renal CaOx crystal deposition and tubular injury in a CaOx nephropathy murine model. Mechanistically, IPA activated the aryl hydrocarbon receptor (AhR), which translocated to the nucleus and transcriptionally upregulated suppressor of cytokine signaling 3 (SOCS3)-a negative regulator of signal transducer and activator of transcription 1 (STAT1)-thereby suppressing STAT1 phosphorylation, alleviating oxalate-induced tubular cell injury and apoptosis, and inhibiting CaOx crystal deposition. Our findings identify tryptophan metabolite alteration as a critical metabolic signature of CaOx nephropathy and demonstrate that microbiota-derived IPA attenuates oxalate-induced renal tubular cell injury and apoptosis via the AhR-SOCS3-STAT1 axis. © 2026 The Pathological Society of Great Britain and Ireland.

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肠道微生物来源的色氨酸代谢物通过AhR-SOCS3-STAT1轴抑制肾小管细胞凋亡，从而减轻草酸钙肾病。

草酸钙肾病是一种非常普遍的泌尿系统疾病。肠道菌群失调和宿主代谢失调被认为是疾病发病的关键驱动因素，但潜在的机制仍不完全清楚。在本研究中，通过整合宏基因组学和代谢组学，我们发现CaOx肾结石患者的色氨酸代谢物失调，微生物源性吲哚-3-丙酸（IPA）是最具差异性的代谢物。口服IPA可显著减少CaOx肾病模型小鼠肾CaOx晶体沉积和肾小管损伤。从机制上说，IPA激活了易位到细胞核的芳烃受体（AhR），并转录上调了细胞因子信号传导3 （SOCS3）的抑制因子（信号传导和转录激活因子1 （STAT1）的负调节因子），从而抑制STAT1磷酸化，减轻草酸盐诱导的小管细胞损伤和凋亡，抑制CaOx晶体沉积。我们的研究结果确定色氨酸代谢物改变是CaOx肾病的一个关键代谢特征，并证明微生物来源的IPA通过AhR-SOCS3-STAT1轴减弱草酸盐诱导的肾小管细胞损伤和凋亡。©2026英国和爱尔兰病理学会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

The Journal of Pathology 医学-病理学

CiteScore

14.10

自引率

1.40%

发文量

144

审稿时长

3-8 weeks

期刊介绍： The Journal of Pathology aims to serve as a translational bridge between basic biomedical science and clinical medicine with particular emphasis on, but not restricted to, tissue based studies. The main interests of the Journal lie in publishing studies that further our understanding the pathophysiological and pathogenetic mechanisms of human disease. The Journal of Pathology welcomes investigative studies on human tissues, in vitro and in vivo experimental studies, and investigations based on animal models with a clear relevance to human disease, including transgenic systems. As well as original research papers, the Journal seeks to provide rapid publication in a variety of other formats, including editorials, review articles, commentaries and perspectives and other features, both contributed and solicited.