Sucrose-free low-fat diet induces metabolic dysfunction through gut dysbiosis and colonic inflammation in mice.

Low-fat diets are widely promoted as health-protective; however, the consequences of removing sucrose within a low-fat dietary framework remain unclear. Here, we investigated the effects of a sucrose-free low-fat diet (SF-LFD) compared with a sucrose-containing low-fat control diet (C-LFD) in mice (n=6/group) over 16 weeks. Despite unchanged body and liver weights, SF-LFD feeding resulted in impaired glucose tolerance, reduced insulin sensitivity, and broad alterations in circulating metabolic hormones, including elevated C-peptide, incretins, ghrelin, and resistin, as well as reduced fasting insulin. 16S rRNA sequencing revealed that SF-LFD markedly disrupted gut microbial diversity and composition, with depletion of short-chain fatty acid-producing commensals, including Lactobacillus murinus and members of the Lachnospiraceae family, and enrichment of taxa associated with inflammatory or stress-adapted states, including Helicobacter ganmani, Odoribacter splanchnicus, and Alistipes species. This dysbiosis was accompanied by pronounced colonic inflammation characterized by crypt architectural disruption, loss of goblet cells, submucosal expansion, increased CD3