The intestinal epithelium undergoes rapid renewal every 3–5 days, a process driven by intestinal stem cells (ISCs) located at the base of crypts. While ISCs play an essential role in epithelial regeneration following injury, such as that induced by chemotherapy or radiation, the underlying regulatory mechanisms remain incompletely understood.
Formyl peptide receptor 2 (FPR2) is a G-protein-coupled receptor (GPCR) that functions as a pattern recognition receptor (PRR). It is characterized by its ability to recognize a structurally diverse array of ligands, including bacteria-derived formyl peptides (such as fMLF), host-produced lipids, and synthetic small molecules. FPR2 research has focused heavily on its expression in phagocytic leukocytes and its roles in host defense, inflammation, and wound healing. Although systemic knockout studies suggested FPR2 might influence colonic recovery, the specific function of FPR2 expressed within the intestinal epithelial cells (IECs) themselves remained unknown prior to this investigation.

A recent study published in Life Metabolism led by Prof. Yingying Le at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences reveals that FPR2 plays a pivotal role in maintaining intestinal homeostasis and promoting tissue regeneration. Through a combination of knockout mouse models and organoid culture systems, the research team demonstrated that FPR2 activation regulates the proliferation and differentiation of both ISCs and transit-amplifying (TA) cells. Moreover, they identified that this process is mediated through the PKC-ERK signaling axis, which in turn triggers the Wnt, Notch, and Hippo signaling pathways, suggesting a potential therapeutic target for intestinal damage (Figure 1).

By using newly generated intestinal epithelial-specific Fpr2 knockout mice (Fpr2^VKO) and ISC-specific knockout models (Lgr5-Fpr2^KO), the study revealed that Fpr2 deficiency resulted in significant structural alterations within the small intestine and colon, including reduced villus height and crypt depth, accompanied by decreased numbers of goblet cells, Paneth cells, and ISCs. Proliferation markers such as Ki67 and BrdU were also suppressed, indicating impaired activity of both ISCs and TA cells.

By applying intestinal organoid culture and single-cell RNA sequencing, the team found that FPR2 activation initiates a PKC-ERK signaling cascade, leading to the upregulation of key genes in the Wnt (e.g., Wnt3), Notch, and Hippo pathways, thereby driving cell cycle progression. Notably, the bacterial peptide fMLF was found to mimic these effects in an FPR2-dependent manner, suggesting a possible role for gut microbiota in modulating epithelial homeostasis.

In injury model experiments, including X-ray irradiation and 5-fluorouracil treatment, they found that Fpr2 knockout delayed epithelial regeneration, whereas administration of the FPR2 agonist MMK-1 enhanced survival rates and accelerated tissue repair. These findings highlight the therapeutic potential of FPR2 agonists as adjuvants to mitigate intestinal damage commonly associated with cancer therapies.

In conclusion, this study establishes intestinal epithelial FPR2 as a central regulator of gut homeostasis and repair. The findings provide a solid foundation for developing FPR2-targeted treatments. Future research will focus on identifying endogenous ligands and advancing clinical translation to improve outcomes for patients with intestinal injury.
DOI
10.1093/lifemeta/loaf045