# Microbial regulation of intestinal lipid metabolism and its physiological consequences

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $648,968

## Abstract

ABSTRACT
Intestinal microbiota are known to promote absorption of dietary fat and to confer susceptibility to diet-induced
obesity. However, there exist fundamental gaps in our knowledge of the underlying mechanisms. Our long-term
goal is to understand the mechanisms underlying host-microbe interactions and lipid metabolism in the intestine
and how they contribute to human physiology and disease. Our preliminary studies in gnotobiotic and
conventional mice and zebrafish reveal that microbiota specifically suppress mitochondrial fatty acid oxidation
(FAO) in intestinal epithelial cells (IECs), and identify potential upstream microbial and transcriptional regulatory
mechanisms. Our genetic analysis in conventional mice also establishes that blocking FAO specifically in IECs
promotes dietary fat absorption and modulates intestinal and systemic energy metabolism. The overall objectives
of this project are to understand how microbiota regulate FAO in IECs, and define the impact of intestinal FAO
on intestinal and systemic physiology. The proposed research will test the central hypothesis that specific
bacterial products downregulate FAO in IECs by suppressing FAO gene transcription, which in turn modulates
IEC fuel selection and differentiation and promotes positive energy balance. Our rationale is that an improved
understanding of how microbes influence intestinal FAO, and how FAO contributes to intestinal physiology and
systemic energy metabolism could lead to new strategies for controlling fat metabolism and energy balance in
humans and other animals. In Specific Aim 1, we will identify the host and microbial mechanisms by which
microbiota suppress FAO in the intestinal epithelium. In Specific Aim 2, we will define the roles of intestinal FAO
in fuel selection and differentiation of IECs, and in mediating the influence of the gut microbiota on systemic
energy balance. The expected outcomes will vertically advance the field in several ways. First, they will establish
intestinal FAO as a major determinant of intestinal and systemic energy balance. Second, they will provide
definitive new evidence that intestinal epithelial FAO is a major target of microbial regulation. Third, they will
show that the striking resistance of germ-free mice to diet-induced obesity is mediated by intestinal FAO. Finally,
they will provide a novel bacteria-host signaling pathway governing intestinal FAO. These results are expected
to have a significant impact because they are likely to lead to new microbe- and host-targeted strategies to
control energy balance in the context of obesity and malnutrition by manipulating FAO and associated gene
expression networks and metabolic pathways in the gut.

## Key facts

- **NIH application ID:** 10763023
- **Project number:** 5R01DK131742-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** John F Rawls
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $648,968
- **Award type:** 5
- **Project period:** 2021-12-03 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10763023

## Citation

> US National Institutes of Health, RePORTER application 10763023, Microbial regulation of intestinal lipid metabolism and its physiological consequences (5R01DK131742-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10763023. Licensed CC0.

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