# Lymphothrombosis in gut health and disease

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $405,000

## Abstract

Project Summary
Unlike lymphatics elsewhere, the lymphatic system in the GI tract transports absorbed lipids and enables
immune surveillance of the billions of bacteria in the gut microbiome. Such specialized functions are thought to
require unique genetic and molecular characteristics, but few such specialized features have been identified.
Our preliminary studies use a new line of PAR1-Tango transgenic mice to demonstrate high thrombin activity
specifically in the lymphatic vessels of the gut, a finding consistent with high expression of the endothelial anti-
thrombotic proteins thrombomodulin (THBD) and endothelial protein C receptor (EPCR) specifically in gut
lymphatic endothelial cells (LECs). Following inducible, global LEC deletion of THBD or EPCR, we observe
fibrin thrombus formation specifically in GI lymphatics that is associated with reduced lymph flow from the gut,
phenotypes reversed by antibiotic treatment to reduce gut bacteria. We also detect fibrin thrombus formation in
the gut lymphatics of wild-type animals following infection by the enteric bacterial pathogens Salmonella or
Yersinia. These studies identify a new in vivo clotting mechanism, lymphothrombosis, that is highly specific for
gut lymphatic vessels and that must be regulated by gut LECs to maintain normal gut lymphatic function. The
aims of this proposal will use novel molecular and genetic tools to (i) fully define the process of
lymphothrombosis in the gut lymphatic vasculature, (ii) test whether and how GI lymphothrombosis is linked to
gut microbiota, and (iii) determine the role of gut lymphothrombosis during GI infection. We predict that these
studies will reveal a novel mechanism of thrombosis outside of the blood vascular system that plays a unique
and functionally important role in gut lymphatics in both health and disease.

## Key facts

- **NIH application ID:** 10018488
- **Project number:** 5R01DK123528-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** IGOR E BRODSKY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2019-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018488

## Citation

> US National Institutes of Health, RePORTER application 10018488, Lymphothrombosis in gut health and disease (5R01DK123528-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10018488. Licensed CC0.

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