The P2X7 Receptor Promotes Intestinal Fibrosis by Modulating the Gut Microbiota and the Inflammasome

Area of Science:

• Gastroenterology
• Immunology
• Cell Biology

Background:

• The P2X7 receptor (P2X7R) plays a role in intestinal inflammation.
• Its involvement in fibrosis development in inflammatory bowel disease (IBD) requires investigation.

Purpose of the Study:

• To examine the role of the P2X7 receptor in the development of intestinal fibrosis in IBD.
• To investigate the molecular mechanisms linking P2X7R, inflammation, and fibrosis.

Main Methods:

• Analysis of colonic biopsies from IBD patients and controls using immunofluorescence.
• In vitro studies on human colon fibroblasts.
• Induction of chronic colitis in P2X7 receptor-deficient (P2X7^-/-) and wild-type (P2X7^+/+) mice treated with dextran sodium sulfate (DSS).
• In vivo assessment using video endoscopy and endoluminal ultrasound biomicroscopy (eUBM), histology, immunohistochemistry, cytokine analysis, gene expression, and microbiome analysis.

Main Results:

• Increased P2X7 receptor and α-SMA co-expression in IBD patients, particularly in Crohn's disease.
• P2X7 receptor activation enhanced fibroblast migration, calcium influx, and collagen production.
• P2X7^+/+ mice showed increased inflammation, wall thickening, and stiffness compared to P2X7^-/- mice and those treated with a P2X7 inhibitor.
• Elevated inflammatory markers (caspase-1, NLRP3, NF-κB, ERK) and reduced PPARγ were observed in P2X7^+/+ mice.
• Increased pro-fibrotic and inflammatory cytokines and collagen production in P2X7^+/+ mice colon explants.
• Distinct microbiome alterations were noted in both P2X7^-/- and P2X7^+/+ mice.

Conclusions:

• P2X7 receptor signaling, influenced by dysbiotic microbiota, activates intracellular pathways and the inflammasome.
• These mechanisms contribute to intestinal inflammation and promote fibrogenesis in IBD.