Streptococcus gallolyticus Increases Expression and Activity of Aryl Hydrocarbon Receptor-Dependent CYP1 Biotransformation Capacity in Colorectal Epithelial Cells.

Rahwa Taddese,Xinqun Wu,Harold Tjalsma,Dorine W Swinkels,Shaoguang Wu,Rian Roelofs,Annemarie Boleij,Derk Draper

doi:10.3389/fcimb.2021.740704

Abstract

ObjectiveThe opportunistic pathogen Streptococcus gallolyticus is one of the few intestinal bacteria that has been consistently linked to colorectal cancer (CRC). This study aimed to identify novel S. gallolyticus-induced pathways in colon epithelial cells that could further explain how S. gallolyticus contributes to CRC development.Design and ResultsTranscription profiling of in vitro cultured CRC cells that were exposed to S. gallolyticus revealed the specific induction of oxidoreductase pathways. Most prominently, CYP1A and ALDH1 genes that encode phase I biotransformation enzymes were responsible for the detoxification or bio-activation of toxic compounds. A common feature is that these enzymes are induced through the Aryl hydrocarbon receptor (AhR). Using the specific inhibitor CH223191, we showed that the induction of CYP1A was dependent on the AhR both in vitro using multiple CRC cell lines as in vivo using wild-type C57bl6 mice colonized with S. gallolyticus. Furthermore, we showed that CYP1 could also be induced by other intestinal bacteria and that a yet unidentified diffusible factor from the S. galloltyicus secretome (SGS) induces CYP1A enzyme activity in an AhR-dependent manner. Importantly, priming CRC cells with SGS increased the DNA damaging effect of the polycyclic aromatic hydrocarbon 3-methylcholanthrene.ConclusionThis study shows that gut bacteria have the potential to modulate the expression of biotransformation pathways in colonic epithelial cells in an AhR-dependent manner. This offers a novel theory on the contribution of intestinal bacteria to the etiology of CRC by modifying the capacity of intestinal epithelial or (pre-)cancerous cells to (de)toxify dietary components, which could alter intestinal susceptibility to DNA damaging events.

Highlights

The resident gut microbiota is essential for human intestinal health and prevents the invasion of pathogens by providing colonization resistance and nutrient competition (Vollaard and Clasener, 1994; Hooper et al, 2002)
Multiple studies have documented that 33%–100% of S. gallolyticus-infected patients have concomitant adenomas and carcinomas, which largely exceed the colorectal cancer (CRC) rates reported in the general population (Lieberman et al, 2000; Corredoira et al, 2005; Boleij et al, 2011)
Our results show that a factor from S. galloltyicus that is present in the S. gallolyticus secretome (SGS), induced cytochrome P450 (CYP)1 persistently through the Aryl hydrocarbon receptor (AhR) in four different colon adenocarcinoma cells

Summary

Introduction

The resident gut microbiota is essential for human intestinal health and prevents the invasion of pathogens by providing colonization resistance and nutrient competition (Vollaard and Clasener, 1994; Hooper et al, 2002). The human epithelium itself wards of infections by the excretion of a continuous protective mucus layer and antimicrobials and by tightly sealing the paracellular space between adjacent cells (Matsuo et al, 1997; Chichlowski and Hale, 2008). In case of intestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer (CRC), these protective mechanisms are impaired, and the bowel wall becomes prone to bacterial infiltration, rendering the host more susceptible to opportunistic bacterial infections (Aksoy and Akinci, 2004; Stecher and Hardt, 2008). Most of these patients did not present with gastrointestinal signs or symptoms, and the (pre-)cancerous lesions were solely detected based on the clinical infection with S. gallolyticus

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