ADT-OH improves intestinal barrier function and remodels the gut microbiota in DSS-induced colitis

Abstract

Owing to the increasing incidence and prevalence of inflammatory bowel disease (IBD) worldwide, effective and safe treatments for IBD are urgently needed. Hydrogen sulfide (H₂S) is an endogenous gasotransmitter and plays an important role in inflammation. To date, H₂S-releasing agents are viewed as potential anti-inflammatory drugs. The slow-releasing H₂S donor 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH), known as a potent therapeutic with chemopreventive and cytoprotective properties, has received attention recently. Here, we reported its anti-inflammatory effects on dextran sodium sulfate (DSS)-induced acute (7 days) and chronic (30 days) colitis. We found that ADT-OH effectively reduced the DSS-colitis clinical score and reversed the inflammation-induced shortening of colon length. Moreover, ADT-OH reduced intestinal inflammation by suppressing the nuclear factor kappa-B pathway. In vivo and in vitro results showed that ADT-OH decreased intestinal permeability by increasing the expression of zonula occludens-1 and occludin and blocking increases in myosin II regulatory light chain phosphorylation and epithelial myosin light chain kinase protein expression levels. In addition, ADT-OH restored intestinal microbiota dysbiosis characterized by the significantly increased abundance of Muribaculaceae and Alistipes and markedly decreased abundance of Helicobacter, Mucispirillum, Parasutterella, and Desulfovibrio. Transplanting ADT-OH-modulated microbiota can alleviate DSS-induced colitis and negatively regulate the expression of local and systemic proinflammatory cytokines. Collectively, ADT-OH is safe without any short-term (5 days) or long-term (30 days) toxicological adverse effects and can be used as an alternative therapeutic agent for IBD treatment.

Keywords

inflammatory bowel disease / ADT-OH / intestinal permeability / gut microbiota

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Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-023-0990-1 and is accessible for authorized users.

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Zhiqian Bi, Chen Jia, Xiaoyao Chang, Dangran Li, Yingying Yao, Fangfang Cai, Huangru Xu, Jian Cheng, Zichun Hua, Hongqin Zhuang declare that they have no conflicts of interest. Animal welfare and experimental procedures were performed in strict accordance with high standard animal welfare and other related ethical regulations approved by the Nanjing University Animal Care and Use Committee.

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