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.