Akkermansia muciniphila ameliorates acute liver injury aggravated by MASLD-associated dysbiosis via daidzein/PPAR-α/NF-κB signaling

Abstract

Existing evidence indicates that pre-existing metabolic dysfunction-associated steatotic liver disease (MASLD) confers susceptibility to acute liver injury (ALI). Nevertheless, the underlying mechanism prompting ALI risk in such a condition is not fully uncovered yet. Gut dysbiosis has been well-documented in MASLD patients which prompts us to hypothesize that gut dysbiosis may serve as a contributing factor and a regulatory target to ALI susceptibility. A case–control study was performed and the increased risk of ALI in MASLD patients was verified. Mice pretreated with MASLD mouse/patient-derived fecal microbiota transplantation (FMT) demonstrated worsened ALI after D-GalN/LPS injection. We identified significant gut dysbiosis with decreased microbial α-diversity, beneficial genus Lactobacillus, and increased potentially harmful bacteria Campylobacter and Helicobacter. Probiotic Akkermansia muciniphila (A. muciniphila) was reported to improve gut dysbiosis. Thus, we tested the effect of A. muciniphila on ALI mice pretreated with MASLD mouse-derived FMT. A. muciniphila significantly ameliorated the worsened ALI and improved gut dysbiosis. Transcriptomic analysis revealed that A. muciniphila restored the impaired liver PPAR-α signaling, alleviating the aggravated NF-κB signaling and downstream inflammation response in the liver. Specifically, A. muciniphila restored the decreased abundance of the PPAR-α agonist daidzein in the colon, thereby restoring PPAR-α activation and inhibiting NF-κB signaling in the liver. Daidzein is also capable of ameliorating ALI aggravated by MASLD-associated dysbiosis, accompanied by PPAR-α activation and NF-κB inhibition. Our findings revealed that gut dysbiosis in MASLD increased the risk of ALI. A. muciniphila exhibited preventive potential for MASLD patients to reduce ALI risk. Daidzein/PPAR-α/NF-κB signaling is important to maintain host resistance to hepatoxic challenge.