Abstract
Carriage of enterotoxigenic Bacteroides fragilis (ETBF) in the colonic mucosa is associated with increased risk of pre-cancerous lesions. Antibiotics will not selectively eradicate these bacteria, but toxin-mediated host responses may provide therapeutic target(s). The B. fragilis toxin (BFT) is a metalloprotease that cleaves E-cadherin, an adherens junction protein that is integral to preserving the integrity of cell-to-cell adhesion in gut epithelium. The aim of this study was to test the hypothesis that aspirin, which is shown to reduce adenomatous polyp formation in some but not all individuals, may protect the gut epithelium from BFT-related cleavage of E-cadherin.
Aspirin at physiological concentrations (0.5-5mM) inhibited the growth of colonic epithelial HT29 cells that are widely used to model BFT-associated loss of E-cadherin. RT-qPCR and fluorescence microscopy were used to show that aspirin increased CDH1 gene expression that was associated with intensified expression of E-cadherin at the plasma membrane of HT29 cells. Aspirin was shown to mitigate BFT-mediated cleavage of E-cadherin in HT29 cells. Aspirin was also found to have a dose-dependent effect on the growth of B. fragilis (toxigenic and non-toxigenic isolates), with an IC50 of approximately 2.5mM. Azocasein assays suggested that aspirin may also have a measurable effect on BFT activity.
The protective role for aspirin in reducing the risk of colorectal carcinogenesis is usually linked to an anti-inflammatory effect. However, the findings of this pilot study suggest that aspirin may act more broadly at a cellular level, via increased expression of E-cadherin. Moreover, aspirin may also act directly by reducing the growth of B. fragilis, as well as mitigating the activity of BFT. With further insight into aspirin’s bactericidal properties, it is hoped that novel and affordable approaches can be developed to reduce toxin-mediated carcinogenesis in infected/at-risk individuals.