Dietary fiber inulin enables intestinal microbiome to clear fructose and protect the host

Excessive consumption of fructose leads to various cardiometabolic diseases. However, inulin, dietary fiber composed of numerous fructose molecules, exerts health-beneficial effects. Here we report that inulin shifts fructose catabolism from the host organs to gut microbiome, reversing fructose-induced hyperlipidemia, hepatic steatosis and systemic glucose intolerance. Both simultaneous and delayed inulin intake enhances fructose clearance by the small intestinal microbiome, effectively reducing fructose dose reaching the liver and colon and thus suppressing hepatic lipogenesis. Inulin also activates the hepatic de novo serine synthesis pathway and cystine uptake to augment glutathione production and reduce oxidative stress. This dual effect of inulin is blocked by antibiotics and transmittable by fecal transplantation. Moreover, inulin-enriched Bacteroides acidifaciens is protective against HFCS-induced lipogenesis. Our data provide mechanistic insights into how fructose-polymer fiber inulin rewires gut microbial fructose catabolism and protects the host from excessive fructose exposure, paving the way to mitigate fructose-induced metabolic disease. 8–week-old male C57BL/6 mice were fed either control (Research diets, D21050401) or 10% (gm%) inulin diet (Research diets, D21050402) for 30 weeks. To investigate the effect of inulin supplementation with HFCS, mice were assigned into five groups (n = 9): (1) consumed control diet with normal water (C); (2) inulin diet with normal water (I); (3) control diet with HFCS water (CF); (4) inulin diet with HFCS water (IF); (5) switched from control diet to inulin diet with continual provision of HFCS water (CIF). For HFCS water, mice were provided either normal water or 15% (weight/volume) 1:1 mixture of glucose and fructose in water to mimic high fructose corn syrup. After 30 weeks of feeding, liver tissues were quickly dissected and snap-frozen in liquid nitrogen with a pre-cooled Wollenberger clamp and subjected to RNA-sequencing.