These data suggest that in the presence of Western diet derived oleic acid, trace amounts of intestinally derived LPS can significantly activate pro-inflammatory transcription factor NF-kB. Consequently, there was also a significant increase in the secretion of pro-inflammatory cytokine as percent of the total area. The findings reported in this study not only demonstrate Western diet-induced changes in intestinal barrier function leading to increased endotoxemia, macrophage activation and subsequent development of glucose intolerance and atherosclerosis but also establish that improvement of this barrier function can significantly attenuate this pathological sequelae. While selective gut decontamination by the use of non-absorbable antibiotics provides the “proof of concept” that reduction in total intestinal NSC 136476 bacterial content could be beneficial in preventing Western diet-induced metabolic diseases, the significant reduction in glucose intolerance as well as atherosclerosis by oral curcumin demonstrates the importance of targeted improvement in intestinal barrier function as a potential therapeutic strategy. This represents a change in the existing paradigm and places the focus on improving intestinal barrier function rather than direct modulation of gut bacteria itself. Intestinal barrier is a multi-layer defense system consisting of lumen as the first line of defense where enzymatic degradation of bacteria and antigens occurs and the commensal bacteria prevent colonization of pathogens. The mucus layer prevents the adherence of bacteria to the epithelial cells and reduces direct bacterial-epithelial interactions. Tight junctions between the epithelial cells restrict para-cellular transport of luminal contents. Intestinal Alkaline Phosphatase is part of the luminal first line of defense and catalyzes the removal of one of the two phosphate groups from the toxic lipid A moiety of LPS producing monophosphoryl-LPS that still binds to TLR4 but predominantly acts as an TLR4 antagonist. We observed attenuation of western-diet induced decrease in IAP activity by non-absorbable antibiotics and an increase by curcumin. Tuin et al have reported a decrease in IAP in patients with inflammatory bowel disease and heat stable, chimeric human alkaline phosphatase is currently being evaluated as a protein therapeutic for gut dysbioses, bowel disease and acute kidney injury. Restoration of Western diet-induced decrease in IAP activity by selective gut decontamination as well as with curcumin supplementation shown here strongly suggests a potential therapeutic use of this strategy for multiple diseases. In this regard, it is noteworthy that we have earlier demonstrated significant improvement in chronic kidney disease by curcumin supplementation. The two interventions examined in this study also decreased paracellular transport and prevented western diet-induced reduction in the expression of tight junction proteins. Taken together, these data provide direct evidence for improvement in the intestinal barrier function by these two interventions at multiple levels namely luminal detoxification of LPS by IAP and paracellular transport of LPS by modulating expression of tight junction proteins.