Dietary L-arginine supplementation exerts preventive effects on colitis through modulation of the gut microbiota

Background Ulcerative colitis (UC) is a chronic, relapsing gastrointestinal disease that imposes an increasing global health burden. Our previous study showed that L-arginine (Arg) could markedly alleviate experimental colitis; however, the relative efficacy of its prophylactic versus therapeutic intervention remains unclear, and the underlying mechanisms require further elucidation. Methods Mice received Arg supplementation either prior to DSS exposure (BeArg) or during DSS treatment (DuArg). Intestinal barrier function, inflammatory cytokines and gut microbiota alterations were evaluated, followed by fecal microbiota transplantation (FMT) validation. Results BeArg markedly alleviated DSS-induced mice body weight loss, disease activity index (DAI) elevation, and colon shortening, exhibiting a protective efficacy comparable to full-course Arg administration. BeArg also lowered serum lipopolysaccharide, consistent with improved intestinal barrier integrity. In addition, BeArg reduced the expression of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) while augmenting interleukin-10 (IL-10) at both the transcriptional and protein levels. By comparison, DuArg produced only modest clinical improvement and showed limited efficacy in modulating barrier dysfunction and inflammatory responses. 16S rRNA sequencing revealed that BeArg and Arg interventions induced similar alterations in the gut microbial community structure, while FMT further confirmed that Arg-mediated remodeling of the gut microbiota effectively protected against DSS-induced colitis. Conclusion These data indicate that Arg exerts a prophylactic effect against colitis by modulating the gut microbiota, underscoring the pivotal role of intervention timing in optimizing its protective effects.