Intestinal IL-33 promotes microbiota-derived trimethylamine N-oxide synthesis and drives metabolic dysfunction-associated steatotic liver disease progression by exerting dual regulation on HIF-1α

• Published in: Hepatology (Baltimore, Md.)
• Main Authors: Hai, Suping, Li, Xitang, Xie, Erliang, Wu, Wenhui, Gao, Qiang, Yu, Binghui, Hu, Junjian, Xu, Feiyang, Zheng, Xizhe, Zhang, Bin-Hao, Wu, Di, Yan, Weiming, Ning, Qin, Wang, Xiaojing
• Format: Journal Article
• Language: English
• Published: United States 10.07.2024
• ISSN: 0270-9139; 1527-3350; 1527-3350
• DOI: 10.1097/HEP.0000000000000985

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.