Background High fructose consumption induces disparate metabolic responses between mouse strains.Objective Our goal is to investigate the role of gut microbiota in the differential metabolic responses to fructose in genetically diverse mouse strains, namely, C57BL/6J (B6), DBA/2J (DBA), and FVB/NJ (FVB).Methods Eight-week old male mice of B6, DBA, and FVB strains were given 8% fructose in the drinking water for 12 weeks. Using 16S ribosomal RNA sequencing, the gut microbiota composition was analyzed from cecum and feces, and correlated with metabolic phenotypes and host gene expression in hypothalamus, liver, and adipose tissue to prioritize microbial taxa that may contribute to differential host fructose responses. Lastly, fecal transplant and Akkermansia muciniphila colonization experiments were conducted to test the causal role of gut microbiota in determining mouse strain-specific fructose responses.Results DBA mice consuming fructose demonstrated significant increases in body weight, adiposity, and glucose intolerance, which were accompanied by low baseline levels of Akkermansia , S24-7, and Turicibacter , compared to B6 and FVB mice which did not exhibit body mass and glycemic alterations. Additionally, fructose altered several microbial taxa that demonstrated strain-specific correlations with metabolic phenotypes and gene expression in host tissues. From the fecal microbiota transplant experiments between B6 and DBA, B6 microbes abrogated the fructose response in DBA mice by conferring resistance to weight and fat gain and glucose intolerance. Further, DBA mice receiving Akkermansia muciniphila , which was enriched in B6 and FVB, also mitigated fructose-induced metabolic dysfunctions.Conclusions Our findings support that differential microbiota composition between mouse strains is partially responsible for host metabolic sensitivity to fructose, and Akkermansia is one of the key responsible microbiota that confers resistance to fructose-induced dysregulation of adiposity and glycemic traits.

Host Genetic Background and Gut Microbiota Contribute to Differential Metabolic Responses to Fructose Consumption in Mice