Abstract

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by immunological dysregulation and microbial dysbiosis in the colon. Although D-mannose has emerged as a promising candidate for the amelioration of UC, the underlying mechanisms remain incompletely defined. This study investigated the regulatory role of D-mannose in the gut microbiota-host gene axis in murine colitis and delineated the key signaling pathways involved. The results demonstrated that D-mannose markedly ameliorated colitis in mice, concomitant with obvious remodeling of the gut microbial ecosystem, as evidenced by altered α-diversity and β-diversity, an elevated gut microbiota health index, and a reduced dysbiosis index. Notably, the microbial taxa most responsive to D-mannose comprise Akkermansia muciniphila, Limosilactobacillus reuteri , and Lactobacillus johnsonii . Transcriptomic profiling revealed that D-mannose impeded the expression of ten hub genes ( Il6, Mmp9, Ccl2, Fgf2, Cxcl1, Ptgs2, Il1β, Timp1, Cxcl5 , and Spp1 ), which were upregulated in colonic tissue following DSS exposure. The abundance of A. muciniphila, L. reuteri , and L. johnsonii exhibited a negative correlation with the expression levels of Il6, Il1β, Ccl2, Mmp9, Timp1, Fgf2, Ptgs2 , and Spp1 . Enrichment analysis revealed the PI3K/AKT signaling pathway as a vital regulatory route in the D-mannose-driven mitigation of colitis. In vitro experiments on RAW264.7 macrophages indicated that D-mannose suppressed lipopolysaccharide-induced activation of AKT and its downstream NF-κB, resulting in a decrease in the expression of pro-inflammatory cytokines Il1β and Il6 . The molecular docking results further validated the molecular interaction between D-mannose and AKT. In summary, D-mannose ameliorates DSS-induced colitis by reshaping the gut microbiota-host gene axis and restraining PI3K/AKT/NF-κB signaling. These findings offer novel mechanistic insights into the role of D-mannose in mitigating colonic i