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Next Generation Sequencing Analysis of colon transcriptomes in BF638R bsh- and bF638R bsh+ colonized Cdx2Apcf/w mice.

ABSTRACT: Bacteroides, that expresses bile salt hydrolase (BSH), is considered as a potential drug target for metabolic diseases. In the present study, BSH-expressing Bacteroides was found to be enriched in two different CRC mouse models and colonization of nonenterotoxigenic Bacteroides species, such as B. fragilis 9343 or B. vulgatus , enhanced CRC growth. Expression of the 9343 bsh gene in B. fragilis 638R, a bsh - lacking strain, enabled more bile acids to escape into the colon and accelerated CRC progression . The presence of BSH activated WNT signaling and upregulated CCL28 expression dependent on b-catenin in colon tumors. The activated b-catenin/CCL28 axis elevated intra-tumororal immunosuppressive CD25+ FOXP3+ T reg cells. Anti-CCL28 antibody reversed microbial BSH amplificationinduced immunosuppression. Inhibition of BSH reduced CRC progression, coincident with suppression of WNT signaling and CCL28 expression. These findings provide a novel insight into the pro-carcinogenetic role of NTBF in CRC and characterize BSH as a potential target for CRC treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE190298 | GEO | 2022/12/17

REPOSITORIES: GEO

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Project description:Bacteroides fragilis is an anaerobic commensal in the human gut which can act as opportunistic pathogen when leaving its intestinal niche to reach other body sites. Bacteroides infections have a high lethality and must be treated by antimicrobial chemotherapy. Metronidazole is one of the most frequently administered antimicrobials in the treatment of Bacteroides infections and is highly reliable. However, metronidazole resistance does occur, favoring fatal disease outcomes. Most of the resistant isolates harbor a nim gene (12 are currently known, i.e. nimA to nimL), a transferable resistance determinant for metronidazole. Previous research suggested that Nim proteins might affect the cellular physiology by changing the activity of key enzymes like pyruvate:ferredoxin oxidoreductase (PFOR). In this study we wanted to assess the impact of the nimA gene on protein expression in a standard B. fragilis isolate, 638R, and compared overall protein expression in 638R with and without a nim gene and with the nimA gene in a proteomic study. Further, high-level metronidazole resistance was induced in both strains and the protein expression profiles of resulting resistant daughter strains were also compared with their respective parent strains. We found that comparably few proteins displayed altered expression in 638R with the nimA gene, but flavodiiron protein FprA was repeatedly found upregulated. FprA is often found in anaerobes and reduces molecular oxygen to water and/or nitric oxide to nitrous oxide. After induction of metronidazole resistance, a far higher number of proteins were found to be differentially expressed in 638R without nimA than in 638R with nimA. In the former, factors for the import of hemin were strongly downregulated, indicating impaired iron import, whereas in the latter the observed changes were not only less numerous but also less specific. Based on the results of this study we present a novel hypothetic model of metronidazole resistance and Nim function.

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Next Generation Sequencing Analysis of colon transcriptomes in BF638R bsh- and bF638R bsh+ colonized Cdx2Apcf/w mice.

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