D‐Psicose Attenuates Hepatic Steatosis and Inflammatory Injury in HFD/STZ‐Induced T2DM Mice and Is Associated With Alterations in Gut Microbiota, Tryptophan Metabolism, and Hepatic AhR‐Related Signaling

Abstract

ABSTRACT D‐psicose (DPS) is a rare sugar with reported metabolic benefits, but its effects on diabetes‐associated liver abnormalities and related gut–liver changes remain insufficiently defined. Here, DPS was evaluated in mice with Type 2 diabetes mellitus induced by a high‐fat diet and streptozotocin. Low‐ and high‐dose DPS interventions were assessed through serum biochemistry, liver histology, inflammatory cytokine measurements, intestinal barrier evaluation, hepatic molecular analysis, 16S rRNA gene sequencing, targeted quantification of tryptophan metabolites, and untargeted serum metabolomics. Relative to untreated diabetic mice, DPS‐treated animals showed improved serum lipid profiles, lower ALT and AST activities, reduced circulating inflammatory cytokines, and less hepatic lipid deposition. DPS treatment was also accompanied by improved intestinal morphology, increased ZO‐1 and Occludin expression, and lower circulating lipopolysaccharide concentrations. In the high‐dose group, gut microbial community composition differed from that of untreated diabetic mice, with relative increases in Akkermansia and Lactobacillus. In parallel, DPS treatment was associated with increased serum tryptophan and indole‐3‐propionic acid concentrations, lower kynurenine concentrations and Kyn/Trp ratios, reduced hepatic TDO2 expression, increased AhR expression, and lower NF‐κB p65 phosphorylation. Overall, DPS improved metabolic and liver‐related abnormalities in diabetic mice and was accompanied by coordinated changes in intestinal barrier‐related indices, gut microbial composition, tryptophan metabolites, and hepatic AhR/NF‐κB‐related markers. As microbiota‐directed and AhR‐targeted intervention experiments were not conducted, these observations remain associative and do not demonstrate a causal gut microbiota–tryptophan–AhR mechanism. Moreover, as these observations were obtained in a single HFD/STZ‐induced mouse model, their relevance to the heterogeneity and natural course of human T2DM‐associated MASLD requires confirmation in additional preclinical models and clinical studies.