# Key gut microbes shape intestinal epithelial lineage development, differentiation and metabolic function

> **NIH NIH K01** · WASHINGTON UNIVERSITY · 2024 · $142,429

## Abstract

PROJECT SUMMARY
 The intestinal epithelium perpetually self-renews and differentiates into specialized progenies. This process
is often viewed as a hard-wired genetic program under the control of host-derived factors. The organizing
principal of my proposal is that specification, differentiation and functional specialization of these epithelial
lineages are modulated by members of the gut microbiota and their metabolic products. Our groups' studies of
healthy and undernourished Bangladeshi children revealed that Prevotella copri is a key species whose
abundance in the developing microbiota is positively associated with ponderal growth. My current work in the
Gordon lab has established a gnotobiotic mouse model of mother-to-infant transmission of defined collections
of human gut bacterial strains that represent different stages in the postnatal assembly of gut microbiota. I
performed single-nucleus RNA-seq to test the effects of including or excluding P copri from these defined
communities. A prominent epithelial response to the presence of P. copri is enhanced enterocytic fatty acid
oxidation. Pseudotime analysis of snRNA-seq datasets disclosed that expression of fatty acid oxidation genes
was spatially regulated by P. copri as enterocytes differentiate/migrate from crypts up villi and that nuclear
receptor PPAR appears to be a top candidate regulator of these genes. I hypothesize that i) exposure to the
P. copri-containing community broadly alters the epigenetic landscape as well as chromatin accessibility to
transcription factor binding as enterocytes execute their differentiation program up the villus, and (ii) PPAR
functions as a key transcription factor that mediates the effects of P. copri on fatty acid oxidation with additional
regulatory inputs from other transcription factors. I propose two aims to test these hypotheses. In Aim 1, I will
characterize, at single-cell resolution, changes in the epigenetic landscape and the transcription factors that
comprise the signaling pathways that P. copri-containing community uses to regulate enterocyte
differentiation/function along the length of the intestine. In Aim 2, I will characterize how the P. copri-containing
defined bacterial community modulates PPAR signaling to control enterocytic fatty acid oxidation along the
crypt-to-villus axis, by using a combination of liquid-chromatography mass spectrometry, 2-dimensional
organoid culture system, and gnotobiotic mouse models. This research will provide (i) mechanistic insights on
how gut microbiota modulates host signaling to control epithelial lineage development, metabolic function, and
functional specialization, and (ii) novel metabolites that have therapeutic potential to benefit intestinal
physiology and function.

## Key facts

- **NIH application ID:** 10757464
- **Project number:** 5K01DK134840-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Yi Wang
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $142,429
- **Award type:** 5
- **Project period:** 2023-01-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757464

## Citation

> US National Institutes of Health, RePORTER application 10757464, Key gut microbes shape intestinal epithelial lineage development, differentiation and metabolic function (5K01DK134840-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10757464. Licensed CC0.

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