ORF07-04 - Sucrose-Free Low-Fat Diet Induces Metabolic Dysfunction through Gut Dysbiosis and Colonic Inflammation in Mice

Low-fat diets are often promoted for their health benefits, yet the effects of sucrose elimination within this dietary framework are not well understood. In this study, we examined the impacts of a sucrose-free low-fat diet (SF-LFD) compared to a sucrose-containing low-fat control diet (C-LFD) in mice over 16 weeks. Although body and liver weights remained unchanged, SF-LFD feeding resulted in impaired glucose tolerance, reduced insulin sensitivity, and significant alterations in circulating metabolic hormones, including increased levels of C-peptide, incretins, ghrelin, and resistin, along with decreased fasting insulin. 16S rRNA sequencing revealed that SF-LFD notably disrupted gut microbial diversity and composition, leading to a depletion of short-chain fatty acid–producing commensals (such as Lactobacillus murinus and Lachnospiraceae) and an enrichment of pro-inflammatory or stress-adapted taxa (including Helicobacter ganmani, Odoribacter splanchnicus, and Alistipes spp.). This dysbiosis was associated with significant colonic inflammation, characterized by crypt architectural disruption, loss of goblet cells, submucosal expansion, and increased infiltration of CD3⁺ T cells and F4/80⁺ macrophages, alongside robust upregulation of inflammatory mediators such as IL-1β, IL-6, CCL2, RORγt, and TBX21. Moreover, consistent with activation of the gut-liver axis, SF-LFD induced hepatic microvesicular steatosis, lobular inflammation, and recruitment of F4/80⁺ and CD11c⁺ immune cells, along with elevated hepatic expression of IL-1β and IL-6. These findings suggest that the elimination of sucrose from a low-fat diet disrupts gut microbiota, impairs metabolic homeostasis, and promotes inflammation in both the gut and liver, highlighting an unrecognized dietary trigger of metabolic dysfunction.