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

Abstract

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.

Administration of alpha-ketoglutarate improves epithelial restitution under stress injury in early-weaning piglets

“…The present results showed an increase in villus height and a decrease in crypt depth and mucosal thickness in the small intestine of piglets fed the AKG diet. These results were consistent with the pervious study [ 7 ], suggesting that AKG in enterocytes may beneficially regulate the intracellular endogenous amino acid concentrations via TCA cycle [ 23 ] and then influence various signaling pathways [ 16 ], such as the AMP-activated protein kinase (AMPK), nuclear factor kappa B (NF-κB), and mammalian target of rapamycin (mTOR) pathways, thereby improving intestinal morphology.…”

“…Alpha-ketoglutarate is considered to be a potent therapeutic agent against GIT disorder diseases [ 15 ] and also has potential to implicate as a new feed additive for weaning piglets [ 16 ]. Many reports have suggested that maternal and neonatal administration of AKG could improve the growth performance of piglets [ 7 , 17 , 18 ].…”

Genetic variants in the TORC2 gene promoter and their association with body measurement and carcass quality traits in Qinchuan cattle

“…Second, a significant (p<0.01) increase in the mRNA expression level of the TORC2 gene in the small intestine is in line with the findings of Liuqin et al, 2017. They further concluded that the AMP-activated protein kinase (AMPK) pathway, which is regulated by the TORC2 gene, is mainly responsible for water and ionic homeostasis in the small intestine in pigs [59]. After the small intestine, we found a significant increase in the TORC2 gene mRNA relative expression in muscle and fat tissue.…”

Effects of Dietary Serine Supplementation on Intestinal Integrity, Inflammation and Oxidative Status in Early-Weaned Piglets

“…The improvement in daily body weight gain and diarrhea score may be a result of the beneficial effects of serine for maintaining gut health [12].…”