Early-life antibiotic exposure aggravates hepatic steatosis through enhanced endotoxemia and lipotoxic effects driven by gut Parabacteroides

Compelling evidence supports a link between early-life gut microbiota and the metabolic outcomes in later life. Using an early-life antibiotic exposure model in BALB/c mice, we investigated the life-course impact of prenatal and/or postnatal antibiotic exposures on the gut microbiome of offspring and the development of metabolic dysfunction-associated steatotic liver disease (MASLD). Compared to prenatal antibiotic exposure alone, postnatal antibiotic exposure more profoundly affected gut microbiota development and succession, which led to aggravated endotoxemia and metabolic dysfunctions. This was primarily resulted from the overblooming of gut Parabacteroides and hepatic accumulation of cytotoxic lysophosphatidyl cholines (LPCs), which acted in conjunction with LPS derived from Parabacteroides distasonis (LPS_PA) to induce cholesterol metabolic dysregulations, endoplasmic reticulum (ER) stress and apoptosis. Integrated serum metabolomics, hepatic lipidomics and transcriptomics revealed enhanced glycerophospholipid hydrolysis and LPC production in association with the upregulation of PLA2G10, the gene controlling the expression of the group X secretory Phospholipase A2s (sPLA2-X). Taken together, our results show microbial modulations on the systemic MASLD pathogenesis and hepatocellular lipotoxicity pathways following early-life antibiotic exposure, hence help inform refined clinical practices to avoid any prolonged maternal antibiotic administration in early life and potential gut microbiota-targeted intervention strategies.