# Lymphatic remodeling and transport of dietary fats in short gut syndrome

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $436,527

## Abstract

ABSTRACT
Short gut syndrome (SGS) results from the surgical removal of a significant length of small intestine required to
treat multiple conditions in adults and children. In children, the mortality associated with SGS is ~25%, making
it one of the most lethal conditions in infancy and childhood. After surgery, remodeling of the remaining bowel
segment can occur to reach a state more favorable to absorptive function and survival. Despite the importance
of the lymphatic vasculature in fat absorption, little is known about how lymphatic transport is affected in SGS.
Our preliminary data suggest that lymphatic vessel integrity is compromised in SGS. Since lymphatics are
centrally involved in transport of fat nutrients into the host, it is relevant to consider how lymphatic vessel
changes in SGS might affect the subject's health. The development of fatty liver progressing to liver failure, or
intestinal failure-associated liver disease (IFALD), is the major morbidity in SGS patients that survive bowel
resection. While mechanisms underlying IFALD remain unclear, data in experimental SGS indicate a pivotal
role for the microbiome and host TLR4 in driving IFALD. It is well known that the bowel's lymphatic vasculature
is the route through which long chain fatty acids are absorbed as triglycerides into the body via large (~1 µm)
specialized lipoproteins called chylomicrons that are packaged and secreted by intestinal epithelial cells. It is
less widely recognized that HDL trafficking from the intestine also serves as an alternative means for
cholesterol and fat soluble vitamins, such as tocopherol (vitamin E), to be absorbed. Typically, the HDL
pathway of absorption is minor compared to the lymphatic-dependent chylomicron pathway. However, this may
change in disease settings. Moreover, it is not known how HDL enters the host during absorption, but data
strongly suggest that it travels via a lymphatic-independent route, perhaps via the portal venous route. If so,
HDL may serve as a key alternative vehicle for fat absorption during times of impaired lymphatic transport.
Because the liver receives the majority of its blood supply from the portal vein rather than the hepatic artery,
the cargo in the portal vein would be expected to strongly impact liver physiology. Besides carrying fat-soluble
nutrients, HDL and other lipoproteins are major vehicles for transport of microbial lipids like the TLR4 ligand
lipopolysaccharide (LPS). Our preliminary data indicate that during SGS, LPS is shuttled to a greater extent to
the portal vein than to lymph. We hypothesize that this shuttling occurs on HDL and drives TLR4-dependent
IFALD in SGS. If so, then a long term goal may be to route it back to chylomicrons and a functional lymphatic
network to protect the liver. To test the hypothesis that intestinal HDL bypasses lymphatics to enter the portal
vein and carry LPS to the liver to promote IFALD, we will utilize an experimental model of SGS in mice to
address (i) whethe...

## Key facts

- **NIH application ID:** 10104485
- **Project number:** 5R01DK119147-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Gwendalyn J Randolph
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $436,527
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104485

## Citation

> US National Institutes of Health, RePORTER application 10104485, Lymphatic remodeling and transport of dietary fats in short gut syndrome (5R01DK119147-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10104485. Licensed CC0.

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