Neonatal low-bacterial-load during lactation impairs peak bone mass via a gut-liver-bone axis.

Peak bone mass (PBM) is a primary determinant of adult osteoporosis susceptibility and fracture risk. The gut microbiota is closely associated with bone homeostasis and PBM. Early-life establishment of the gut microbiota during lactation is crucial for gut microbiota developmental, however, its long-term impact on PBM remains unclear. In this study, we established a neonatal antibiotic exporsure (NeoATB) mouse model to mimic low-bacterial load during lactation period and investigated skeletal outcomes in adulthood. NeoATB mice exhibited significantly reduced femoral PBM and increased osteoclast activity at 24 weeks of age. Persistent alterations of gut microbiota was analyzed by longitudinal 16S rRNA sequencing, accompanied by fecal metabolomic profiling. These changes were associated with hepatic lipid accumulation and upregulation of fatty acid synthase (Fasn), resulting in increased circulating levels of liver-derived fatty acids, particularly palmitic acid (PA). Functional assays demonstrated that PA directly promoted osteoclast differentiation from bone marrow-derived monocytes. Our study showed that low-bacterial load during lactation induces gut microbial dysregulation, hepatic lipid metabolism reprogramming, and subsequent serum fatty acid-mediated excessive osteoclast differentiation, resulting in reduced PBM. Collectively, these findings demonstrated that low-bacterial load during lactation impairs adulthood PBM acquisition by promoting osteoclast differentiation through gut-liver-bone axis.