# Characterization of the role of neuropeptide VIP-mediated fucosylation in alcohol associated liver disease

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2024 · $456,719

## Abstract

Alcohol-induced changes in gut flora and intestinal metabolites increase portal endotoxin level, which is directly
associated with intestinal barrier dysfunction and is one of the well-recognized contributing factors to the
pathogenesis of ALD. Gut fucosylation is a key force in maintaining a homeostatic relationship between the gut
and its microbiota. Nevertheless, it is unclear how host fucosylation machinery contributes to alcohol-associated
barrier function and microbial translocation. It is shown that epithelial α1,2-fucosylation regulates the colonization
of E. faecalis, which causes more severe alcoholic hepatitis. Our initial studies found that alcohol consumption
reduces the levels of neurons-derived peptide VIP in the gut. Neuropeptide VIP has previously been implicated
in circadian regulation, food consumption and goblet cell mucus secretion. Our preliminary data further found
that neuropeptide VIP administration or deletion of VIP receptor (VIPR1) can regulate intestinal fucosylation.
Membrane-bound fucosylated glycoproteins on mucosal ECs function as important communication tools
between the host and luminal microbes. Many intestinal Bifidobacteria use α1,2-L-fucosidases to ferment the
glycans of host glycoconjugates to produce fucose for its colonization. We found that fucose-derived propionate
could contribute to the induction of IL-22 producing group 3 innate lymphoid cells (ILC3s), which can regulate
epithelial integrity in ALD. Therefore, we hypothesize that a high amount of alcohol consumption is
associated with disturbances in gut VIP secretion, reductions in IECs fucosylation and beneficial
symbionts, and subsequently overgrowth of cytolysin-positive E. faecalis, all of which lead to intestinal
barrier dysfunction and contribute to the development of ALD. We postulate that prebiotic and probiotic
supplementation will attenuate alcohol-induced intestine and liver injury, in part by inhibiting of E.
faecalis colonization and increasing IL-22+ ILC3 in the intestine. Following specific aims will be carried out:
Aim 1: Determine the impact of VIP signaling on the gut fucosylation and the effects of this impact on intestinal
barrier integrity in ALD. We will document the impact of VIP/VIPR1 signaling changes on intestinal fucosylation
and integrity in ALD; We will explore the mechanisms by which fucosylation is enhanced by VIP. Aim 2:
Investigate whether probiotic fucosidase-producing Bifidobacterium attenuates ALD via inhibition of E. faecalis
colonization and activation of IL-22+ILC3. We will examine the effect of fucosidase-producing Bifidobacterium
and fucose-derived propionate on E. faecalis colonization; We will investigate whether fucosidase-producing
Bifidobacterium attenuates ALD via the activation of gut ILC3 and IL-22/ IL-22RA signaling. Aim 3: Evaluate the
efficacy of VIP-fucosylation-based therapeutic interventions in ALD. We will first evaluate and compare the
efficacy of dietary prebiotic 2'-FL with VIP supplementati...

## Key facts

- **NIH application ID:** 10907434
- **Project number:** 5R01AA030756-02
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Zhong-Bin Deng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $456,719
- **Award type:** 5
- **Project period:** 2023-08-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907434

## Citation

> US National Institutes of Health, RePORTER application 10907434, Characterization of the role of neuropeptide VIP-mediated fucosylation in alcohol associated liver disease (5R01AA030756-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10907434. Licensed CC0.

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