Sulforaphane alleviates DSS-induced colitis and gut-brain axis dysfunction potentially via microbiota-metabolism-HIF-1α crosstalk.

Ulcerative colitis (UC) is a chronic inflammatory disorder of the gastrointestinal tract, often accompanied by anxiety- and depression-like symptoms, which are closely associated with gut microbiota dysbiosis, metabolic disturbances, immune activation, and dysfunction of the gut-brain axis. Sulforaphane (SFN), a natural isothiocyanate, has been demonstrated in our previous studies to alleviate colitis in mice; however, its effects on UC-associated neurobehavioral abnormalities remain unclear. In this study, a dextran sulfate sodium (DSS)-induced colitis model was employed to investigate the effects of SFN on colitis and associated behavioral abnormalities. SFN significantly alleviated colitis symptoms and improved anxiety- and depression-like behaviors, accompanied by enhanced hippocampal structure and function. Mechanistically, SFN improved intestinal barrier integrity by increasing goblet cell abundance, upregulating MUC2 expression, and normalizing the expression of tight junction proteins, including Occludin, Claudin-1, Claudin-5, and ZO-1. SFN attenuated both peripheral and central inflammation responses and promoted anti-inflammatory macrophage polarization. In addition, SFN partially restored gut microbiota composition, increased short-chain fatty acid production, and improved amino acid and energy metabolism. DSS-induced colitis was associated with increased HIF-1α expression and glycolytic activation, whereas SFN inhibited HIF-1α signaling and downregulated the expression of glycolysis-related genes (Glut1, Pfkl, Ldha). GEO database analysis revealed that HIF-1α expression was significantly elevated in patients with active UC compared with both health controls and patients with inactive UC. Collectively, SFN ameliorates colitis and associated behavioral abnormalities, potentially through modulation of gut microbiota composition, metabolic reprogramming, and HIF-1α-related immunometabolic pathways.