Protection by enteral glutamine is mediated by intestinal epithelial cell peroxisome proliferator-activated receptor-γ during intestinal ischemia/reperfusion

We have demonstrated that enteral glutamine provides protection to the postischemic gut, and that peroxisome proliferator-activated receptor-γ (PPARγ) plays a role in this protection. Using Cre/lox technology to generate an intestinal epithelial cell (IEC)-specific PPARγ null mouse model, we now investigated the contribution of IEC PPARγ to glutamine's local and distant organ-protective effects. These mice exhibited absence of expression of PPARγ in the intestine but normal PPARγ expression in other tissues. After 1 h of intestinal ischemia under isoflurane anesthesia, wild-type and null mice received enteral glutamine (60 mM) or vehicle followed by 6 h of reperfusion or 7 days in survival experiments and compared with shams. Small intestine, liver, and lungs were analyzed for injury and inflammatory parameters. Glutamine provided significant protection against gut injury and inflammation, with similar protection in the lung and liver. Changes in systemic tumor necrosis factor-α reflected those seen in the injured organs. Importantly, mice lacking IEC PPARγ had worsened injury and inflammation, and glutamine lost its protective effects in the gut and lung. The survival benefit found in glutamine-treated wild-type mice was not observed in null mice. Using an IEC-targeted loss-of-function approach, these studies provide the first in vivo confirmation in native small intestine and lung that PPARγ is responsible for the protective effects of enteral glutamine in reducing intestinal and lung injury and inflammation and improving survival. These data suggest that early enteral glutamine may be a potential therapeutic modality to reduce shock-induced gut dysfunction and subsequent distant organ injury.