# Microbiota-dependent Epigenetic Regulation of Circadian Rhythms in Nutrient Uptake and Energy Homeostasis

> **NIH NIH K99** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $90,000

## Abstract

Project Summary
Metabolic syndrome has become a major public challenge in modern society. One main cause is an imbalance
between energy uptake and expenditure, which is actively modulated by environmental factors such as diet
composition, circadian rhythms of feeding and sleeping, and the intestinal microbiota. The gut microbiota is a
vast community of microorganisms that colonize the intestine, and it plays an essential role in mammalian me-
tabolism by liberating absorbable nutrients from complex diets for host uptake. Interestingly, recent studies
have shown that the microbiota can also impact host metabolic activities by regulating the circadian clock, and
disrupting this crosstalk can cause metabolic disorders. Despite this general understanding, the underlying
mechanisms remain elusive. My preliminary studies have revealed that circadian oscillation of histone acetyla-
tion in intestinal epithelial cells depends on the microbiota. Furthermore, I have identified a potential mecha-
nism involving microbial activation of histone deacetylase 3 (HDAC3) expression. I found that many genes en-
coding nutrient uptake and metabolic functions are targeted by the cycling histone acetylation signals. Epitheli-
al cell-specific HDAC3-deficient mice exhibit a complete loss of histone acetylation oscillation and disrupted
rhythms of blood glucose levels. The mutant mice take up less lipid and are resistant to high fat diet-induced
obesity. Dissecting the microbial-epithelial signaling circuits reveals that specific components of the gut micro-
biota and immune system activate epithelial HDAC3. For these reasons, I hypothesize that the gut microbiota
drives the circadian rhythms of transcription and nutrient uptake by activating intestinal epithelial HDAC3,
which in turn helps to maintain energy homeostasis and metabolic health. In Aim 1, I will study the mecha-
nisms by which the microbiota regulates the rhythms of intestinal gene expression and nutrient absorption. In
Aim 2, I will determine how the gut microbiota regulates lipid uptake and energy homeostasis through epithelial
HDAC3 and its downstream targets. In Aim 3, I will combine immunological, proteomic and computational ap-
proaches to identify the mechanisms by which the microbiota activates epithelial HDAC3, identify co-factors of
HDAC3, and determine their metabolic functions. These studies will provide novel insights into how the micro-
biota regulates host circadian and metabolic states and will help develop new strategies to protect against
metabolic diseases by targeting HDACs or the microbiota.

## Key facts

- **NIH application ID:** 9963216
- **Project number:** 5K99DK120897-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Zheng Kuang
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $90,000
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963216

## Citation

> US National Institutes of Health, RePORTER application 9963216, Microbiota-dependent Epigenetic Regulation of Circadian Rhythms in Nutrient Uptake and Energy Homeostasis (5K99DK120897-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9963216. Licensed CC0.

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