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.

Public Health Relevance

Broad objectives: The pathophysiology of many diseases that are common in the Veteran population is thought to be due in part to a ?leaky gut?, which enables toxic substances in the gut lumen to enter 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 [1], are related to ?metabolic endotoxemia?, a condition in which elevated concentrations of the Gram-negative bacterial outer cell wall component lipopolysaccharide (LPS) are present in the circulation, attributed to increased intestinal permeability [2;3]. Increased circulating LPS has been implicated in the activation of inflammatory pathways in obese individuals, 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 [4]. Most of research into the metabolic derangements in obesity have however been directed at curbing the inflammatory response once it is established rather than preventing it in the first place by limiting LPS uptake from the intestine. Specific junctional proteins that link intestinal epithelial cells are believed to regulate the passage of substances between epithelial cells. One hypothesis is that LPS in the gut lumen enters the circulation via the paracellular pathway, and that increased intestinal permeability, as measured by the absorption of water phase marker molecules such as fluorescent dextran, correlates with increased entry of LPS into the circulation, giving rise to the ?leaky gut? hypothesis [5]. As plausible and attractive as is this hypothesis, there are extremely few direct studies of intestinal LPS absorption. Indeed, the few studies available support that LPS is absorbed via a dual mechanism: the paracellular pathway and by what I will term the transcellular pathway, the same pathway by which long-chain triglycerides (LCT) are absorbed, a multistep process involving numerous bioactive proteins and biotransformations [6]. Obesity is strongly linked to the ingestion of a calorie-dense, high-fat diet [7]. In this proposal, we plan to test the hypothesis that LPS is hyperabsorbed in obese individuals as a result of increased uptake via the paracellular pathway, the transcellular pathway, or both, explaining the increased circulating LPS in obese individuals and following ingestion of a fatty meal [8-10]. As a consequence, this mechanism could be exploited in the treatment of obesity and diabetes by impairing LPS uptake into the circulation with drugs and interventions that reduce LPS transport through or around absorptive enterocytes. We further plan to test the hypothesis that glucagon-like peptide (GLP)-2, an intestinotrophic hormone, improves barrier function, decreasing intestinal LPS uptake via the paracellular or transcellular pathway(s), We also plan to help confirm the hypothesis that GLP-2 is released by the dominant bacterial metabolites in the gut lumen, short chain fatty acids (SCFAs), and to test the novel hypothesis that luminal LPS releases GLP-2 through activation of cognate receptors expressed on a subtype of GLP-2-releasing intestinal endocrine cells termed L cells. The remarkable effects of GLP-2, particularly on the gut mucosa in terms of affecting intestinal solute absorption and secretion, underlie its FDA approval for the treatment of short gut syndrome[11;12]. We hypothesize that inhibiting LPS uptake into the circulation by limiting oral LPS intake, fat absorption, or by enhancing intestinal barrier function could translate into useful and practical treatments for the metabolic consequences of obesity. Rationale: The disease we plan to study, obesity, is thought to be due to a combination of low-level systemic inflammation and increased mucosal permeability. Furthermore, the increased gut permeability in obesity has been ameliorated either by fiber-rich diets or by exogenous GLP-2, with consequent improvement in glycemic control. Since the exogenous GLP-2 stable analogue teduglutide, though effective, is inordinately expensive and limited in indication, we propose to amplify endogenous GLP-2 release and plasma concentrations with a combination of high-affinity SCFA receptor ligands, inhibition of the metabolic enzyme dipeptidyl peptidase (DPP)IV, and dietary alteration of the gut metabolome to decrease paracellular permeability.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001245-06
Application #
9502826
Study Section
Gastroenterology (GAST)
Project Start
2012-07-01
Project End
2021-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
VA Greater Los Angels Healthcare System
Department
Type
DUNS #
066689118
City
Los Angeles
State
CA
Country
United States
Zip Code
90073
Said, Hyder; Akiba, Yasutada; Narimatsu, Kazuyuki et al. (2017) FFA3 Activation Stimulates Duodenal Bicarbonate Secretion and Prevents NSAID-Induced Enteropathy via the GLP-2 Pathway in Rats. Dig Dis Sci 62:1944-1952
Said, Hyder; Kaunitz, Jonathan D (2016) Gastrointestinal defense mechanisms. Curr Opin Gastroenterol 32:461-466
Akiba, Yasutada; Kaunitz, Jonathan D (2014) Prostaglandin pathways in duodenal chemosensing. J Gastroenterol Hepatol 29 Suppl 4:93-8
Inoue, Takuya; Higashiyama, Masaaki; Kaji, Izumi et al. (2014) Dipeptidyl peptidase IV inhibition prevents the formation and promotes the healing of indomethacin-induced intestinal ulcers in rats. Dig Dis Sci 59:1286-95
Akiba, Yasutada; Kaunitz, Jonathan D (2014) Duodenal luminal chemosensing; acid, ATP, and nutrients. Curr Pharm Des 20:2760-5
Kaunitz, Jonathan D (2014) Paradigm shifts in perspective III: the discovery of tumor necrosis factor. Dig Dis Sci 59:710-1
Kemmerly, Thomas; Kaunitz, Jonathan D (2013) Gastroduodenal mucosal defense. Curr Opin Gastroenterol 29:642-9
Soldavini, Jessica; Kaunitz, Jonathan D (2013) Pathobiology and potential therapeutic value of intestinal short-chain fatty acids in gut inflammation and obesity. Dig Dis Sci 58:2756-66
Inoue, Takuya; Wang, Joon-Ho; Higashiyama, Masaaki et al. (2012) Dipeptidyl peptidase IV inhibition potentiates amino acid- and bile acid-induced bicarbonate secretion in rat duodenum. Am J Physiol Gastrointest Liver Physiol 303:G810-6
Kaunitz, Jonathan D (2012) From bedside to bench: reverse engineering medical progress. Dig Dis Sci 57:2481-3

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