肠道微生物群在代谢功能障碍相关脂肪肝病（MASLD）的发病机制中发挥着重要作用。白细胞介素 33 (IL-33) 在粘膜屏障位点高表达并调节肠道稳态。在此，我们旨在研究肠道IL-33在MASLD中的作用和机制。在患有MASLD的人和小鼠中，与对照相比，IL-33的肝脏表达及其对致瘤性2（ST2）的受体抑制没有显着变化。而在 MASLD 中，人类血清可溶性 ST2 水平以及小鼠肠道 IL-33 和 ST2 表达显着增加。小鼠体内整体或肠道 IL-33 的缺失可通过降低肠道屏障通透性和纠正肠道微生物群失调来缓解与 MASLD 相关的代谢紊乱、炎症和纤维化。移植 IL-33 缺陷小鼠的肠道微生物群可阻止野生型 (WT) 小鼠的 MASLD 进展。此外，IL-33 缺乏导致产生三甲胺 N-氧化物 (TMAO) 的细菌丰度减少。 3,3-二甲基-1-丁醇 (DMB) 抑制 TMAO 合成可减轻 MASLD 小鼠的肝脏氧化应激。核IL-33与缺氧诱导因子1α（HIF-1α）结合并抑制其激活，直接破坏肠道屏障的完整性。细胞外IL-33破坏肠道Th1/Th17的平衡，并通过ST2-Hif1a-Tbx21轴促进Th1分化。 ST2 敲除导致 MASLD 表型减弱，类似于在 IL-33 缺乏小鼠中观察到的情况。肠道 IL-33 通过对 HIF-1α 的双重调节增强肠道微生物群衍生的 TMAO 合成，并加剧 MASLD 进展。针对 IL-33 及其相关微生物群可能为管理 MASLD 提供潜在的治疗策略。版权所有 © 2024 作者。由 Wolters Kluwer Health, Inc. 出版

Gut microbiota play a prominent role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). Interleukin-33 (IL-33) is highly expressed at mucosal barrier sites and regulates intestinal homeostasis. Herein, we aimed to investigate the role and mechanism of intestinal IL-33 in MASLD.In both human and mice with MASLD, hepatic expression of IL-33 and its receptor suppression of tumorigenicity 2 (ST2) showed no significant change compared to controls, while serum soluble ST2 levels in humans, as well as intestinal IL-33 and ST2 expression in mice were significantly increased in MASLD. Deletion of global or intestinal IL-33 in mice alleviated metabolic disorders, inflammation and fibrosis associated with MASLD by reducing intestinal barrier permeability and rectifying gut microbiota dysbiosis. Transplantation of gut microbiota from IL-33 deficiency mice prevented MASLD progression in wild type (WT) mice. Moreover, IL-33 deficiency resulted in a decrease in the abundance of trimethylamine N-oxide (TMAO)-producing bacteria. Inhibition of TMAO synthesis by 3,3-dimethyl-1-butanol (DMB) mitigated hepatic oxidative stress in mice with MASLD. Nuclear IL-33 bound to hypoxia inducible factor-1α (HIF-1α) and suppressed its activation, directly damaging the integrity of intestinal barrier. Extracellular IL-33 destroyed the balance of intestinal Th1/Th17 and facilitated Th1 differentiation through the ST2-Hif1a-Tbx21 axis. Knockout of ST2 resulted in a diminished MASLD phenotype resembling that observed in IL-33 deficiency mice.Intestinal IL-33 enhanced gut microbiota-derived TMAO synthesis and aggravated MASLD progression through dual regulation on HIF-1α. Targeting IL-33 and its associated microbiota may provide a potential therapeutic strategy for managing MASLD.Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.