# "A microbiome-dependent bile acid metabolite improves type 2 diabetes."

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $700,144

## Abstract

Project Summary/Abstract
The molecular mechanisms that explain the potent anti-diabetic effects of bariatric surgery remain elusive. The
rapid nature of type 2 diabetes mellitus (T2D) remission after surgery have led to the suggestion that unidentified
small molecules are responsible. For sleeve gastrectomy (SG), the most common bariatric operation performed
today, knockout mouse studies have shown that bile acid receptors are critical for surgery’s metabolic benefits.
The key ligand(s) that are changed post-SG to engage these bile acid receptors is unknown. Work from our
laboratory has identified a bile acid metabolite, cholic acid 7-sulfate (CA7S), that is induced in the intestine by
SG. We have found that CA7S is a potent TGR5 agonist that improves glucose handling in diabetic mice, and
the production of CA7S occurs in the liver by sulfation of cholic acid in response to the gut microbial product,
lithocholic acid (LCA), that signals via the hepatic vitamin D receptor (VDR). Our long-term goal is to understand
and replicate less invasively the anti-diabetic mechanisms of bariatric surgery. The overall objective of this
application is to define the anti-diabetic properties of CA7S, the microbiome-dependent mechanisms of CA7S
production, and CA7S contribution to T2D remission following SG. Our central hypothesis is that CA7S is
produced in response to gut microbial metabolites and improves T2D following SG via intestinal TGR5 activation.
We will test this hypothesis in the following specific aims. In Aim 1, we will determine the effects of long-term
CA7S administration on insulin sensitivity, glucose tolerance, and weight in diet induced obese (DIO) mice and
TGR5 deficient mice to understand the global metabolic effects of CA7S and sustained intestinal TGR5
activation. In Aim 2, we will determine how the microbiome induces CA7S production by (1) quantifying LCA-
producing Clostridia bacterial species and expression of LCA-producing enzymes post-SG in mice and humans,
and (2) generating DIO mice with and without intestinal LCA and assessing their metabolic phenotype and
response to SG. In Aim 3, we will determine the role of CA7S in T2D improvement post-SG. We will perform
SG in VDR deficient mice, which lack endogenous CA7S, or in mice with knockdown of SULT2A1, the key
enzyme responsible for CA7S production. We will reconstitute CA7S by exogenous replacement in CA7S
deficient animals to determine the contribution of CA7S to surgical improvements in glucose metabolism. This
work will characterize the effects of a natural, gut-restricted TGR5 agonist, CA7S, on T2D and lay the foundation
for its translation as a therapeutic. By characterizing specific metabolite-receptor interactions within the intestine,
portal vein, and liver, we will define a novel, microbiome-dependent, gut-liver signaling pathway that explains
improvement in glucose metabolism after SG. This work will significantly advance our molecular understanding
of the causal mechanisms ...

## Key facts

- **NIH application ID:** 10099069
- **Project number:** 1R01DK126855-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Eric Garland Sheu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $700,144
- **Award type:** 1
- **Project period:** 2021-01-08 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10099069

## Citation

> US National Institutes of Health, RePORTER application 10099069, "A microbiome-dependent bile acid metabolite improves type 2 diabetes." (1R01DK126855-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10099069. Licensed CC0.

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