# The microbiota-microglia axis in the regulation of metabolic homeostasis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $387,600

## Abstract

Project Summary/Abstract
Dietary excess rapidly induces the inflammatory activation and accumulation of a heterogeneous
population of myeloid cells, broadly termed microglia, in the mediobasal hypothalamus (MBH), a critical
brain region involved in the regulation of energy and glucose homeostasis. We showed that microglial
activation in this context is sufficient to stimulate food intake and body weight gain, however the metabolic
factors initiating this response remain to be elucidated. Diet is a major factor affecting the composition of
the gut microbiota, and high-fat diet (HFD) consumption induces unfavorable alterations in the type and
proportion of commensal microorganisms in the gut. These changes influence the inflammatory and
metabolic properties of the host and may also impact microglial function in the MBH. To this end, microglia
in germ-free (GF) mice are hyperactivated in the MBH compared to other brain regions such as cortex.
This microglial activation is already manifested during neonatal period and colonizing the gut of pregnant
GF dams at embryonic day 16 (E16) restored postnatal microglial homeostasis in the MBH of their pups.
Moreover, we found that supplementation of short chain fatty acids (SCFAs), metabolites produced by
bacterial fermentation of non-digestible carbohydrates, is sufficient to reduce microglial activation in the
MBH and body weight gain in HFD- fed mice. Based on substantial work, both published and preliminary,
we propose here to test the hypothesis that MBH microglia, which reside close to fenestrated blood
vessels, are uniquely regulated by specific microbial metabolites such as SCFAs. Specifically, we aim to
A) determine the cellular and molecular mechanisms by which SCFA-FFAR2 (free fatty acid receptor 2)
signaling regulates microglial homeostasis in the MBH, B) determine whether SCFA-AhR (aryl
hydrocarbon receptor) interactions regulate microglial homeostasis in the MBH, and C) determine whether
microbial metabolites regulate postnatal immunological imprinting of MBH microglia. Completing these
aims has the potential to reveal unprecedented mechanistic insights of how microbial metabolites modulate
identity and function of MBH microglia engaged in regulating metabolic function, providing novel
therapeutic targets for the prevention and treatment of metabolic diseases.

## Key facts

- **NIH application ID:** 10766783
- **Project number:** 5R01DK134782-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Martin Valdearcos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $387,600
- **Award type:** 5
- **Project period:** 2023-01-23 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10766783

## Citation

> US National Institutes of Health, RePORTER application 10766783, The microbiota-microglia axis in the regulation of metabolic homeostasis (5R01DK134782-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10766783. Licensed CC0.

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