Cellular and molecular gastroenterology and hepatology · 2025
The P2X7 Receptor Promotes Intestinal Fibrosis by Modulating the Gut Microbiota and the Inflammasome.
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Ribeiro Beatriz Elias, de Lima Isadora Schmukler, da Silva E Souza Karen Cristina, Rosas Siane Lopes Bittencourt, Santana Patrícia Teixeira, Amaral Gilda, Machado João Carlos, de Oliveira Rodrigo Pereira, Leal Camille, Thompson Cristiane, Thompson Fabiano, Castelo-Branco Morgana Teixeira Lima, Coutinho-Silva Robson, de Souza Heitor Siffert Pereira
Аннотация
BACKGROUND & AIMS: Considering the role of the P2X7 receptor in intestinal inflammation, we examined its potential involvement in fibrosis development.
METHODS: Colonic biopsies from patients with inflammatory bowel disease (IBD) were analyzed via double immunofluorescence under confocal microscopy. Colon fibroblasts were used to analyze P2X7 receptor modulation and chemotaxis. Experimental chronic colitis was induced with 3 cycles of oral dextran sodium sulfate (DSS) treatment in P2X7+/+ and P2X7-/- mice. The mice were evaluated via follow-up video endoscopy with an endoluminal ultrasound biomicroscopic (eUBM) system, histological scoring, immunohistochemistry, cytokine measurement in colon explants, gene expression analysis of P2X7 signaling targets via quantitative real-time polymerase chain reaction (qRT-PCR), and microbiome composition analysis.
RESULTS: Colocalization studies revealed a greater density of P2X7+/alpha smooth muscle actin (α-SMA)+ cells in colon sections from patients than in those from controls, especially in patients with Crohn's disease (P < .05). Activation of the adenosine triphosphate (ATP)-P2X7 pathway in human fibroblasts increased cell migration, calcium influx, and collagen production. Video colonoscopy with the eUBM system revealed significantly more inflammation, with greater wall thickness and stiffness, in P2X7+/+ mice than in P2X7-/- and P2X7+/+ mice treated with A740003 (a P2X7-selective inhibitor). P2X7+/+ mice exhibited increased caspase-1 and NLRP3 expression, as well as nuclear factor κB (NF-κB) and extracellular signal-regulated kinase (ERK) activation, accompanied by decreased peroxisome proliferator-activated receptor gamma (PPARγ) expression. In the supernatants of colon explants, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interferon (IFN)-γ, transforming growth factor (TGF)-β, IL-10, and collagen production were increased in P2X7+/+ mice. Various microbial changes were observed in P2X7-/- and P2X7+/+ mice.
CONCLUSIONS: Regulatory mechanisms downstream of P2X7, combined with signals from a dysbiotic microbiota, activate intracellular signaling pathways and the inflammasome, leading to intestinal inflammation and promoting fibrogenesis.
METHODS: Colonic biopsies from patients with inflammatory bowel disease (IBD) were analyzed via double immunofluorescence under confocal microscopy. Colon fibroblasts were used to analyze P2X7 receptor modulation and chemotaxis. Experimental chronic colitis was induced with 3 cycles of oral dextran sodium sulfate (DSS) treatment in P2X7+/+ and P2X7-/- mice. The mice were evaluated via follow-up video endoscopy with an endoluminal ultrasound biomicroscopic (eUBM) system, histological scoring, immunohistochemistry, cytokine measurement in colon explants, gene expression analysis of P2X7 signaling targets via quantitative real-time polymerase chain reaction (qRT-PCR), and microbiome composition analysis.
RESULTS: Colocalization studies revealed a greater density of P2X7+/alpha smooth muscle actin (α-SMA)+ cells in colon sections from patients than in those from controls, especially in patients with Crohn's disease (P < .05). Activation of the adenosine triphosphate (ATP)-P2X7 pathway in human fibroblasts increased cell migration, calcium influx, and collagen production. Video colonoscopy with the eUBM system revealed significantly more inflammation, with greater wall thickness and stiffness, in P2X7+/+ mice than in P2X7-/- and P2X7+/+ mice treated with A740003 (a P2X7-selective inhibitor). P2X7+/+ mice exhibited increased caspase-1 and NLRP3 expression, as well as nuclear factor κB (NF-κB) and extracellular signal-regulated kinase (ERK) activation, accompanied by decreased peroxisome proliferator-activated receptor gamma (PPARγ) expression. In the supernatants of colon explants, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interferon (IFN)-γ, transforming growth factor (TGF)-β, IL-10, and collagen production were increased in P2X7+/+ mice. Various microbial changes were observed in P2X7-/- and P2X7+/+ mice.
CONCLUSIONS: Regulatory mechanisms downstream of P2X7, combined with signals from a dysbiotic microbiota, activate intracellular signaling pathways and the inflammasome, leading to intestinal inflammation and promoting fibrogenesis.