# Exploring the role of C3 in intestinal homeostasis

> **NIH NIH R21** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $228,000

## Abstract

The mammalian gastrointestinal (GI) tract is host to a complex community including microbes
and immune cells that converge at the epithelial barrier. Despite nearly constant interaction between
these two populations, homeostasis is largely maintained. This is accomplished, in part, through non-
inflammatory barrier host defense mechanisms, many of which have yet to be explored. Using a well-
established model system of non-inflammatory commensal colonization with Enterococcus faecalis
(EF), we confirmed a significant increase in complement component 3 (C3) gene expression in the
epithelium of the distal small intestine (DSI). Complement has been associated with intestinal cells in
more recent years, but C3 gene expression in the DSI in the absence of inflammatory stimuli has not
been observed until now. Using state of the art spatial transcriptomics, we characterized clusters of
cells in the DSI that were responsible for the increase in C3 gene expression in the DSI and found
that they were made up of enterocytes, Paneth cells and fibroblasts. We also found that C3 protein in
both DSI tissue and luminal contents were present during homeostasis and DSI luminal content C3
increased in response to EF colonization. Within the DSI luminal contents, we showed that
commensal bacteria are bound by C3. Because we found novel cellular expression of C3 in the DSI
during commensal colonization, we hypothesize that C3 produced by gut epithelium is secreted into
the lumen to mediate non-inflammatory commensal-host interaction. To characterize the relevance of
these sources and the role of C3 in the DSI, we propose two aims. Aim 1 will characterize the cellular
sources of intestinal C3 and the specificity of C3 bacterial binding in the DSI lumen. Aim 2 will
investigate the function of C3 in the DSI to facilitate host-microbe homeostasis. Completion of these
aims will drive future mechanistic studies of C3 in the DSI, and its contribution to non-inflammatory
host defense.

## Key facts

- **NIH application ID:** 10887870
- **Project number:** 1R21AI177453-01A1
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Nita H Salzman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $228,000
- **Award type:** 1
- **Project period:** 2024-06-05 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887870

## Citation

> US National Institutes of Health, RePORTER application 10887870, Exploring the role of C3 in intestinal homeostasis (1R21AI177453-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10887870. Licensed CC0.

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