# Role of the complement C3a receptor on immune and non immune intestinal barrier functions and microbiota in colorectal cancer development

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2022 · $361,672

## Abstract

While it was initially believed that only a minority of CRC are driven by inflammation, studies showing that
treatment with anti-inflammatory medications may prevent or delay the development of CRC in hereditary and
sporadic cases, clearly identify inflammation as a key driver in the development and progression of all types of
CRC. Yet, it is still unclear what are the mechanisms that in the complex intestinal environment contribute to the
activation of the inflammatory pathways that initiate CRC.
The intestine holds a delicate balance between host protection and control of excessive inflammation, and we
posit that a dysregulated communication between the epithelial and the immune component of the intestinal
barrier may link a sub-acute state of inflammation and CRC initiation. The complement system is emerging as
an important player in the gastrointestinal tract. Specifically, the complement anaphylatoxin C3a and its receptor,
C3aR, regulate the immune and epithelial compartments in the intestine and exert antibacterial properties. By
mining publicly available datasets, we found that C3aR is down-regulated in patients with CRC and the fact that
this down-regulation occurs already in stage 1 tumors, suggests that it may be an early event during CRC
development. By crossing C3aR-/- mice with the APCMin/+ mice, that carry a mutation in the apc gene, similarly
to the majority of human CRC, we showed that C3aR is protective in CRC. Indeed, while in APCMin/+ mice tumors
mostly developed in the small intestine, in APCMin/+/C3aR-/- mice tumorigenesis dramatically shifted almost
exclusively to the colon. We also found intestinal barrier dysfunction and microbial dysbiosis in mice lacking
C3aR, suggesting that C3aR may be a novel gatekeeper in intestinal homeostasis. However, it is currently
unknown how C3aR contributes to CRC development.
We hypothesize that loss of C3aR causes intestinal barrier dysfunction by affecting the communication between
epithelial and immune cells. This then leads to development of microbiota-driven inflammatory immune
responses that promote the development of CRC. To test this hypothesis we propose:
1) to investigate how loss of C3aR affects the epithelial component of the intestinal barrier and the
communication with the immune cells; 2) To investigate the contribution of C3aR on immune, non immune cell
types, and microbiota to CRC development; 3) To investigate the C3aR status in human pre-invasive lesions
and CRC. Bone marrow chimera in combination with single cell high dimensional analysis of immune infiltrates
using mass cytometry and REAPseq will determine the contribution of C3aR on immune and non immune cells
to colon inflammation and CRC development and progression. We will assess how C3aR down-regulation affects
human CRC and survival by using human specimens from our well characterized patient cohorts. As loss of
C3aR represents an early event during CRC, identifying the mechanisms linking loss of C3aR to the develo...

## Key facts

- **NIH application ID:** 10522693
- **Project number:** 1R01CA258882-01A1
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Silvia Guglietta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $361,672
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522693

## Citation

> US National Institutes of Health, RePORTER application 10522693, Role of the complement C3a receptor on immune and non immune intestinal barrier functions and microbiota in colorectal cancer development (1R01CA258882-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10522693. Licensed CC0.

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