β-Nicotinamide mononucleotide reduces aflatoxin B1 induced liver injury via the gut microbiota-bile acid-farnesoid X receptor (FXR/NR1H4) axis

Abstract

Background

Aflatoxin B1 (AFB1) is a potent hepatotoxin that poses significant health risks to both livestock and humans. β-Nicotinamide mononucleotide (NMN) has potential therapeutic benefits for liver diseases. However, its mechanism against AFB1-induced liver injury remains unclear.

Objective

This study investigates whether NMN supplementation reduces AFB1-induced liver injury through the modulation of the gut-liver axis and elucidates the underlying molecular mechanism.

Methods

Mice were exposed to AFB1 (0.75 mg·kg⁻¹, p.o.) for 2 weeks to induce liver injury, with or without NMN (300 mg·kg⁻¹, p.o.). Changes in gut microbiota were assessed via 16S rRNA sequencing, while bile acids (BAs) profiles were quantified using targeted metabolomics. The farnesoid X receptor (FXR/NR1H4) pathway was analysed using qPCR, western blot and immunofluorescence. To establish causality, antibiotic depletion, faecal microbiota transplantation (FMT) and intestine-specific FXR knockout (FXR^ΔIE) mice were utilized.

Results

NMN supplementation attenuated AFB1-induced liver injury, inflammation and oxidative stress, while restoring intestinal barrier integrity and reducing hepatic bile acids accumulation. Mechanistically, NMN reshaped the gut microbiota, increased bile salt hydrolase (BSH) activity and lowered intestinal conjugated bile acids, which correlated with activation of intestinal FXR/fibroblast growth factor 15 (FGF-15) signalling and suppression of hepatic Cyp7a1 expression. Importantly, antibiotic depletion of gut microbiota abolished NMN protection, whereas FMT from NMN-treated donors conferred resistance. Importantly, NMN failed to protect FXR^ΔIE mice, demonstrating that intestinal FXR is essential.

Conclusion

NMN alleviates AFB1-induced liver injury via a gut microbiota-bile acid-FXR axis, highlighting a novel mechanism for its hepatoprotective effects.