Dysregulated Tryptophan Metabolism: Driving T Cell Subsets and PI3K-Akt Pathway Alterations in Hashimoto's Thyroiditis

Lijian Zhang¹Xinrui Zhou¹Tingwei Cheng¹Qiong Wang²Xiaoyan Pei²Lei Yu²Guoxi Jin^2*

• ¹Bengbu Medical University, Bengbu, Anhui Province, China
• ²Department of Endocrinology and Metabolism, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China

This study explored the role of tryptophan (Trp) metabolism in Hashimoto's thyroiditis (HT) pathogenesis using clinical samples and animal models, given the unclear mechanisms and limited treatments of HT. Methods: Clinically, serum Trp, lactic acid, and alanine levels in 10 HT patients and 10 healthy controls were measured by ELISA. In animal experiments, female C57BL/6 mice were divided into Con, HT, HT+T (Trp supplemented), and HT+I (Trp metabolism inhibitor IDO1/TDO-IN-4 treated) groups. After inducing autoimmune thyroiditis, various tests were conducted, including ELISA for inflammation factors, HE staining for thyroid pathology, flow cytometry for T cell subsets, RNA-seq for gene expression, Western Blotting for PI3K-Akt pathway proteins, and CIBERSORT for immune cell analysis. Results: HT patients had significantly lower serum Trp levels. The HT group showed thyroid damage and increased inflammation factors. Trp supplementation alleviated thyroid damage and reduced inflammation factors, while the inhibitor worsened them. Trp also regulated T cell subsets and immune cell environment. RNA-seq and Western Blotting indicated Trp's impact on immune response and PI3K-Akt pathway. Conclusion: Trp metabolism abnormality is associated with HT. Trp supplementation can alleviate HT progression by regulating T cell function and the PI3K-Akt pathway, while inhibiting Trp metabolism exacerbates it. This suggests Trp metabolism's potential as a therapeutic target for HT. Significance Statement: This study demonstrates significantly decreased serum Trp levels in HT patients, suggesting an association between Trp metabolic abnormalities and HT pathogenesis. By showing Trp's impact on inflammation, T cell subsets, and the PI3K-Akt pathway in animal models, it uncovers a novel mechanistic link. These findings highlight Trp supplementation as a potential therapeutic strategy to mitigate HT progression, offering a new avenue for managing this common endocrine disorder. The mechanistic insights into Trp's immunomodulatory effects advance understanding of HT and may inform future treatments targeting metabolic pathways in autoimmune endocrine diseases.