# A Novel Relationship Between the Gut Microbiota and Pancreatic Beta Cells contributes to Gestational Glucose Homeostasis

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2020 · —

## Abstract

The human gut microbiota undergoes compositional changes during pregnancy, and these bacterial changes
have been shown to influence maternal metabolic responses; however, how this occurs is unclear. Part of
these maternal metabolic changes include enhanced glucose stimulated insulin secretion (GSIS) and an
expansion of pancreatic β cell mass (BCM). Providing a potential understanding of how the gut microbiota
mediates this maternal response, we have new data suggesting a relationship may exist during pregnancy
through the β cell-expressed free fatty acid receptor-2 (Ffar2), where this receptor is activated by nutrients
derived from the gut microbiota, short chain fatty acids (SCFAs). Exploring this potential relationship, we have
observed the following; 1) Ffar2 expression is altered in mouse islets by gestational insulin resistance, which
suggests FFA2 may help in β cell adaption during pregnancy, 2) mice with a null mutation of FFA2 (Ffar2-/-)
exhibit impaired glucose tolerance, lower insulin levels and diminished BCM expansion during pregnancy, 3)
SCFAs, the primary ligands for FFAR2, are altered during pregnancy within the gut and blood of mice, and
finally 4) the bacterial species in the mouse gut microbiota are influenced during pregnancy, as observed for
humans. Because of these compelling data, our goal in this proposal is to dissect and test how the gut
microbiota, SCFAs, and Ffar2 on β-cells are contributing to gestational glucose homeostasis during pregnancy.
First, through a novel mouse model created by our group, a β cell specific knockout of Ffar2, we will explore
how β cell expressed Ffar2 mediates GSIS and BCM changes during pregnancy. Next, we will identify the key
fermentative gut bacterial taxa and the metagenomic profiles of these taxa that contribute to SCFA level
changes during pregnancy. And finally, we will test the collective relationship between gut microbiota, SCFAs,
and β cell expressed Ffar2 by modulating the gut microbiota through germ-free conditions, testing the influence
of the gut microbiota on glucose homeostasis in our β cell specific knockout of Ffar2. If this novel relationship
exists during pregnancy, we will reveal a new paradigm in gestational glucose metabolism, and provide new
insight into how the gut microbiota influences host metabolism.
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## Key facts

- **NIH application ID:** 9898235
- **Project number:** 5I01BX003382-04
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** Brian Thomas Layden
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898235

## Citation

> US National Institutes of Health, RePORTER application 9898235, A Novel Relationship Between the Gut Microbiota and Pancreatic Beta Cells contributes to Gestational Glucose Homeostasis (5I01BX003382-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898235. Licensed CC0.

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