Department of Ultrasound, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China.
Key Laboratory of National Health Commission for Forensic Sciences, School of Medicine and Forensics, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
J Transl Med. 2024 Nov 20;22(1):1045. doi: 10.1186/s12967-024-05876-3.
Hashimoto's thyroiditis (HT) is an autoimmune disorder with unclear molecular mechanisms. While current diagnosis is well-established, understanding of the gut-thyroid axis in HT remains limited. This study aimed to uncover novel molecular signatures in HT by integrating gut metagenome and host transcriptome data (miRNA/mRNA), potentially elucidating disease pathogenesis and identifying new therapeutic targets.
We recruited 31 early HT patients and 30 healthy controls in a two-stage study (discovery and validation). Blood and fecal samples underwent RNA and metagenomic sequencing, respectively. Integrative analysis included differential expression, weighted correlation network, correlation and random forest analyses. Regression models and ROC curve analysis were used to evaluate the significance of identified molecular signatures in HT.
Integrative analysis revealed subtle changes in gut microbiota diversity and composition in early HT, increased abundance of Bacillota_A and Spirochaetota at the phylum level, and significant differences in 24 genera and 67 species. Ecological network analysis indicated an imbalance in the gut microbiota with reduced inhibitory interactions against pathogenic genera in HT. Functional analysis showed changes in infection- and immune-related pathways. Three characteristic species (Salaquimonas_sp002400845, Clostridium_AI_sp002297865, and Enterocloster_citroniae) were identified as most relevant to HT. Analysis of miRNA and mRNA expression profiles uncovered pathways related to immune response, inflammation, infection, metabolism, proliferation, and thyroid cancer in HT. Based on correlations with HT and interactions between them, six characteristic RNAs (hsa-miR-548aq-3p, hsa-miR-374a-5p, GADD45A, IRS2, SMAD6, WWTR1) were identified. Furthermore, our study uncovered significant gut microbiota-host transcriptome interactions in HT, revealing enrichment in metabolic, immune, and cancer-related pathways, particularly with strong associations among those 9 key molecular signatures. The validation stage confirmed improved HT classification accuracy by combining these signatures (AUC = 0.95, ACC = 0.85), suggesting their potential significance in understanding HT pathogenesis.
Our study reveals novel molecular signatures linking gut microbiome and host transcriptome in HT, providing new insights into the disease pathogenesis. These findings not only enhance our understanding of the gut-thyroid axis but also suggest potential new directions for therapeutic interventions in HT.
桥本甲状腺炎（HT）是一种病因不明的自身免疫性疾病。目前的诊断方法已经很成熟，但对 HT 中肠道-甲状腺轴的了解仍有限。本研究旨在通过整合肠道宏基因组和宿主转录组数据（miRNA/mRNA）来揭示 HT 中的新分子特征，从而可能阐明疾病发病机制并确定新的治疗靶点。
我们在一项两阶段研究（发现和验证）中招募了 31 名早期 HT 患者和 30 名健康对照者。血液和粪便样本分别进行 RNA 和宏基因组测序。整合分析包括差异表达、加权相关网络、相关性和随机森林分析。回归模型和 ROC 曲线分析用于评估在 HT 中识别的分子特征的重要性。
整合分析显示，早期 HT 中肠道微生物多样性和组成发生了微妙变化，厚壁菌门和螺旋体门的丰度增加，24 个属和 67 个种存在显著差异。生态网络分析表明，HT 中肠道微生物群落的平衡被打破，对致病性属的抑制作用减弱。功能分析显示，感染和免疫相关途径发生了变化。三种特征物种（Salaquimonas_sp002400845、Clostridium_AI_sp002297865 和 Enterocloster_citroniae）被确定与 HT 最相关。miRNA 和 mRNA 表达谱分析揭示了与 HT 相关的免疫反应、炎症、感染、代谢、增殖和甲状腺癌相关的途径。基于与 HT 的相关性及其相互作用，确定了六个特征 RNA（hsa-miR-548aq-3p、hsa-miR-374a-5p、GADD45A、IRS2、SMAD6 和 WWTR1）。此外，我们的研究还揭示了 HT 中肠道微生物群与宿主转录组之间的显著相互作用，这些作用在代谢、免疫和癌症相关途径中得到了富集，特别是这 9 个关键分子特征之间存在强烈的关联。验证阶段通过结合这些特征（AUC=0.95，ACC=0.85），证实了对 HT 分类准确性的改善，这表明它们在理解 HT 发病机制方面具有潜在的意义。
本研究揭示了 HT 中肠道微生物群和宿主转录组之间的新分子特征，为疾病发病机制提供了新的见解。这些发现不仅增强了我们对肠道-甲状腺轴的理解，而且为 HT 的治疗干预提供了新的潜在方向。
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