# Nuclear Receptor Control of T Cell Function in Discrete Intestinal Microenvironments

> **NIH NIH R01** · DARTMOUTH-HITCHCOCK CLINIC · 2024 · $848,214

## Abstract

Project Summary
The gut is a central immunological organ, where host-microbe interactions shape immune tolerance and
inflammation, both locally and systemically. Yet prevailing immunological views conflate the two distinct organs
that comprise the gut—small and large intestine (or SI and LI)—which impedes more robust understanding of
mucosal immune regulation, and misses opportunities to develop safer, more targeted therapies for human
inflammatory bowel diseases (IBDs). The premise of this application, founded on recent discoveries from, and
synergy between, the two PIs (Sundrud, Weaver), is that mucosal CD4+ T cells use distinct sets of nuclear
receptors (NRs) in the SI and LI to interface with divergent classes of host- and microbe-derived metabolites,
respectively. Recent work from the Sundrud lab establishes that Foxp3- T effector (Teff) subsets—Th1, Th17
cells—use a NR with no previously known immunological function, the constitutive androstane receptor
(CAR/Nr1i3), to direct a ‘hepatocyte-like’ transcriptional response to contend with potentially cytotoxic bile acid
(BA) concentrations in the SI. A large gradient of BAs exists between the SI (millimolar) and LI (micromolar) due
to ‘enterohepatic’ circulation—primary BAs synthesized in the liver, stored in the gallbladder, and secreted post-
prandially into the duodenum are actively reabsorbed by specialized enterocytes in the ileum for portal
recirculation to the liver. Because BAs are lipophilic, they can be toxic and pro-inflammatory in enterohepatic
tissues; a host of nuclear receptors—including CAR—have evolved to suppress BA toxicity in hepatocytes and
enterocytes. Our data suggest that enterohepatic circulation creates a uniquely harsh SI microenvironment to
which infiltrating T cells must adapt to maintain tolerance and tissue homeostasis. The LI, by contrast, harbors
103-107 times more bacteria than the SI, and ~1000-fold less BAs. Accordingly, microbes and their metabolites—
short chain fatty acids (SCFAs; e.g., butyrate), secondary BAs (produced via microbial metabolism of residual
primary BAs)—become central to immune regulation in the LI. SCFAs inhibit histone deacetylase enzymes
(HDACs) and stabilize Foxp3 gene expression in peripherally-induced T regulatory cells (iTregs), whereas
secondary BAs promote LI Treg maintenance through another NR, vitamin D receptor (VDR). Thus, while
antigens from the enteric flora are required for priming both pro- and anti-inflammatory T cell responses
throughout the intestinal tract, we hypothesize that marked differences in the abundance of bugs and bile in the
SI vs. LI establish consequential metabolite gradients that are sensed by different NRs to instruct
compartmentalized T cell regulatory functions. We test this hypothesis through complementary, but not inter-
dependent, Aims, leveraging new mouse models, as well as a library of recombinant protein-based NR activity
assays, to define the mechanisms governing the transcriptional regulatio...

## Key facts

- **NIH application ID:** 10908574
- **Project number:** 5R01AI164772-06
- **Recipient organization:** DARTMOUTH-HITCHCOCK CLINIC
- **Principal Investigator:** Mark Scott Sundrud
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $848,214
- **Award type:** 5
- **Project period:** 2021-09-23 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908574

## Citation

> US National Institutes of Health, RePORTER application 10908574, Nuclear Receptor Control of T Cell Function in Discrete Intestinal Microenvironments (5R01AI164772-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10908574. Licensed CC0.

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