A microbiome-dependent bile acid metabolite improves type 2 diabetes
Active Project Grant Awarded Last action
- Award ID
- R01DK126855
- Recipient
-
Brigham & Womens Hospital Inc. UEI QN6MS4VN7BD1 Part of Partners Healthcare System Incorporated
- Awarding agency
-
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $11,541,248
Award facts
- Assistance listing
- 93.847 Diabetes, Digestive, and Kidney Diseases Extramural Research
- Completion date 56% complete
- Originally
- Funding
-
- $10,841,104.00 Federal
- $700,144.00 Non-federal
- Place of performance
- Boston, MA 02115, USA
Award details come from USAspending.gov.
Description
- 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 of bariatric surgery and identify multiple novel targets for the treatment of T2D.
Transactions
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| Amendment | $700,144 | $0 | |
| Original award | $700,144 | $700,144 |
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Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| President And Fellows Of Harvard College | $403,079 | |
| President And Fellows Of Harvard College | $1,495,216 |
Quick answers
Who received award R01DK126855?
R01DK126855 was awarded to Brigham & Womens Hospital Inc. by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on January 8, 2021.
How much is award R01DK126855 worth?
$11,541,248 has been obligated on R01DK126855: $10,841,104 in federal funding and $700,144 in non-federal funding.
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