Theraputic effect of D-allose on IBD
Background and Objectives: Inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn's disease, are associated with a high risk of carcinogenesis especially in ulcerative colitis. The rare sugar D-allose, a D-glucose epimer, has been reported to have antioxidant and antitumor effects. This study investigated the effects of D-allose on gut microbiota and macrophage function and its therapeutic efficacy using a colitis-associated carcinogenesis model mouse.  Methods: Mouse macrophage RAW 264.7 cells were subjected to RNA sequencing, quantitative PCR, and evaluation of migration, reactive oxygen species (ROS) production, mitochondrial potential, and endoplasmic reticulum (ER) stress. The intestinal tissues of IBD patients were used to evaluate the expression of macrophages and ER stress markers with immunohisochemistry. A colitis-associated carcinogenesis model mouse was created by intraperitoneal administration of azoxymethane (AOM) and oral administration of 2% dextran sodium sulfate (DSS) in drinking water (three weekly repeated doses) (AOM/DSS group). Oral administration of D-allose (1 g/kg BW) in drinking water was started one week after the final DSS administration. Fecal samples were used for amplicon sequencing of microbiota.  Results: In RAW 264.7 cells, D-allose inhibited LPS-induced upregulation of the ER stress associated genes, inflammatory cytokine production, migration, ROS production, and decrease in mitochondrial potential. D-allose suppressed the thapsigargin-induced upregulation of ER stress markers BIP and CHOP. The colon tissues of IBD patients showed increased macrophage infiltration and co-expression with BIP and CHOP in both inflamed and carcinomatous area. D-allose treatment suppressed tumor number, gastrointestinal  bleeding, inflammatory cytokine expression, macrophage infiltration, and the number of BIP- and CHOP-expressing cells in AOM/DSS group. Alpha diversity (Chao1 index, Shannon index) of the intestinal microbiota was significantly reduced in the AOM/DSS group. D-allose treatment significantly increased alpha diversity (Chao1 index, Shannon index) in the normal group and alpha diversity (Faith's Phylogenetic Diversity) in the AOM/DSS group. Significant differences in beta diversity (Jaccard, Bray-Curtis) were observed among all four groups: control, D-allose, AOM/DSS, and AOM/DSS+D-allose.  Conclusion: D-allose suppressed inflammation and tumor growth in a mouse model of colitis-associated carcinogenesis by restoring gut microbiota diversity and macrophage function. This suggests that D-allose is a promising therapeutic and preventive agent for IBD and inflammation-associated carcinogenesis