Phytosphingosine alleviates DSS-induced colitis by regulating the gut microbiota and inflammatory responses

Inflammatory bowel disease is becoming increasingly prevalent and represents a major concern in global public health. However, conventional therapies often come with various adverse effects. Phytosphingosine (PS), a key metabolite in sphingolipid metabolism, is widely found in plants and fungi and possesses notable anti-inflammatory properties. In this study, we aimed to evaluate the protective effects of PS against dextran sulfate sodium (DSS)-induced experimental colitis in mice and elucidate its underlying mechanisms. Our results showed that oral administration of PS significantly alleviated DSS-induced colonic injury and reduced levels of proinflammatory cytokines such as TNF-α and IL-1β. Additionally, PS improved intestinal barrier function disrupted by DSS, as indicated by increased expression of mucin-2 and tight junction proteins. Furthermore, PS suppressed the activation of the NF-κB signaling pathway, oxidative stress and enhanced PPARγ expression. We also observed that PS mitigated DSS-induced gut dysbiosis in mice, characterized by an increase in Bacteroidota and a decrease in Proteobacteria . To explore the role of the gut microbiota in PS-mediated protection against colitis, fecal microbiota transplantation (FMT) was conducted in DSS-treated mice. Recipients of FMT from PS-treated donors exhibited reduced inflammatory responses and improved intestinal integrity, accompanied by a higher abundance of Bacteroidota in the gut. Additionally, PS treatment modified the profile of short-chain fatty acids in the mice, with a notable increase in the levels of butyrate and propionate. Overall, our findings demonstrate that PS attenuates DSS-induced colitis in mice through modulation of the gut microbiota, providing a potential strategy for IBD intervention via microbiota regulation.