# The Role of Bile Salt Hydrolase in Glucose Metabolism

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2023 · —

## Abstract

PROJECT SUMMARY/ABSTRACT
 Currently, 34.2 million US adults, or approximately 10.3% of the total population, have diabetes. The
prevalence of diabetes is two-fold higher among Veterans (20.5%) and it is the leading cause of kidney failure,
lower-limb amputations, and adult-onset blindness both in Veterans and the general population. Over the last
two decades, multiple metabolic studies have demonstrated that bile acids play an unexpected but important
role in glucose homeostasis and metabolic syndrome. Correlational 16S and metagenomic studies suggest that
gut microflora can affect host glucose homeostasis through modification of bile acids. The overall goal of this
proposal is to determine the mechanisms by which the gut microflora affect host glucose homeostasis. To have
a better functional understanding of this relationship, investigators need to assess the role of specific bacterial
bile acid biotransformations and investigate their effects on the gut luminal ecology, the flux of metabolites and
nutrients, and ultimately, physiology in conventionally-raised (as opposed to microbiome-depleted) hosts. Thus,
there is a critical need for a tool that will facilitate knocking-in of specific bacterial functions into the gut
microbiome and investigate their effects on the host glucose metabolism and insulin sensitivity.
 The investigators demonstrate an innovative strategy that addresses this need using engineered native
bacteria. This novel approach allows quick and effective knocking-in of a beneficial function into the gut
microbiome. The function is sustained, potentially for perpetuity, in conventionally-raised hosts with a single
treatment and without the need for microbiome depletion. To date, the investigators have demonstrated that
tractable native bacteria can be engineered to modify bile acids ex vivo, reintroduced to the host, engraft the
entire gut, deliver an intended beneficial function, alter luminal and serum metabolites as intended, affect host
metabolism, and even reverse disease. These functions affect host physiology and potentially alleviate disease.
Using this new approach, the investigators will pursue the overall goal by addressing the central hypothesis that
gut microbiome affects host insulin sensitivity through bile acid deconjugation and that these functions can be
used to treat type 2 diabetes.
 In the next four years, the investigators will pursue the proposal's central hypothesis with three specific aims.
The first aim will determine if bacterial bile acid deconjugation affects ileal and hepatic glucoregulatory transcripts
in conventionally-raised C57Bl6 mice. Ultimately this aim will determine the relationship between bacterial bile
acid modification and host bile acid signaling, gluconeogenesis, and incretin production. The second aim will
determine if the glucoregulatory effects of microbial bile acid deconjugation are mediated by the farnesoid X
receptor (FXR), a major bile acid receptor. This will be done using en...

## Key facts

- **NIH application ID:** 10617180
- **Project number:** 5I01BX005707-02
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Amir Zarrinpar
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10617180

## Citation

> US National Institutes of Health, RePORTER application 10617180, The Role of Bile Salt Hydrolase in Glucose Metabolism (5I01BX005707-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10617180. Licensed CC0.

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