A Moderately High‐Protein Diet During the Critical Development Period Protects Hepatic Functional Integrity and Improves Metabolic Health in Middle‐Aged Offspring via the Gut–Liver Axis

Abstract

A high‐protein diet (HP) in early life has long‐term effects on the metabolism and liver health of offspring. However, few studies focus on the impact of early nutritional status on the more disease‐susceptible midlife period. Here, we elucidate a moderately HP during critical development and the underlying mechanisms for liver function and metabolic health in middle‐aged offspring. Pregnant Wistar rats are given a 6‐week dietary intervention with a control diet and a moderately HP during gestation and lactation. The maternal high‐protein diet (mHP) group increases energy expenditure, preventing liver fat accumulation and alleviating systemic inflammation of middle‐aged offspring. Additionally, the mHP group reshapes offspring gut microbiota, significantly increasing the abundance of Clostridia_vadinBB60_group, Ruminococcaceae_UBA1819, Flavonifractor, and Butyricicoccaceae_UCG‐009. Metabolomics and transcriptomics reveal that mHP maintains energy homeostasis in middle‐aged offspring by altering serum amino acid, organic acid, and fatty acid profiles and activating the hepatic AMPK/SREBP‐1c pathway to preserve liver integrity via the gut–liver axis. We also demonstrate in the Drosophila model that mHP increases AMPK levels and alleviates lipid accumulation in the gut and fat body of middle‐aged flies. These findings provide valuable insights into the pivotal role of prenatal nutrition in offspring's long‐term health.