AMPK/α-Ketoglutarate Axis Regulates Intestinal Water and Ion Homeostasis in Young Pigs

Water and ion absorption via sensitive aquaporins (AQPs) and ion channels is of critical importance in intestinal health. However, whether α-ketoglutarate (AKG) could improve intestinal water and ion homeostasis in lipopolysaccharide (LPS)-challenged piglets and whether the AMP-activated protein kinase (AMPK) pathway is involved remains largely unknown. This study was conducted to investigate the effect of dietary AKG supplementation on the small intestinal water and ion homeostasis through modulating the AMPK pathway in a piglet diarrhea model. A total of 32 weaned piglets were used in a 2 × 2 factorial design; the major factors were diet (basal diet or 1% AKG diet) and challenge (Escherichia coli LPS or saline). The results showed that LPS challenge increased the diarrhea index and affected the concentrations of serum Na⁺, K⁺, Cl^-, glucose, and AKG and its metabolites in piglets fed the basal or AKG diet. However, the addition of AKG attenuated diarrhea incidence and reversed these serum parameter concentrations. Most AQPs (e.g., AQP1, AQP3, AQP4, AQP5, AQP8, AQP10, and AQP11) and ion transporters (NHE3, ENaC, and DRA/PAT1) were widely distributed in the duodenum and jejunum of piglets. We also found that AKG up-regulated the expression of intestinal epithelial AQPs while inhibiting the expression of ion transporters. LPS challenge decreased (P < 0.05) the gene and protein expression of the AMPK pathway (AMPKα1, AMPKα2, SIRT1, PGC-1α, ACC, and TORC2) in the jejunum and ileum. Notably, AKG supplementation enhanced the abundance of these proteins in the LPS-challenged piglets. Collectively, AKG plays an important role in increasing water and ion homeostasis through modulating the AMPK pathway. Our novel finding has important implications for the prevention and treatment of gut dysfunction in neonates.