Gut microbiota alterations modulate high-fat diet-induced precocious puberty.

The link between gut microbiota and precocious puberty has garnered increasing attention; however, the underlying mechanisms remain poorly understood, and most existing studies are cross-sectional, making it difficult to capture the longitudinal changes in gut microbiota throughout precocious puberty. Here, female rats were fed high-fat diets supplemented with antibiotics to establish a model of precocious puberty with gut microbiota perturbation. Gut microbiota dynamics were characterized based on stool samples collected at postnatal day (PND) 21, 25, 29, and 33. Serum metabolomic profiles on PND 33 were analyzed to investigate the potential mechanisms by which gut microbiota may influence precocious puberty. We found that alterations in gut microbiota alleviated high-fat diet-induced precocious puberty. Temporal changes in gut microbiota that potentially regulate precocious puberty were identified, with specific contributions from , , , and others. Additionally, the modified gut microbiota ameliorated the dysregulation of steroid hormones, bile acids, and lipid molecules at PND 33. Notably, lysoPE 16:0, 23-nordeoxycholic acid, and psoralidin were not only influenced by the gut microbiota but also closely associated with indicators of pubertal development. This study highlights key gut microbiota and metabolites that may inform future mechanistic studies and intervention strategies for managing precocious puberty.IMPORTANCEPrevious studies have highlighted the link between gut microbiota and precocious puberty. Our research further explored this connection, demonstrating that microbial shifts modulated the onset and progression of precocious puberty, characterized by increased hypothalamic sirtuin-1 gene expression and decreased kisspeptin-1 and gonadotropin-releasing hormone gene expressions. At the same time, we explored the longitudinal trajectories of the gut microbiota and identified the key microbes involved in regulating precocious puberty, including , , and others. In addition, an integrated analysis of the microbiome and metabolome revealed specific bacteria and metabolites that contribute to the onset of puberty. These findings offer valuable insights into the mechanisms driving precocious puberty and may inform future research and potential therapeutic interventions.