Luminal Factors Affecting Duodenal Protection and Chemosensing

Va Greater Los Angeles Healthcare System, Los Angeles CA

Investigators

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Abstract

The pathophysiology of many diseases that are common in the Veteran population such as diabetes, multiple sclerosis, chronic fatigue syndrome, fibromyalgia, arthritis, asthma, and the metabolic syndrome is thought to be due in part to a “leaky gut”, an impairment of small intestinal barrier function that facilitates the entrance of luminal microbial-derived toxins into the systemic circulation. Specifically, many of the morbidities associated with obesity, which affects 35% of the US population and a much great percentage of the Veteran population, are related to “metabolic endotoxemia”, a condition in which elevated lipopolysaccharide (LPS) levels are present in the circulation, attributed to increased intestinal paracellular permeability. Increased circulating LPS has been implicated in the activation of inflammatory pathways, which in turn have been associated with many of the metabolic derangements characteristic of obesity, including insulin resistance and excess hepatic and adipose lipid storage, leading to serious clinical morbidity such as type II diabetes and cirrhosis. LPS entering the portal vein is a component of the “gut liver axis” implicated in the pathogenesis the aforementioned diseases associated with metabolic endotoxemia. The mechanism by which LPS enters the systemic circulation, though attributed to increased paracellular permeability, is primarily based on the association between small intestinal paracellular permeability to small solutes and endotoxemia. As plausible and attractive as is this hypothesis, there are few direct studies of intestinal LPS absorption; the few studies available, including those from our laboratory, support that LPS is cotrancytosed with luminal lipids via three transcellular pathways, the chylomicron pathway that absorbs long-chain triglycerides (LCT) into the lymphatics, and two transcellular endocytic pathways that absorbs LPS into the portal vein (PV) by clathrin-dependent and -independent mechanisms. These latter pathways support the mechanism whereby LPS enters the PV as part of the “gut-liver axis”, that links the gut microbiome with hepatic and systemic inflammation. Certain dietary lipids are considered to be either anti-inflammatory and pro-inflammatory. For example, the ingestion of long-chain saturated fatty acids are associated with chronic inflammatory conditions such as the metabolic syndrome whereas polyunsaturated fatty acids (PUFA) that often accompany the “Mediterranean diet” are believed to be anti-inflammatory. The highly expressed ecto-enzyme intestinal alkaline phosphatase (IAP) is released into the circulation following a fat meal. Since IAP detoxifies LPS, we propose to study which lipids maximally release IAP into the portal vein, detoxifying LPS, in order to help understand why certain dietary lipids are anti-inflammatory. Building on our prior studies, we plan to study the mechanisms by which enterocytes cotrancytose luminal lipids and LPS by using mouse models in which the endocytic protein caveolin has been deleted. This model will be used to study the relation between lipid structure and transcytotic pathway to test the hypothesis that the LPS uptake pathways is determined by the co-transcytosed lipid and that pathways are either pro or anti-inflammatory based on their ability to mobilize detoxifying IAP. We will examine the uptake in the presence of lipids of varying structure, will study the inhibition of intestinal active glucose transport by certain lipids, and finally study the effect of dietary supplementation with lipids of varying structure on the induction of the metabolic syndrome. Through these studies we hope to gain a deeper understanding of LPS uptake mechanisms that we hope can be used to discover interventions that impair LPS uptake chronically or acutely with the hope of treating and preventing diseases associated with the “leaky gut”.