On September 15, 2025, a research team led by Cholsoon Jang from the University of California, Irvine, published an article in Nature Metabolism entitled "Dietary fibre-adapted gut microbiome clears dietary fructose and reverses hepatic steatosis." In non-obese individuals, high fructose corn syrup (HFCS) intake is a significant risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD). This study reveals for the first time that dietary fiber inulin promotes the clearance of fructose by small intestinal microbes and reduces Fructose spillover to the liver and colon by remodeling the gut microbiota; simultaneously, it activates the hepatic serine-glutathione synthesis pathway, significantly improving HFCS-induced metabolic disorders. The study not only identified Bacteroides acidifaciens as a key effector strain but also elucidated the core mechanism of the "gut-liver axis" in the protective effect of inulin, providing a new target for dietary intervention in metabolic diseases.

Overview

Metabolic diseases are on the rise globally, with approximately 25% of patients with MASLD facing a higher risk of liver disease despite having a normal weight. This study systematically elucidated the mechanism by which inulin improves HFCS-induced metabolic disorders using a multi-omics approach:

• Animal Model: A time-series experiment was established involving HFCS-induced water and inulin-based dietary interventions.
• Metabolic Analysis: Hepatic steatosis and oxidation were quantitatively detected using ²H₂O and ¹³C tracing techniques.
• Microbiome: Key bacterial species were identified through 16S rRNA sequencing, and fecal microbiota transplantation validated the causal association.
• Molecular Mechanism: RNA-seq revealed activation of the serine synthesis pathway, and metabolomics tracked fructose carbon shifts.

The study found that inulin works through a dual mechanism, enhancing the catabolism of fructose by small intestinal microbes and promoting hepatic serine-GSH synthesis. B. acidifaciens was identified as a key strain mediating these effects.

Fig. 1 Chemical structures of HFCS and inulin, and experimental groups. (Jung, et al. 2025)

Main Content

Inulin Intervention Reverses HFCS-Induced Metabolic Phenotype

Using a mouse model of HFCS in drinking water combined with inulin dietary intervention, this study systematically evaluated the ameliorative effect of inulin on metabolic disorders. The experimental design included two modes: simultaneous intervention (HFCS + inulin feeding) and delayed intervention (induction of MASLD for 16 weeks followed by inulin supplementation for 14 weeks). The results showed that inulin intervention significantly improved HFCS-induced body composition abnormalities, insulin resistance (reduced HOMA-IR index), and hepatic lipid accumulation (reduced liver triglycerides by 50%). Hepatic lipidomics analysis further confirmed that inulin reduced harmful lipid species such as Ceramides and Sphingomyelin, and downregulated the gene expression of fibrosis markers (Col1a1, α-SMA). This indicates that inulin can not only prevent but also reverse existing metabolic dysfunction.

Hepatic Lipid Metabolism Reprogramming

Using stable isotope tracing technology (²H₂O and ¹³C-palmitate), this study deeply elucidated the dynamic regulatory mechanism of inulin on hepatic lipid metabolism. ²H₂O labeling experiments showed that inulin reduced HFCS-induced de novo lipogenesis (DNL) by more than 50%, and ¹³C-palmitate breath tests confirmed a 40% increase in fatty acid oxidation (FAO) efficiency. Molecular mechanism studies showed that inulin downregulated the expression of adipogenic genes such as Khk-c (a key fructose-degrading enzyme), Acss2, and Scd1, while inducing Tkfc expression to reduce the accumulation of fructose-toxic metabolites. Mitochondrial functional analysis showed a 30% increase in acylcarnitine levels, indicating that inulin activates FAO by alleviating malonyl-CoA inhibition of CPT1. This dual regulatory mechanism of inhibiting synthesis and promoting catabolic metabolism jointly improves hepatic steatosis.

Gut Microbiota-Mediated Fructose Clearance and Metabolic Protection

Through combined ¹³C-fructose tracing and microbiome analysis, this study revealed a novel mechanism by which inulin enhances fructose clearance by remodeling the gut microbiota. Inulin intervention increased the fructose-degrading capacity of jejunal microbes by 2-fold (increased jejunal SCFAs) while reducing fructose spillover into the colon by 70% (decreased cecal ¹³C-SCFAs). Antibiotic clearance experiments confirmed that the microbiome is a necessary condition for the protective effect of inulin. Fecal microbiota transplantation experiments further demonstrated that transplanting the gut microbiota of inulin-treated mice into recipient mice successfully transferred the fructose clearance phenotype (reduced colonic spillover by 60%) and the inhibitory effect of hepatic steatosis. The jejunal microbiota transplantation experiment also reproduced the phenotype of enhanced hepatic serine synthesis, indicating that the microbiome is both sufficient and necessary for the metabolic benefits of inulin.

Key Strains Identification and Hepatic Metabolic Reprogramming Mechanism

Through 16S rRNA sequencing and correlation analysis, this study identified B. acidifaciens as a key strain mediating the inulin effect. This bacterium showed a significant negative correlation with hepatic DNL (r=-0.82) and a positive correlation with serine synthesis (r=0.79), with its abundance significantly increasing after inulin intervention. Single-strain colonization experiments confirmed that B. acidifaciens colonization inhibited 60% of hepatic steatosis and promoted small intestinal fructose breakdown. Metabolic Flux Analysis showed that inulin guided fructose carbon flow to the serine-GSH synthesis pathway, resulting in a 3-fold increase in hepatic ¹³C-serine and a 2.5-fold increase in GSH synthesis. Molecularly, inulin upregulated the expression of genes such as Slc7a11 (cystine transporter) and Phgdh (serine synthase), while simultaneously reducing oxidative stress markers such as 4-HNE by 40%, ultimately mitigating lipid peroxidation damage by enhancing antioxidant capacity.

Summary

This study systematically elucidated the molecular mechanism by which inulin improves the metabolic toxicity of HFCS:

• At the intestinal level: by enriching acidifaciens, it enhances the clearance of fructose by small intestinal microorganisms, reducing spillover to the liver.
• At the liver level: It reprograms fructose-carbon flow, promoting serine-GSH synthesis to resist oxidative stress.
• Clinical significance: It provides a theoretical basis for dietary fiber intervention in lean MASLD, and acidifaciensmay become a novel probiotic target.

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Reference

1. Jung, S., et al. (2025). Dietary fibre-adapted gut microbiome clears dietary fructose and reverses hepatic steatosis. Nature Metabolism, 1-18. DOI: 1038/s42255-025-01356-0.