# Developmental effects of intestinal microbes on metabolic and behavioral circadian rhythms

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $145,218

## Abstract

PROJECT SUMMARY
Metabolic diseases are increasing worldwide in prevalence and severity. Globally, approximately 650 million
people are obese or overweight, over half of whom are children. The healthcare burden of obesity is enormous
and only growing. Circadian rhythms play a central role in healthy metabolism and in maintaining proper host-
microbe interactions. Circadian rhythms in feeding and behavior create a feedback loop, driving rhythms in
hepatic transcription, which in turn drive rhythms in host and microbial metabolism that ultimately feedback onto
circadian rhythms in host behavior. This network of rhythms is severely disrupted in obese mice consuming a
Western diet. Early-life diet interacts with the developing microbiome to program metabolism and disease risk,
but how the early-life microbiota contribute to development of the host metabolic circadian network remains
unknown. There is an urgent need to identify mechanisms by which gut microbes interact with diet early in life to
shape these circadian networks that coordinate daily rhythms in metabolism.
 Mice devoid of all microbes (‘germ-free’) exhibit disrupted circadian rhythms in numerous aspects of host
metabolism compared to mice that have had microbes since birth. Remarkably, repopulating germ-free mice
later in adulthood with microbes (‘conventionalization') only partially normalizes their circadian rhythms. This
indicates that the age at which gut microbes are acquired must play a critical role in the development of
circadian networks that govern metabolism. But when and how healthy and obesogenic microbes first begin
to normalize and disrupt, respectively, the circadian network remain unexamined.
Our research will bridge this gap in knowledge by testing the hypothesis that the organismal circadian
network is shaped by interactions between the type of gut microbes acquired and the developmental
age of acquisition. Aim 1 tests the hypothesis that the age when mice acquire a normal, healthy microbiome
determines the robustness of their circadian network in adulthood. We will conventionalize germ-free mice with
microbes during gestation, at weaning, or in adulthood. Phenotypes across the entire circadian network will be
examined later in life, including: hepatic clock and clock-controlled gene expression via RNA-seq, microbial
community oscillations via 16S rRNA, and host behavioral circadian rhythms thermoregulation and via wireless
telemetry inside sterile isolators. Aim 2 will test the hypothesis that obesogenic diets early in life disrupt normal
development of the circadian network through a combination of microbe-dependent and microbe-independent
mechanisms. Beginning early in life, germ-free mice will be administered an obesogenic diet alone, obesogenic
microbes alone, or both obesogenic diet and microbes. Metabolic circadian networks will be examined as in Aim
1. These studies will specify how diet and microbes interact to affect the developing host-microbial circadian
net...

## Key facts

- **NIH application ID:** 10802403
- **Project number:** 5R21DK135039-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Vanessa Anne Leone
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $145,218
- **Award type:** 5
- **Project period:** 2023-03-07 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10802403

## Citation

> US National Institutes of Health, RePORTER application 10802403, Developmental effects of intestinal microbes on metabolic and behavioral circadian rhythms (5R21DK135039-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10802403. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*