Abstract
Oxidative stress and intestinal inflammation are main pathological features of ulcerative colitis (UC). Ferroptosis, characterized by iron accumulation and lipid peroxidation, is closely related to the pathologic process of UC. 16S rRNA sequencing for intestinal microbiota analysis and gas chromatography-mass spectrometry (GC-MS) for short-chain fatty acid (SCFA) contents clearly demonstrated lower amounts of butyrate-producing bacteria and butyrate in colitis mice. However, the precise mechanisms of sodium butyrate (NaB) in treating UC remain largely unclear. We found that ferroptosis occurred in colitis models, as evidenced by the inflammatory response, intracellular iron level, mitochondria ultrastructural observations and associated protein expression. NaB inhibited ferroptosis in colitis, significantly rescued weight loss and colon shortening in mice and reduced inflammatory lesions and mitochondrial damage. Furthermore, NaB improved intestinal barrier integrity and markedly suppressed the expression of pro-ferroptosis proteins. Conversely, the protein expression of anti-ferroptosis markers including nuclear factor erythroid-related Factor 2 (Nrf2) and glutathione peroxidase 4 (GPX4), was significantly upregulated with NaB treatment. Moreover, the knockdown of Nrf2 reversed the anti-colitis effect of NaB. Taken together, NaB exhibited a protective effect by ameliorating ferroptosis in experimental colitis through Nrf2/GPX4 signaling and improving intestinal barrier integrity, which provides a novel mechanism for NaB prevention of UC.
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