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THE SODIUM CHANNEL SUBUNIT SCNN1B SUPPRESSES COLORECTAL TUMORIGENESIS VIA MODULATION OF THE GUT MICROBIOTA AND IMMUNE MICROENVIRONMENT

Yun Qian 1, Chi Chun Wong 2

Affiliations

1 Shenzhen University General Hospital, Shenzhen, China

2 The Chinese University of Hong Kong, Shatin, Hong Kong

Summary

AI Generated

Colon-specific SCNN1B knockout in mice increases colorectal tumorigenesis and is associated with gut dysbiosis, impaired barrier function, and immunosuppression.

SCNN1B knockout significantly increased tumor number and tumor load (both P<0.05) in an AOM/DSS-induced colorectal cancer mouse model compared to wildtype controls.
SCNN1B knockout increased gut permeability as evidenced by elevated circulation FITC-dextran levels in permeability assays.
SCNN1B knockout led to decreased microbial diversity and enrichment of Lawsonibacter, Duncaniella, and Desulfovibrionaceae genera, with depletion of Geosporobacter and enrichment of dark sulphur oxidation activity.
SCNN1B knockout was associated with increased infiltration of myeloid-derived suppressor cells and decreased CD8+ T cell activation.
The findings support SCNN1B as a tumor suppressor in colorectal cancer and suggest that dysregulated gut microbiota and impaired antitumor immune response may contribute to CRC pathogenesis.

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Abstract

Introduction

We previously demonstrated that SCNN1B is a potential tumor suppressor in colorectal cancer (CRC), however, its role in the tumor microenvironment is largely unknown. In this study, we have constructed a conditional, colon specific SCNN1B knockout mouse model, and investigated the effects of SCNN1B knockout on colorectal tumorigenesis, and the associated alterations in the gut microbiome and tumor immune microenvironment.

Aims & Methods

Conditional SCNN1B knockout mouse was established, and then crossed to CDX2-CreERT2 mouse to generate colon specific SCNN1B knockout mouse model. To knockout SCNN1B, mice were injected with tamoxifen (100mg/kg, i.p., 6 times). After SCNN1B knockout, the mice were subjected to the Azoxymethane (AOM)/Dextran Sodium Sulfate (DSS)-induced colorectal tumorigenesis. Gut barrier function was determined by FITC-dextran permeability assay. Mucosal and fecal microbiota in SCNN1B knockout mice and control mice were determined by 16S rRNA sequencing and shot gun metagenomic sequencing, respectively. The tumor immune cell infiltration was determined by flow cytometry.

Results

Colon-specific SCNN1B knockout mice were successfully constructed. Compared to wildtype controls, SCNN1B knockout significantly increased tumor number (P<0.05) and load (P<0.05) in colon. Notably, gut permeability was increased in SCNN1B knockout mice, as evidenced by increased levels of circulation FITC-dextran in the gut permeability assays. Analysis of the mucosal microbiota revealed that knockout of SCNN1B led to decreased microbial diversity according to alpha- and beta-diversities as compared to wildtype counterparts, suggesting that knockout of SCNN1B promoted gut dysbiosis. SCNN1B knockout mice were enriched in the bacterial genera of Lawsonibacter, Duncaniella, and Desulfovibrionaceae, together with the depletion of Geosporobacter. In terms of microbial function, SCNN1B knockout mice microbiota was enriched in dark sulphur oxidation activity, which is frequently associated with pathogenic processes. Meanwhile, flow cytometry demonstrated the loss of SCNN1B promoted immunosuppression, characterized by increased infiltration of myeloid-derived suppressor cells (MDSCs) and decreased CD8+ T cell activation.

Conclusion

SCNN1B functions as a tumor suppressor in CRC. Colon specific knockout of SCNN1B in mice dysregulated gut microbiota and impaired antitumor immune response, which might contribute to the pathogenesis of CRC.

Conference

UEG Week Copenhagen 2023

Topics

Colorectal

Submission format

Abstract

Session

PP 06 Other lower GI disorders (Posters)

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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