# Luminal Factors Affecting Duodenal Protection and Chemosensing

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2020 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 9932899
- **Project number:** 5I01BX001245-08
- **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:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-07-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932899

## Citation

> US National Institutes of Health, RePORTER application 9932899, Luminal Factors Affecting Duodenal Protection and Chemosensing (5I01BX001245-08). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9932899. Licensed CC0.

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