# Role of SLC46A3 in the pathogenesis of inflammatory bowel disease

> **NIH AI R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2026 · $251,250

## Abstract

Inflammatory bowel diseases (IBD), including Crohn’s disease (CD), remain a significant
clinical challenge with increasing prevalence, affecting millions worldwide despite recent
therapeutic advances. Loss-of-function polymorphisms in the Nod2 gene are strongly
associated with CD, which has long created a conundrum as NOD2 is a cytosolic innate
immune receptor that senses small fragments of the bacterial cell wall (muropeptides)
and triggers an inflammatory response. Several non-exclusive explanations for this
conundrum have been proposed in the literature, including altered TLR signaling,
reduced antimicrobial peptide production, or altered barrier function in the gut in the
absence of Nod2. All of these reported changes may contribute to the microbial
dysbiosis observed in mouse models and patients with alterations in Nod2. While it is
clear that NOD2 protects against colitis through some or all of these reported pathways,
the mechanisms by which muropeptides, like the NOD2 agonist MDP, transit from the
gut lumen to cytosolic NOD2 are unclear. Emerging evidence from studies of skin and
skin keratinocytes suggests that solute carrier (SLC) transport proteins, especially the
SLC46 family, mediate the internalization of MDP and other muropeptides, although this
hypothesis has not yet been examined in the gut epithelia or macrophages. Here, we
propose to examine the role of the SLC46A3 transporter in facilitating MDP transport
and subsequent NOD2 activation, with implications for IBD. Preliminary data from
murine colitis models show that Slc46a3 knockout mice exhibit increased susceptibility
to colitis, resembling the pathology seen in Nod2-deficient animals. This suggests a
critical role for SLC46A3 in NOD2 signaling and gut homeostasis. In this exploratory
R21 proposal, we will investigate the role of the SLC46A3/NOD2 axis in the context of
MDP transport, sensing and mouse models of IBD.

## Key facts

- **NIH application ID:** 11381101
- **Project number:** 1R21AI193666-01A1
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Ravi  Bharadwaj; Neal  Silverman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** AI
- **Fiscal year:** 2026
- **Award amount:** $251,250
- **Award type:** 1
- **Project period:** 2026-04-01T00:00:00 → 2028-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11381101

## Citation

> US National Institutes of Health, RePORTER application 11381101, Role of SLC46A3 in the pathogenesis of inflammatory bowel disease (1R21AI193666-01A1). Retrieved via AI Analytics 2026-07-02 from https://api.ai-analytics.org/grant/nih/11381101. Licensed CC0.

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