Modified citrus pectin orchestrates hepatic redox homeostasis through an Alistipes dispar-nicotinamide-sirtuin 1 axis to mitigate metabolic dysfunction-associated steatotic liver disease.

Background

Modified citrus pectin (MCP) is a bioactive functional component with potential metabolic benefits, but its therapeutic mechanisms in metabolic dysfunction-associated steatotic liver disease (MASLD) remain unclear.

Purpose

To determine whether MCP alleviates MASLD through gut microbiota remodelling and to identify the key microbial and metabolic mediators involved. STUDY

Design

MASLD mouse models, multi-omics analyses, fecal microbiota transplantation (FMT), bacterial supplementation, and pharmacological inhibition were integrated to establish microbiota-metabolite-host causality.

Methods

MCP efficacy was evaluated by assessing hepatic steatosis, inflammation, oxidative stress, and lipid metabolism. Metagenomics and metabolomics were used to identify MCP-responsive microbes and metabolites. FMT, administration of live or heat-killed Alistipes dispar, validation in db/db mice, and SIRT1 knockdown and inhibition with EX-527 were performed to verify causality and mechanism.

Results

MCP markedly reduced hepatic lipid accumulation, inflammation, and oxidative stress. Metagenomics identified enrichment of A. dispar as a key microbial signature associated with MCP efficacy. Live, but not heat-killed, A. dispar reproduced the protective effects of MCP and improved metabolic abnormalities in db/db mice. Mechanistically, MCP promoted A. dispar proliferation and increased nicotinamide levels, activating hepatic nicotinamide salvage and the SIRT1/PGC-1α/PPARα/CPT1A axis to enhance fatty acid oxidation. This response also suppressed COX-2/HMGB1-mediated inflammation and activated Nrf2/HO-1 antioxidant defence. EX-527 abolished the beneficial effects of MCP and A. dispar.

Conclusion

MCP alleviates MASLD through an A. dispar-nicotinamide-SIRT1 axis that restores metabolic, inflammatory, and redox homeostasis.