# Microbial regulation of mammalian circadian rhythms and the sexual dimorphism: from metabolism to immunity

> **NIH NIH DP2** · CARNEGIE-MELLON UNIVERSITY · 2022 · $1,352,700

## Abstract

Project Summary
The intestine plays essential roles in health and disease based on its two main functions: nutrient absorption and
immune defense. These two processes are highly intertwined with each other and are influenced by a variety of
genetic and environmental factors. Abnormal absorption causes nutrient deficiency or excess, which leads to
various metabolic diseases. Compromised immune defense increases the exposure to pathogens and other
noxious agents, and promotes systemic immune activation, infections and metabolic disorders. Therefore,
understanding how the two processes are regulated in the intestine is critical for fighting these digestive system
diseases. Intriguingly, many of the metabolic and immune functions are integrated in the same group of cells,
the intestinal epithelial cells. However, how these cells coordinate the two distinct processes, especially in the
face of environmental challenges, remains a puzzle. We recently identified that the gut microbiota, a community
of microorganisms in the gut, controls a 24-hour diurnal rhythm in the intestinal epithelium through an epigenetic
mechanism. This leads to a hypothesis that the microbiota may temporally orchestrate metabolic and immune
functions in the intestine to maintain just-in-time capacities of nutrient uptake and immune defense in response
to the diurnal oscillations of nutrient availability and microbial burden. In this proposal, we will examine how
metabolic and immune activities are temporally coordinated in the intestine and how these rhythms are affected
by environmental interventions. We will scrutinize the components and activities of the microbiota to understand
how gut microbes regulate the circadian system to influence host metabolic health and immune integrity. We will
identify and characterize other epigenetic programs that integrate microbial and circadian cues to regulate
intestinal physiology. From a preliminary screen, we found that the microbiota drives the rhythm of another
chromatin modification that is only present in male mice but not females. This finding provides a new avenue for
understanding how microbial, circadian and sexual dimorphic signals converge in the intestine to control
metabolic and immune functions. We will exploit multidisciplinary techniques including bacteria and mouse
genetics, genomics, gnotobiotics, and more importantly we will develop new computational approaches and
screening assays to understand the crosstalk between the gut microbiota and host circadian rhythms. These
studies will provide novel mechanistic insights into the microbial regulation of host circadian programs and shed
light on unexpected roles of the microbiota and epigenetic modification in regulating sexual dimorphisms of
mammalian metabolism and immunity. Ultimately, the findings will help develop new strategies to protect against
metabolic and immune diseases by targeting the microbiota or epigenetic pathways.

## Key facts

- **NIH application ID:** 10473122
- **Project number:** 1DP2DK136278-01
- **Recipient organization:** CARNEGIE-MELLON UNIVERSITY
- **Principal Investigator:** Zheng Kuang
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,352,700
- **Award type:** 1
- **Project period:** 2022-09-19 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10473122

## Citation

> US National Institutes of Health, RePORTER application 10473122, Microbial regulation of mammalian circadian rhythms and the sexual dimorphism: from metabolism to immunity (1DP2DK136278-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10473122. Licensed CC0.

---

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