Yang Weili, Xu Xinyu, Xie Rongrong, Lin Jiaqi, Hou Zhijia, Xin Zhong, Cao Xi, Shi Tingting
Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100176, China.
J Endocrinol Invest. 2025 May 27. doi: 10.1007/s40618-025-02593-6.
Graves' orbitopathy (GO) is a sight-threatening organ-specific autoimmune disease with complicated pathogenesis. Gut microbiota-derived tryptophan (Trp) metabolites play important roles in immune-related diseases, but their role in GO remains unknown.
Trp metabolism-associated gut flora was analyzed by 16 S sequencing in GO patients and controls. Serum metabolomics profiling was performed to assess Trp metabolic pathway. Trp metabolites levels were measured by ELISA in 401 serum samples from a case-control study, and their effects on inflammation and proliferation in orbital fibroblasts were evaluated in vitro.
Trp metabolism-associated gut flora, including phylum Firmicutes and genus Anaerostipes, were significantly down-regulated in GO patients. Serum metabolomics revealed significant enrichment of Trp metabolic pathway in both GO and Graves' disease (GD) groups. Serum levels of indolepropionic acid (IPA), indole-3-lactate (ILA), and indoleacetic acid (IAA) were significantly decreased in both GD and GO patients compared to controls, with IAA levels further reduced in GO compared to GD patients. Notably, active GO patients had significantly lower IAA levels compared to inactive ones. Moreover, the levels of IAA were negatively correlated with clinical activity score and serum thyrotropin receptor antibody (TRAb) in GO patients. In vitro, IPA, ILA, and IAA mitigated TNFα-induced inflammation and proliferation in orbital fibroblasts by suppressing the Akt signaling pathway.
Trp metabolites IAA maybe a novel biomarker for GO progression. And IPA, ILA and IAA may play a protective role in GO by regulating inflammation and proliferation in orbital fibroblasts, suggesting their potential as therapeutic targets for GO treatment.
格雷夫斯眼眶病（GO）是一种威胁视力的器官特异性自身免疫性疾病，发病机制复杂。肠道微生物群衍生的色氨酸（Trp）代谢产物在免疫相关疾病中起重要作用，但其在GO中的作用尚不清楚。
通过16S测序分析GO患者和对照组中与Trp代谢相关的肠道菌群。进行血清代谢组学分析以评估Trp代谢途径。在一项病例对照研究的401份血清样本中，采用酶联免疫吸附测定法测量Trp代谢产物水平，并在体外评估它们对眼眶成纤维细胞炎症和增殖的影响。
GO患者中与Trp代谢相关的肠道菌群，包括厚壁菌门和厌氧棒菌属，显著下调。血清代谢组学显示GO组和格雷夫斯病（GD）组中Trp代谢途径均显著富集。与对照组相比，GD和GO患者血清中吲哚丙酸（IPA）、吲哚-3-乳酸（ILA）和吲哚乙酸（IAA）水平均显著降低，与GD患者相比，GO患者的IAA水平进一步降低。值得注意的是，活动期GO患者的IAA水平明显低于非活动期患者。此外，GO患者中IAA水平与临床活动评分和血清促甲状腺素受体抗体（TRAb）呈负相关。在体外，IPA、ILA和IAA通过抑制Akt信号通路减轻TNFα诱导的眼眶成纤维细胞炎症和增殖。
Trp代谢产物IAA可能是GO进展的一种新型生物标志物。IPA、ILA和IAA可能通过调节眼眶成纤维细胞的炎症和增殖在GO中发挥保护作用，提示它们作为GO治疗靶点的潜力。
