# Bile acid-dependent T cell regulation in the intestine

> **NIH NIH R01** · SCRIPPS FLORIDA · 2022 · $140,326

## Abstract

Project Summary
Immune-mediated inflammation of the distal small intestine, or ileitis, is a common and debilitating feature of
the inflammatory bowel disease, Crohn’s disease. However, the mechanisms governing local immune function
and inflammation in the ileum remain poorly defined. This proposal interrogates a novel pathway by which
circulating CD4+ T effector (Teff) cells—including IFN-producing Th1 and IL-17A-secreting Th17 cells—
compensate for cytotoxic concentrations of bile acids (BAs) in the ileum to safeguard immune homeostasis.
Long considered simple emulsifying agents that circulate between the liver and ileum and that facilitate
absorption and elimination of dietary lipids, BAs have now emerged as pleiotropic signaling metabolites that
regulate host metabolism and inflammation via dynamic interactions with both germline-encoded receptors and
the intestinal microbiota. We have shown that Teff cells upregulate expression of the xenobiotic transporter,
MDR1, in the ileum to limit oxidative stress, prevent pathogenic cytokine secretion and suppress ileitis in the
presence of locally-reabsorbed BAs. We have also identified the constitutive androstane receptor (CAR)–a BA-
sensing nuclear receptor with no known function in immune cells—as a driver of MDR1 (Abcb1a) gene
expression in mucosal Teff cells. Loss or knockdown of either MDR1 or CAR in Teff cells precipitates severe
ileitis upon transfer into immunodeficient Rag1-/- mice. Mechanistically, our data suggest that CAR responds to
mucosa-associated BAs in the ileum by activating the expression of numerous drug-processing enzymes and
transporters in mucosal Teff cells, including MDR1, to detoxify BAs and enforce local immune homeostasis.
This mechanism is directly relevant to the understanding and treatment of Crohn’s disease, as: (i) MDR1
expression in human Teff cells is increased markedly in the intestinal mucosa; (ii) MDR1 loss-of-function is
evident in a subset of Crohn’s disease patients; and (iii) cholestyramine, an FDA-approved bile acid
sequestrant that blocks BA reabsorption into the ileal mucosa, attenuates ileitis in both T cell transfer and
spontaneous mouse models of Crohn’s disease. In addition, this mechanism establishes an unexpected new
regulatory function of BAs. Our proposed studies use genetic and pharmacologic approaches, as well as
clinically-relevant mouse models of Crohn’s disease, to define the mechanisms by which CAR and its
transcriptional targets interact with BAs to enforce immune homeostasis in the ileum. Together, these studies
will bring to light an important new pathway underlying local immune homeostasis in the ileum, whilst having
important implications for improving our understanding and treatment of human Crohn’s disease.

## Key facts

- **NIH application ID:** 10336387
- **Project number:** 5R01AI143821-04
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Mark Scott Sundrud
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $140,326
- **Award type:** 5
- **Project period:** 2019-02-06 → 2022-04-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10336387

## Citation

> US National Institutes of Health, RePORTER application 10336387, Bile acid-dependent T cell regulation in the intestine (5R01AI143821-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10336387. Licensed CC0.

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