Background: Over the past decades, dietary fructose consumption has increased dramatically due to the widespread use of sucrose and high-fructose corn syrup in processed foods and beverages. Excessive fructose intake is strongly associated with obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), insulin resistance, type 2 diabetes, and cardiovascular disease. Although fructose is well known to stimulate hepatic de novo lipogenesis, emerging evidence indicates that its metabolic effects are critically influenced by intestinal metabolism and the gut microbiota. Intestinal gluconeogenesis limits hepatic fructose exposure by metabolizing dietary fructose, whereas microbial fermentation converts fructose into the short-chain fatty acid (SCFA) acetate, a precursor of hepatic acetyl-CoA that fuels de novo lipogenesis, promoting lipid accumulation and metabolic dysfunction.

Hypothesis and Aim: We hypothesized that harnessing the metabolic capacity of gut bacteria to consume dietary fructose could protect the liver and adipose tissue from fructose-induced lipotoxicity. Desulfovibrio fructosovorans is a unique member of the Desulfovibrio genus because of its ability to utilize fructose as a carbon and energy source. We therefore investigated whether supplementation with D. fructosovorans modulates fructose metabolism and improves metabolic outcomes in diet-induced obese (DIO) mice exposed to a high-fat, high-fructose diet.

Methods: DIO mice (n = 18) were fed a high-fat diet (HFD) supplemented with 15% fructose in the drinking water for six weeks before being randomized to receive placebo or D. fructosovorans (10⁸ or 10⁹ CFU). Treatment continued for an additional six weeks while mice remained on the HFD/fructose regimen. Fructose metabolism and SCFA production were assessed by ¹³C metabolic flux analysis, together with metabolic phenotyping and analysis of intestinal gene expression.

Results: Supplementation with D. fructosovorans reduced microbial conversion of dietary fructose into SCFAs, indicating decreased production of lipogenic metabolites. Mice receiving the high bacterial dose exhibited reduced body weight gain, lower liver and subcutaneous adipose tissue weights, and improved fasting glucose levels compared with placebo-treated controls. In addition, intestinal passage of D. fructosovorans altered the expression of genes involved in intestinal gluconeogenesis, suggesting enhanced host intestinal fructose metabolism.

Conclusions: D. fructosovorans reshapes both microbial and host intestinal fructose metabolism, thereby limiting the availability of fructose-derived substrates that fuel hepatic lipogenesis and adiposity. These findings identify fructose-metabolizing gut bacteria as a promising microbiome-based therapeutic strategy to protect against fructose-induced metabolic dysfunction through modulation of the gut–liver axis.