Dietary fibre-adapted gut microbiome clears dietary fructose and reverses hepatic steatosis

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Abstract
Excessive consumption of the simple sugar fructose, which induces excessive hepatic lipogenesis and gut dysbiosis, is a risk factor for cardiometabolic diseases. Here we show in male mice that the gut microbiome, when adapted to dietary fibre inulin, catabolizes dietary fructose and mitigates or reverses insulin resistance, hepatic steatosis and fibrosis. Specifically, inulin supplementation, without affecting the host’s small intestinal fructose catabolism, promotes the small intestinal microbiome to break down incoming fructose, thereby decreasing hepatic lipogenesis and fructose spillover to the colonic microbiome. Inulin also activates hepatic de novo serine synthesis and cystine uptake, augmenting glutathione production and protecting the liver from fructose-induced lipid peroxidation. These multi-modal effects of inulin are transmittable by the gut microbiome, where Bacteroides acidifaciens acts as a key player. Thus, the gut microbiome, adapted to use inulin (a fructose polymer), efficiently catabolizes dietary monomeric fructose, thereby protecting the host. These findings provide a mechanism for how fibre can facilitate the gut microbiome to mitigate the host’s exposure to harmful nutrients and disease progression.
Funding Information
  • American Association for the Study of Liver Diseases
  • Edward Mallinckrodt, Jr. Foundation
  • Pew Charitable Trusts
  • U.S. Department of Health & Human Services | National Institutes of Health (R01-AA029124, R21-AA030358, T32GM008620, F31DK134173, K22-CA234399)
  • National Research Foundation of Korea (2021R1A6A3A-14039681, 021R1A6A3A14039132, RS-2024-00411784)
  • American Diabetes Association (11-23-PDF-03)
  • Ministry of Health and Welfare (HI19C1352)
  • U.S. Department of Health & Human Services | NIH | National Cancer Institute (R01CA244519, R01CA259370)
  • V Foundation for Cancer Research
  • Johnson and Johnson
  • UC | UC Irvine | Chao Family Comprehensive Cancer Center (P30CA062203)

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