# Luminal Factors Affecting Duodenal Protection and Chemosensing

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2024 · —

## 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...

## Key facts

- **NIH application ID:** 10903736
- **Project number:** 5I01BX001245-10
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** Jonathan D. Kaunitz
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903736

## Citation

> US National Institutes of Health, RePORTER application 10903736, Luminal Factors Affecting Duodenal Protection and Chemosensing (5I01BX001245-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10903736. Licensed CC0.

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