Curcumin modulates hepatic pyroptosis-autophagy crosstalk induced by aflatoxin B1 via rumen microbiota-blood-liver axis

BACKGROUND: Aflatoxins, fungal secondary metabolites from Aspergillus species, primarily causes liver and gastrointestinal damage in ruminant. Curcumin, a plant polyphenol, has been shown to possess both anti-inflammatory and antioxidant properties, in addition to regulatory effects on gut microbiota. However, research on curcumin's impact against AFB1 toxicity in ruminants is limited. This study aims to elucidate whether AFB1 induces hepatic pyroptosis and autophagy in ruminants via the rumen microbiota-blood-liver axis and the regulatory role of curcumin. The experimental design involves the administration of AFB1 and curcumin to sheep, followed by a comprehensive observation of alterations in rumen microbiota, barrier function, and the occurrence of hepatic pyroptosis and autophagy, with the aim of elucidating the mechanism of curcumin in ameliorating AFB1-induced liver injury in sheep. RESULTS: -N and VFAs production, whereas curcumin improved VFA generation and fermentation efficiency. Curcumin mitigated AFB1-induced rumen barrier impairment by upregulating tight junction proteins (ZO-1, Occludin, Claudin-1) and reducing LPS levels, which was consistent with metagenomic data showing amelioration of microbiota dysbiosis and reduced lysis of Gram-negative bacteria. At hepatic level, curcumin downregulated the principal mediators of the TLR4-NF-κB-NLRP3 signaling pathway (TLR4, p65, and NLRP3), attenuating pyroptosis and reducing serum AST, ALT, and LDH concentrations, while reversing inflammatory infiltration and hepatic cord disruption. Furthermore, curcumin restored autophagic flux by increasing the LC3-II/LC3-I ratio and decreasing p62 accumulation, counteracting AFB1-induced autophagy inhibition. CONCLUSIONS: Curcumin counteracts AFB1-induced rumen-liver axis dysfunction. It works by stabilizing the microbiota, maintaining barrier integrity, and dually regulating pyroptosis and autophagy. Video Abstract.