Bifidobacterium adolescentis abundance was significantly reduced in patients from two independent cohorts.
Supplementation with Bifidobacterium adolescentis suppressed tumor development in mouse models of colorectal cancer.
Single-cell RNA sequencing revealed that Bifidobacterium adolescentis promotes a subset of (CD143CAFs) by inhibiting Th2 cell infiltration.
CD143CAFs showed high expression of GAS1, which is associated with tumor suppression.
GAS1 activation in CD143CAFs is regulated by the Wnt/β-catenin signaling pathway.
The abundance of Bifidobacterium adolescentis correlates with the expression levels of CD143 and GAS1, indicating potential prognostic value for colorectal cancer patients.
Simplified
BACKGROUND: The interplay between gut microbiota and tumor microenvironment (TME) in the pathogenesis of (CRC) is not well explored. Here, we elucidated the functional role of Bifidobacterium adolescentis (B.a) on CRC and investigated its possible mechanism on the manipulation of (CAFs) in CRC.
METHODS: Different CRC animal models and various cell line models were established to explore the function of B.a on CRC. The single-cell RNA sequencing (scRNA-seq) or flow cytometry was used to detect the cell subsets in the TME of CRC. Western blot, quantitative real-time polymerase chain reaction (qRT-PCR), or immunofluorescence staining were performed to examine the activation of and growth arrest specific 1 (GAS1) on CD143CAFs. Chromatin immunoprecipitation quantitative real-time PCR (CHIP-qPCR) was performed to investigate the regulation of transcription factor 4 (TCF4) on GAS1. Multi-immunofluorescence assay examined the expression level of CD143 and GAS1 on tissue microarray. +
RESULTS: We found that B.a abundance was significantly reduced in CRC patients from two independent cohorts and the bacteria database of GMrepo. Supplementation with B.a suppressed Apcspontaneous or AOM/DSS-induced tumorigenesis in mice. scRNA-seq revealed that B.a facilitated a subset of CD143CAFs by inhibiting the infiltration of Th2 cells, while promoting the TNF-alphaB cells in TME. CD143CAFs highly expressed GAS1 and exhibited tumor suppressive effect. Mechanistically, GAS1 was activated by the Wnt/β-catenin signaling in CD143CAFs. B.a abundance was correlated with the expression level of CD143 and GAS1. The level of CD143CAFs predicted the better survival outcome in CRC patients. Min/+ + + + + +
CONCLUSIONS: These results highlighted that B.a induced a new subset of CD143CAFs by Wnt signaling-regulated GAS1 to suppress tumorigenesis and provided a novel therapeutic target for probiotic-based modulation of TME in CRC. +
Key numbers
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Decrease in B.a Abundance
Fecal B.a abundance in patients vs. healthy individuals.
8
Tumor Suppression
Tumor number in AOM/DSS mice treated with B.a.
8×
GAS1 Expression Increase
GAS1 expression in CD143CAFs after B.a treatment.
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