Fusobacterium nucleatum alleviates alcohol-associated liver disease through mannose-mediated elevation of Fbp1 and modulation of gut microbiota.

BACKGROUND & AIMS: Alcohol-associated liver disease (ALD) is a worldwide public health concern with limited therapeutic options. The gut microbiota plays a crucial role in its pathogenesis, yet the therapeutic potential of specific microbial species and metabolites remains largely unexplored.

METHODS

We investigated the role of Fusobacterium nucleatum (F. nucleatum) in ALD using human stool samples, a NIAAA mouse model, and multi-omics approaches. Liver injury was evaluated by biochemical, histological, and molecular analyses. Gut microbiota composition was assessed by 16S rDNA sequencing, while metabolomics and proteomics identified functional pathways. Mannose rescue experiments and Fbp1 inhibition were used to validate the proposed mechanism.

RESULTS

F. nucleatum abundance was increased in patients with ALD and showed an inverse association with liver injury severity. Supplementation with F. nucleatum in ALD mice significantly attenuated hepatic steatosis, inflammation, and oxidative stress. Mechanistically, F. nucleatum-derived mannose upregulated and stabilized the hepatic gluconeogenic enzyme Fbp1 in ALD mice, suppressing the PI3K/AKT/mTOR pathway and restoring metabolic homeostasis. Inhibition or knockdown of Fbp1 abolished mannose-mediated protection. Furthermore, mannose promoted the proliferation of Akkermansia muciniphila, improved gut barrier integrity, and reduced systemic endotoxemia. Heat-killed F. nucleatum failed to reproduce these effects, indicating that active metabolite secretion was required.

CONCLUSION

This study identifies F. nucleatum as a commensal with hepatoprotective effects in ALD, acting through a mannose-Fbp1 signaling axis and gut microbiota modulation. These findings highlight mannose as a microbiota-derived therapeutic candidate and suggest that targeting bacterial metabolites, rather than live bacterial administration, may represent a promising strategy for ALD intervention.

IMPACT AND IMPLICATIONS: Alcohol-associated liver disease (ALD) remains a critical clinical issue with few effective treatments. Our study reveals Fusobacterium nucleatum (F. nucleatum) as a novel commensal bacterium that mitigates ALD through modulation of gut metabolites and microbial reorganization. Specifically, we demonstrate that mannose, a key metabolite derived from F. nucleatum, activates the metabolic regulator Fbp1 and suppresses the PI3K/AKT/mTOR pathway, thereby conferring hepatoprotection. Furthermore, supplementation with F. nucleatum enriches Akkermansia muciniphila, strengthening intestinal barrier function and promoting gut-liver axis homeostasis. These findings position mannose as a promising microbiota-derived therapeutic agent for ALD, effectively linking microbial intervention with host metabolic reprogramming.