Bacteroides fragilis Enterotoxin Upregulates Matrix Metalloproteinase-7 Expression through MAPK and AP-1 Activation in Intestinal Epithelial Cells, Leading to Syndecan-2 Release

Abstract

Bacteroides fragilis enterotoxin (BFT) produced by enterotoxigenic B. fragilis (ETBF) causes colonic inflammation. BFT initially contacts intestinal epithelial cells (IECs) and affects the intestinal barrier. Although molecular components of the gut epithelial barrier such as metalloproteinase-7 (MMP-7) and syndecan-2 are known to be associated with inflammation, little has been reported about MMP-7 expression and syndecan-2 shedding in response to ETBF infection. This study explores the role of BFT in MMP-7 induction and syndecan-2 release in IECs. Stimulating IECs with BFT led to the induction of MMP-7 and the activation of transcription factors such as NF-κB and AP-1. MMP-7 upregulation was not affected by NF-κB, but it was related to AP-1 activation. In BFT-exposed IECs, syndecan-2 release was observed in a time- and concentration-dependent manner. MMP-7 suppression was associated with a reduction in syndecan-2 release. In addition, suppression of ERK, one of the mitogen-activated protein kinases (MAPKs), inhibited AP-1 activity and MMP-7 expression. Furthermore, the suppression of AP-1 and ERK activity was related to the attenuation of syndecan-2 release. These results suggest that a signaling cascade comprising ERK and AP-1 activation in IECs is involved in MMP-7 upregulation and syndecan-2 release during exposure to BFT.

Entero-toxigenic Bacteroides fragilis contributes to intestinal barrier injury and colorectal cancer progression by mediating the BFT/STAT3/ZEB2 pathway

“…In contrast, we further explored the roles of ETBF, NTBF, and BFT in the integrity of the intestinal mucosal barrier. Jeon et al [ 26 ] revealed that BFT secreted by ETBF facilitated the upregulation of MMP-7 and release of syndecan-2 in intestinal epithelial cells, which disrupted the intestinal mucosal barrier. Similar results have been reported by Patterson et al [ 27 ].…”

Berberine: Potential preventive and therapeutic strategies for human colorectal cancer

“…32 For example, fragilysin secreted by Bacteroides fragilis, a Gramnegative anaerobic bacterium, stimulates the expression of IL-8, TGFβ, and C5a, causing an inflammatory environment. 33 Besides, B. fragilis adjusts the imbalance of T-helper 17/T regulatory (Th17/Treg) cells, helping to maintain the intestinal immune microenvironment. 34 Further, Fusobacterium nucleatum causes an immunosuppressive environment through NK cell inactivation, reduction of T cell…”

Human microbiomes in cancer development and therapy

“… 198 In a mouse model of CRC, enterotoxin Bacteroides fragilis (ETBF) stimulated the immune response through T helper 17 cells (Th17) and promoted colon tumor growth. 137 , 138 , 199 Similarly, E. coli expressing the genomic island polyketide synthase (pks+) enhanced tumorigenesis in preclinical CRC models and were found to be enriched in human CRC tissues . 200 , 201 Furthermore, pks + E. coli produces the genotoxin colibactin, which alkylates DNA, resulting in the formation of DNA adducts (a form of potentially mutagenic DNA damage) in colonic epithelial cells.…”

“…This recruited CD8+ T cells and induced an inflammatory response, which damaged the gastric mucosa and promoted gastric carcinogenesis 198 . In a mouse model of CRC, enterotoxin Bacteroides fragilis (ETBF) stimulated the immune response through T helper 17 cells (Th17) and promoted colon tumor growth 137,138,199 . Similarly, E. coli expressing the genomic island polyketide synthase (pks+) enhanced tumorigenesis in preclinical CRC models and were found to be enriched in human CRC tissues 200,201 .…”