Both host genotypes and gut microbiota play a role in dietary responses and the control of host phenotypes. High fructose consumption has been strongly implicated in metabolic disorders including obesity, insulin resistance and diabetes, but individual variability in susceptibility has not been examined in diverse genetic backgrounds. We investigated the strain-specific response to fructose in terms of the shifts in gut microbiota as well as host phenotypes related to body mass, glycemic traits, and glucose intolerance using three mouse strains, C57BL/6 (B6), DBA, and FVB. After treatment with 8% fructose water for 12 weeks, the DBA mice demonstrated increased body weight, adiposity, plasma insulin, and glucose intolerance, whereas B6 and FVB mice were resistant to fructose-induced metabolic alterations. We also conducted 16S rRNA-sequencing analysis of gut microbiota and found that DBA had higher Firmicutes/Bacteriodetes ratio and lower basal levels of Turicibacter, Akkermansia, and S24-7_g compared to B6 and FVB. These microbes were correlated with body weight, adiposity, or glucose tolerance. To test the influence of gut microbiota on metabolic phenotypes, we performed fecal transplant by administering the B6 fecal content to DBA mice and vice versa. DBA mice with B6 fecal transplant stayed glucose tolerant and lean with fructose treatment, suggesting that B6 microbes attenuated fructose response in DBA mice. Our findings suggest that fructose induces strain-specific metabolic and microbiota responses, and gut microbiota are partially responsible for fructose sensitivity among mice with different genetic backgrounds.


I. Ahn: None. J. Lang: None. Z. Ying: None. H. Byun: None. G. Zhang: None. C. Olson: None. E. Hsaio: None. A. Lusis: None. F. Gomez-Pinilla: None. X. Yang: None.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at