# Conceptual and mechanistic insights into the development of diet-induced obesity through disruption of hepatic circadian rhythms by the gut microbiome

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2022 · $587,960

## Abstract

PROJECT SUMMARY
Among the many effects that the gut microbiome elicits on its host, the regulation of metabolism is arguably the
most significant because of its potential impact on human health and relevance to diet-induced obesity (DIO).
DIO is such an enormous and vexing public health concern that there is unanimity that effective and practical
solutions must be found. Microbiome-based interventions hold great promise as a way to correct energy
balance in a more natural, physiological manner than pharmacological agents that often have off target side
effects. In order to accomplish this, we must find novel solutions to unravel the complex and dynamic
relationships between the gut microbiome and host metabolic systems in order to advance the field beyond
description and association. To move the needle, our group proposes a deep dive into studies that will reveal
targets and mechanisms of action of specific microbial drivers of host metabolism in an organ-specific context.
We propose to define how diet-induced changes of the gut microbiota affect host metabolism through the lens
of hepatic circadian and metabolic networks (the liver being the main metabolic organ). These studies build
upon a paradigm-shifting discovery our group made showing that the gut microbiome undergoes diurnal
variation, which is essential and intricately intertwined with host circadian rhythms (CRs) that influence host
metabolism. We will test the hypothesis that HF diet reprograms the gut microbiota to promote loss of
critical microbial inducers (Aim 1) and gain of disruptors (Aim 2) that impact downstream host hepatic
circadian and metabolic networks, leading to DIO. To gain mechanistic clarity, each will be studied
separately. Additionally, we will test the hypothesis that microbiota-derived inducers and disruptors
differentially interact with the core or auxiliary hepatic circadian components, which functionally affect
the phase and/or amplitude of the pacemaker. For these studies, we have selected two indigenous gut
microbial strains (the recently identified and cultivated Ilealbaculum butyricum [E14] and Bilophila wadsworthia
[Bw]) promoted either by LF or HF diet and their known metabolic products (butyrate and H2S, respectively).
To achieve higher mechanistic and temporal resolution, we will use genetic manipulation of the circadian
system i.e. conditional liver-specific Bmal1 knock-out mice, gnotobiotic mouse technology, and hepatic
organoid systems which have all been validated. In Aim 3, we will explore if the culmination of this knowledge
can be leveraged into microbiome-based interventions for DIO by testing the hypothesis that butyrate and
potentially other LF diet-induced microbe-derived inducers can override the actions of existing HF diet-
induced microbial CR disruptors (H2S). These studies serve as a starting point towards a thorough
understanding of cellular, tissue, and systems complexity involved in dietary and microbial regulation of
metabolism media...

## Key facts

- **NIH application ID:** 10308705
- **Project number:** 5R01DK115221-04
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** EUGENE B CHANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $587,960
- **Award type:** 5
- **Project period:** 2019-01-17 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10308705

## Citation

> US National Institutes of Health, RePORTER application 10308705, Conceptual and mechanistic insights into the development of diet-induced obesity through disruption of hepatic circadian rhythms by the gut microbiome (5R01DK115221-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10308705. Licensed CC0.

---

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