# A probiotic-derived protein regulates epigenetic programming in intestinal epithelial cells for long-term prevention of colitis

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $471,191

## Abstract

PROJECT SUMMARY
 Dysbiosis in infants and children is associated with increased susceptibility to inflammatory bowel
disease (IBD) in adults. However, the mechanisms whereby the gut microbiota colonization in early life confers
health outcomes throughout the lifespan remain unclear. Studies from the previous funding period isolated and
cloned a Lactobacillus rhamnosus GG (LGG)-derived secretory protein, p40, and demonstrated that neonatal
p40 supplementation prevents colitis in adult mice. Our preliminary studies discovered that p40 interacts with
two transcriptional factors, Mga and Max, to regulate expression of Setd1β gene, which encodes a
methyltransferase for catalyzing mono and trimethylation of histone 3-lysine 4 (H3K4me1/3). We identified
TGFβ as a potential target of p40-up-regulated Setd1β. IECs are rapidly renewed and continuously
regenerated from intestinal stem cells (ISCs). We found that p40 modulates H3K4m31/3 in ISCs in early stage,
and p40 treatment in neonates, but not adult mice, stimulates sustained increase in TGFβ gene expression in
IECs. TGFβ has been shown to have multiple functions against inflammation. Thus, we hypothesize that p40
up-regulates Setd1β gene expression in IECs through increasing Mga:Max dimerization. Supplementation with
p40 in early life stimulates Setd1β-dependent H3K4me1/3 deposition at the TGFβ locus in ISCs, which is
inherited by IECs to enable the sustained increase in TGFβ production, and subsequently prevention of
intestinal inflammation in adulthood. In Aim 1, we will determine whether p40-stimulated Setd1β gene
expression and H3K4me1/3 are required to drive the increase in expressing TGFβ gene in IECs, and elucidate
whether the interaction between p40 and the Mga:Max dimers mediates up-regulation of Setd1β production. In
Aim 2, we will identify the temporal window of p40 exposure in early life that causes the sustained increase in
TGFβ production in IECs, and define whether p40-regulated sustained increase in TGFβ gene expression in
IECs requires the increase of Setd1β gene expression inISCs in early life. Human and mouse enteroids and
colonoids and 2D cultures and cell lines with silencing Setd1β or Mga genes, and mouse models of constitutive
and inducible Setd1β gene knock down in IECs or ISCs will be utilized for these two aims. In Aim 3, we will
determine whether the sustained increase in TGFβ production after p40 supplementation in early life is
required to prevent colitis in adult mice. We will use neutralizing antibodies and inhibitors to block TGFβ
function in mice with induced and spontaneously developed colitis. We will also determine whether sustained
increase in TGFβ production enhances Tregs induction in the intestine and protective epithelial responses for
the prevention of colitis in adulthood. This aim will be tested in mice with TGFβ receptor II deletion in CD4+ T
cells and Smad4 deletion in IECs. Together, our proposed research will elucidate a novel mechanism
underlying the con...

## Key facts

- **NIH application ID:** 9972333
- **Project number:** 2R01DK081134-10A1
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** FANG YAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $471,191
- **Award type:** 2
- **Project period:** 2009-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972333

## Citation

> US National Institutes of Health, RePORTER application 9972333, A probiotic-derived protein regulates epigenetic programming in intestinal epithelial cells for long-term prevention of colitis (2R01DK081134-10A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9972333. Licensed CC0.

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