Illustration of Gut-Thyroid Axis in Alcohol Use Disorder: Interplay of Gut Dysfunction, Pro-Inflammatory Responses, and Thyroid Function.
Illustration of Gut-Thyroid Axis in Alcohol Use Disorder: Interplay of Gut Dysfunction, Pro-Inflammatory Responses, and Thyroid Function.
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DOI：
10.3390/cells11193100
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发表时间：
2022-10-01
期刊：
影响因子：
6
通讯作者：
Vatsalya V
中科院分区：
文献类型：
--
作者：
Sagaram M;Royer AJ;Hu H;Rajhans A;Parthasarathy R;Krishnasamy SS;Mokshagundam SP;Kong M;Schwandt ML;Parajuli D;Cave MC;Vatsalya V
（1）背景：长期大量饮酒会导致肠道功能紊乱，并伴有促炎状态。甲状腺相关激素和蛋白质可能会因长期大量饮酒而失调；然而，到目前为止，肠道功能改变对甲状腺功能影响的机制尚未得到研究。本研究探讨了酒精诱导的肠道功能障碍和促炎细胞因子谱在酒精使用障碍（AUD）患者甲状腺功能中的作用。
（2）方法：将男性和女性AUD患者（n = 44）分为两组，第1组为促甲状腺激素（TSH）水平正常的患者（n = 28，0.8≤TSH≤3 mIU/L）；第2组为临床TSH水平升高的患者（n = 16，TSH>3 mIU/L）。分析了人口统计学数据、饮酒量、综合代谢指标以及候选甲状腺标志物（TSH、循环三碘甲状腺原氨酸（T3）和游离甲状腺素（fT4））。还评估了与肠道功能障碍相关的标志物（脂多糖（LPS）、LPS结合蛋白（LBP）和可溶性LPS诱导的病原体相关蛋白（sCD14））以及候选促炎细胞因子（白细胞介素 - 1β、肿瘤坏死因子 - α、白细胞介素 - 6、白细胞介素 - 8、单核细胞趋化蛋白 - 1、纤溶酶原激活物抑制剂 - 1）。
（3）结果：两组患者的身体质量指数（BMI）都处于临界超重类别。第2组报告的慢性和大量饮酒模式指数在数值上高于第1组。两组的fT4水平均升高，而T3在正常范围内。与第1组相比，第2组的肠道功能障碍标志物LBP和sCD14在数值上升高，表明存在细微的持续变化。第2组的候选促炎细胞因子显著升高，包括白细胞介素 - 1β、单核细胞趋化蛋白 - 1和纤溶酶原激活物抑制剂 - 1。在以LBP、sCD14和纤溶酶原激活物抑制剂 - 1水平作为肠道 - 甲状腺通路上游变量的多元回归模型中，第2组对肠道 - 免疫 - 甲状腺反应（r = 0.896，p = 0.002）对TSH水平有强烈且具有统计学意义的影响。此外，受试者工作特征曲线（AUROC）分析表明，第2组中的许多细胞因子对TSH有很强的预测作用，包括白细胞介素 - 6（面积 = 0.774，p < 0.001）和肿瘤坏死因子 - α（面积 = 0.708，p = 0.017）等。在第1组中未观察到这种情况。第2组显示fT4以及TSH升高，这表明存在亚临床甲状腺炎，伴有潜在的中枢神经系统功能障碍以及缺乏负反馈回路。
（4）结论：这些发现揭示了长期大量饮酒的毒性作用，通过肠 - 脑轴在甲状腺失调中起到病理作用。这些结果还强调了在AUD的整体医疗管理中仔细评估甲状腺失调的潜在方向。
(1) Background: Heavy and chronic alcohol drinking leads to altered gut dysfunction, coupled with a pro-inflammatory state. Thyroid-associated hormones and proteins may be dysregulated by heavy and chronic alcohol intake; however, the mechanism for altered gut-derived changes in thyroid function has not been studied thus far. This study investigates the role of alcohol-induced gut dysfunction and pro-inflammatory cytokine profile in the thyroid function of patients with alcohol use disorder (AUD). (2) Methods: Male and female AUD patients (n = 44) were divided into Gr.1, patients with normal thyroid-stimulating hormone (TSH) levels (n = 28, 0.8 ≤ TSH ≤ 3 mIU/L); and Gr.2, patients with clinically elevated TSH levels (n = 16, TSH > 3 mIU/L). Demographics, drinking measures, comprehensive metabolic panels, and candidate thyroid markers (TSH, circulating triiodothyronine (T3), and free thyroxine (fT4)) were analyzed. Gut-dysfunction-associated markers (lipopolysaccharide (LPS), LPS-binding protein (LBP), and soluble LPS-induced pathogen-associated protein (sCD14)), and candidate pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-8, MCP-1, PAI-1) were also evaluated. (3) Results: Patients in both groups presented with a borderline overweight BMI category. Gr.2 reported numerically higher indices of chronic and heavy drinking patterns than Gr.1. The fT4 levels were elevated, while T3 was within normal limits in both groups. The gut dysfunction markers LBP and sCD14 were numerically elevated in Gr.2 vs. Gr.1, suggesting subtle ongoing changes. Candidate pro-inflammatory cytokines were significantly elevated in Gr.2, including IL-1 β, MCP-1, and PAI-1. Gr.2 showed a strong and statistically significant effect on the gut–immune–thyroid response (r = 0.896, 36 p = 0.002) on TSH levels in a multivariate regression model with LBP, sCD14, and PAI-1 levels as upstream variables in the gut–thyroid pathway. In addition, AUROC analysis demonstrated that many of the cytokines strongly predicted TSH in Gr.2, including IL-6 (area = 0.774, 39 p < 0.001) and TNF-α (area = 0.708, p = 0.017), among others. This was not observed in Gr.1. Gr.2 demonstrated elevated fT4, as well as TSH, which suggests that there was subclinical thyroiditis with underlying CNS dysfunction and a lack of a negative feedback loop. (4) Conclusions: These findings reveal the toxic effects of heavy and chronic drinking that play a pathological role in thyroid gland dysregulation by employing the gut–brain axis. These results also emphasize potential directions to carefully evaluate thyroid dysregulation in the overall medical management of AUD.
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