# Defining the lymphatic basis of protein losing enteropathy after Fontan palliation or inflammatory gut disease

> **NIH NIH DP1** · WASHINGTON UNIVERSITY · 2021 · $787,500

## Abstract

ABSTRACT
Protein-losing enteropathy (PLE) is the term given to the pathological phenomenon of protein dumping from the
systemic circulation into the intestinal lumen. Various degrees of PLE are observed in a variety of otherwise
unrelated diseases. For instance, PLE is a complication of the life-saving Fontan palliation procedure performed
on children born with only a single ventricle of the heart to create a vascular diversion to the lungs to promote
improved oxygenation of blood. Fontan-associated PLE is linked with high mortality: 30-50% over 5- to 10-years.
Yet, PLE remains understudied. The dominant causal mechanisms underlying PLE appear to relate to (1) loss
of barrier integrity at the intestinal epithelium or (2) functional disturbance of the lymphatic vasculature. Intestinal
epithelial cell erosion would expose proteinaceous tissue fluid to the intestinal lumen. Furthermore, poor
epithelial intercellular junctions might allow for the contents of the lamina propria interstitium to leak into the
intestinal lumen. With respect to lymphatics, failure of lymph to flow away from the intestine uni-directionally
toward the heart and instead to flow backwards from the body trunk toward the intestine with sufficient force to
break across the epithelium may be a major cause of PLE. The literature presents Fontan palliation-associated
PLE as a problem driven by lymphatic backflow, whereas PLE in IBD (such as Crohn's disease) is presented as
being of mixed etiology that involves breach of epithelial integrity with possible additional contributions stemming
from lymphatic dysfunction. However, it is acknowledged in the literature that the full basis of PLE in any of these
conditions is uncertain and that there are several reasons why the current explanations may be questioned. We
will carry out focused research on PLE that includes studies involving human participants as well as studies in
experimental animal models. Our hypotheses are, first, that the lymphatic vasculature is a primary player in PLE
affecting Fontan patients and IBD patients, and second, that the lymphatic vasculature must receive “two hits”
to drive sufficient backflow of lymph to cause outflow from the intestinal barrier. The first of these hits has already
been considered (but not completely tested) in the context of Fontan palliation: increased pressure within the
chain of lymphangions (vessel units between lymphatic valves). We propose this second hit is an inflammatory
signal that negatively affects lymphatic valves. The two-hit model may resolve a confusing observation in Fontan
patients with PLE wherein treatments with steroids like budesonide can be effective. A steroid seems unlikely to
strongly alter pressure in the venous and lymphatic systems, but it is easy to envision how steroids may help by
reducing adverse inflammatory signalling associated with valve failure. If this model is correct, a path to therapies
not previously considered to treat PLE may become evident.

## Key facts

- **NIH application ID:** 10325733
- **Project number:** 1DP1DK130660-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Gwendalyn J Randolph
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $787,500
- **Award type:** 1
- **Project period:** 2021-09-30 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10325733

## Citation

> US National Institutes of Health, RePORTER application 10325733, Defining the lymphatic basis of protein losing enteropathy after Fontan palliation or inflammatory gut disease (1DP1DK130660-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10325733. Licensed CC0.

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