# An engineered Clostridial consortia to interrogate immune modulation by secondary bile acids

> **NIH NIH R21** · UNIVERSITY OF CHICAGO · 2024 · $237,296

## Abstract

We, and others, have linked the increasing prevalence of non-communicable chronic diseases (NCCDs),
to changes in the composition and function of resident intestinal microbes. To gain insight into the mechanisms
responsible for a bacteria-induced barrier protective response, we have examined the roles of various
Lachnospiraceae products, including the short chain fatty acid butyrate and tryptophan metabolites and
commensal flagellins. In this proposal we explore the immunomodulatory capacity of Lachnospiraceae-derived
secondary bile acids (SBAs). Bile acids (BAs) have long been known as emulsifying agents which facilitate the
absorption of dietary lipids in the small intestine. Emerging evidence shows that BAs also potently regulate
mucosal and systemic immunity. In collaboration with the Mimee laboratory at the University of Chicago, we
have used a group II intron-based approach to target 3b-HSDH, a terminal enzyme in the biosynthesis of isoDCA,
in the prominent Lachnospiraceae species [Ruminococcus] gnavus. R. gnavus is among a small group of gut
bacteria which possess both the 3a- and 3b- HSDHs required to epimerize DCA into isoDCA. By pairing this
novel mutant R. gnavus with the Clostridial strain P. hiranonis we have created a two-strain consortium that
allows us to toggle isoDCA production on and off (while keeping other bacterial products and metabolites
constant) in mice with a replete microbiome. This innovative approach will enable an interrogation of the
mechanisms by which Lachnospiraceae-derived isoDCA modulates host immunity at homeostasis and an
assessment of its immunomodulatory potential in well-established models of intestinal inflammation. We
hypothesize that isoDCA has anti-inflammatory effects on all levels of the intestinal immune system including
intestinal epithelial cells and CD11c+ antigen presenting cells through the Farnesoid X receptor (FXR) and the
G-protein coupled bile acid receptor (GPBAR1/TGR5). In the first Aim we will identify key cell types and signaling
mechanisms involved in the immunomodulatory activity of isoDCA. We will then examine the mechanisms by
which isoDCA ameliorates intestinal inflammation in Aim 2.

## Key facts

- **NIH application ID:** 10952955
- **Project number:** 1R21AI186046-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** CATHRYN R NAGLER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $237,296
- **Award type:** 1
- **Project period:** 2024-06-12 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10952955

## Citation

> US National Institutes of Health, RePORTER application 10952955, An engineered Clostridial consortia to interrogate immune modulation by secondary bile acids (1R21AI186046-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10952955. Licensed CC0.

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