Broad objectives: We plan to test the novel hypothesis that the potent bacterial toxin lipopolysaccharide (LPS) enters the circulation either through paracellular uptake into the portal vein, or by a transepithelial mechanism similar to that of long-chain fat absorption, with entry into the lymph. We have shown data that the intestinotrophic and protective hormone glucagon-like peptide (GLP)-2 is released from enteroendocrine cells in response to the systemic administration of LPS, presumably by activation of its receptor TLR-4 expressed on enteroendocrine L- cells. We thus plan to study the uptake mechanism of LPS from the intestinal lumen into the blood, its ability to release GLP-2 from L-cells, and then study its uptake in an experimental model of obesity. We plan interventions that enhance portal venous and circulating GLP-2 concentrations that we predict will reduce LPS entry into the circulation. We also plan to test the effect of compounds that inhibit fat uptake, which we predict will additional will impair LPS uptake into the circulation. Rationale: Obesity, affecting 80% of Veterans, is the single most costly disease for which the VHA must care. Its complications, including coronary artery disease, hypertension, diabetes, and fatty liver/cirrhosis are thought due to systemic inflammation caused by low levels of LPS in the circulation. These complications are responsible for multiple billions of dollars in healthcare-related expenses. These complications are thought to be due to leakage of bacterial endotoxin (LPS) from the intestinal lumen to the circulation. By studying the intestinal uptake mechanism of LPS, we plan to base novel therapies designed to impair LPS uptake from the gut lumen, decreasing the concentration of LPS in the blood, therefore decreasing the systemic inflammatory response that is thought to cause the complications of obesity. By reducing the complications of obesity, these therapies have the potential to improve the health of Veterans and to decrease VHA healthcare expenditures.