Gut Epithelial-derived CXCL9 Maintains Gut Homeostasis Through Preventing Overgrown E. coli

Abstract

Background and Aims The increased E. coli in colon are related to the occurrence and development of multiple diseases. Chemokines are shown to possess potentially antimicrobial activity, including Gram positive and negative bacterial pathogens. We here investigated function(s) of chemokine CXCL9 expressed in the gut epithelial cells and mechanism(s) of CXCL9 to kill E. coli. Methods We generated CXCL9 fl/flpvillin-cre T mice (pvillin-cre positive mice) and their control CXCL9 fl/flpvillin-cre wmice (pvillin-cre negative mice), and then employed dextran sulfate sodium (DSS)-mediated colitis model to determine sensitivity of the CXCL9 fl/flpvillin-cre T mice. We analyzed composition of the gut microbiota by using 16S ribosomal RNA (V3-V4 variable region) sequencing and shotgun metagenomic analyses. We generated E. coli ∆FtsX (FtsX depleted E. coli) and E. coli ∆aceE (aceE depleted E. coli) by using bacterium red recombining system to investigate the mechanism(s) of CXCL9 to kill E. coli. Results CXCL9 fl/flpvillin-cre Tmice were more sensitive to chemically induced colitis than their control littermates CXCL9 fl/flpvillin-cre wmice. After DSS treatment, there were markedly increased gut E. coli (Escherichia-Shigella) in the colonic contents of CXCL9 fl/flpvillin-cre T mice as compared to control CXCL9 fl/flpvillin-cre w mice. The increased E. coli could promote colitis through NLRC4 and caspase 1/11-mediated IL-18, which was derived from gut epithelial cells. We finally demonstrated that CXCL9 expressed in gut epithelial cells could kill the overgrown E. coli. E. coli expressed Ftsx and PDHc subunits aceE. E.coli∆aceE but not E. coli∆FtsX were resistant to CXCL9-mediated killing. Conclusions Gut epithelial cells-derived CXCL9 can kill the expanded E. coli through aceE to remain gut homeostasis.

Repeated Social Defeat Stress Induces an Inflammatory Gut Milieu by Altering the Mucosal Barrier Integrity and Gut Microbiota Homeostasis

“…Notably, ICAM-1 modulates inflammatory responses by promoting the infiltration of immune cells, while CXCL-9 has been reported to promote age-related inflammation ( 68 , 69 ). The gut epithelial-derived CXCL-9 has also been reported in the prevention of microbial overgrowth during infection ( 70 , 71 ). Our findings, in which Stat-3 and NF-κB signaling is modulated in the RSDS mice, further support a widespread dysregulation of the mucosal immunity and susceptibility to inflammation in response to RSDS at the molecular level.…”

Analysis of the interferon-γ-induced secretome of intestinal endothelial cells: putative impact on epithelial barrier dysfunction in IBD

“…Serum CXCL9 levels also reflect disease activity in both UC and CD ( Caruso, 2019 ; Bergemalm et al, 2021 ; Boucher et al, 2022 ; Chen et al, 2022 ) and circulating CXCL9 was identified in preclinical CD and UC as an IBD-risk biomarker ( Bergemalm et al, 2021 ; Leibovitzh et al, 2023 ) that predicts relapse in UC and CD ( Kessel et al, 2021 ; Walshe et al, 2022 ). At the molecular level, CXCL9 has been shown to inhibit the reconstitution of the intestinal mucosa after injury ( Lu et al, 2015 ) and to control E. coli overgrowth through the pyruvate dehydrogenase-encoding aceE gene in a DSS-induced colitis model ( Wei et al, 2022 ). Hence, CXCL9 released by endothelial cells might not only increase immune cell recruitment but also may compromise the epithelial barrier and alter the microbiota in intestinal inflammation.…”

Epithelial Barrier Dysfunction in Disease

“…Serum CXCL9 levels also reflect disease activity in both UC and CD (Caruso, 2019;Bergemalm et al, 2021;Boucher et al, 2022; and circulating CXCL9 was identified in preclinical CD and UC as an IBD-risk biomarker (Bergemalm et al, 2021;Leibovitzh et al, 2023) that predicts relapse in UC and CD (Kessel et al, 2021;Walshe et al, 2022). At the molecular level, CXCL9 has been shown to inhibit the reconstitution of the intestinal mucosa after injury and to control E. coli overgrowth through the pyruvate dehydrogenase-encoding aceE gene in a DSS-induced colitis model (Wei et al, 2022). Hence, CXCL9 released by endothelial cells might not only increase immune cell recruitment but also may compromise the epithelial barrier and alter the microbiota in intestinal inflammation.…”