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Microbial activities associated with human intestinal mucosal biofilms change mRNAs and microRNAs to promote carcinogenesis in mice [miRNA]

ABSTRACT: Disrupted interactions between host and intestinal bacteria are implicated in the development of colorectal cancer (CRC). However, the functional impacts of these inter-kingdom interactions remain poorly defined. To examine this interplay, we performed small RNA sequencing on the stool of from germ-free (GF) and gnotobiotic ApcMin/+;Il10-/- mice associated with microbes from biofilm-positive human CRC tumor (BT) and biofilm-negative healthy (BX) tissues. revealed a group of significant differentially expressed miRNAs specific to BT compared to BX associated ApcMin/+;Il10-/- mice and several miRNAs that correlated with bacterial genera abundances. Our findings suggest complex interactions within bacterial communities affecting host-derived miRNA and CRC development.

ORGANISM(S): Mus musculus

PROVIDER: GSE108164 | GEO | 2019/12/30

REPOSITORIES: GEO

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Microbial activities associated with human intestinal mucosal biofilms change mRNAs and microRNAs to promote carcinogenesis in mice [RNA]

Project description:Disrupted interactions between host and intestinal bacteria are implicated in the development of colorectal cancer (CRC). However, the functional impacts of these inter-kingdom interactions remain poorly defined. To examine this interplay, we performed mouse and microbiota RNA-sequencing on colon tissue from germ-free (GF) and gnotobiotic ApcMin/+;Il10-/- mice associated with microbes from biofilm-positive human CRC tumor (BT) and biofilm-negative healthy (BX) tissues. The bacteria in BT mice differentially expressed >2,900 genes related to bacterial secretion, virulence and biofilms, but only affected 62 host genes. Importantly, the bacterial communities from BT mice were transmissible and carcinogenic when administered to a new GF ApcMin/+;Il10-/- cohort, maintaining a set of 13 bacterial genera. Our findings suggest complex interactions within bacterial communities affecting bacterial composition and CRC development.

2019-12-30 | GSE108156 | GEO

Altered fecal small RNA profiles in colorectal cancer reflect gut microbiome composition in stool samples

Project description:Dysbiotic configurations of the human gut microbiota have been linked with colorectal cancer (CRC). Human small non-coding RNAs are also implicated in CRC and recent findings suggest that their release in the gut lumen contributes to shape the gut microbiota. Bacterial small RNAs (bsRNAs) may also play a role in carcinogenesis but their role is less explored. Here, we performed small RNA and shotgun sequencing on 80 stool specimens of patients with CRC, or adenomas, and healthy subjects collected in a cross-sectional study to evaluate their combined use as a predictive tool for disease detection. We reported a considerable overlap and correlation between metagenomic and bsRNA quantitative taxonomic profiles obtained from the two approaches. Furthermore, we identified a combined predictive signature composed by 32 features from human and microbial small RNAs and DNA-based microbiome able to accurately classify CRC from healthy and adenoma samples (AUC= 0.87). In summary we reported evidence that host-microbiome dysbiosis in CRC can be observed also by altered small RNA stool profiles. Integrated analyses of the microbiome and small RNAs in the human stool may provide insights for designing more accurate tools for diagnostic purposes.

2019-08-30 | GSE132236 | GEO

Polyketide synthase-derived sphingolipids determine microbiota-mediated protection against pathogens inC. elegans

Project description:Protection against pathogens is a major function of the gut microbiota. Although bacterial natural products have emerged as crucial components of host-microbiota interactions, their exact role in microbiota-mediated protection is largely unexplored. We addressed this knowledge gap with the nematodeCaenorhabditis elegansand its microbiota isolatePseudomonas fluorescensMYb115 that is known to protect againstBacillus thuringiensis (Bt) infection. We find that MYb115-mediated protection depends on sphingolipids that are derived from an iterative type I polyketide synthase (PKS), thereby describing a noncanonical pathway of bacterial sphingolipid production. We provide evidence that MYb115-derived sphingolipids affectC. eleganstolerance to Bt infection by altering host sphingolipid metabolism. This work establishes sphingolipids as structural outputs of bacterial PKS and highlights the role of microbiota-derived sphingolipids in host protection against pathogens.

2023-10-14 | GSE245296 | GEO

Deletion of TNF in Winnie-ApcMin/+ mice reveals its protective role in the progression of colorectal cancer

Project description:To examine the effects of chronic, low-grade inflammation on the pathogenesis of colorectal cancer (CRC), we developed a novel murine model of colitis-associated cancer by crossing Winnie mice with ApcMin/+ mice thus combining the inflammatory background with a genetic predisposition to develop small intestinal polyposis, respectively. Winnie-ApcMin/+ mice showed early, spontaneous occurrence of colonic dysplastic lesions with a distinct molecular signature. Since TNF is a major clinical target for suppression of chronic intestinal inflammation, we investigated its impact on Winnie-ApcMin/+ model. Surprisingly, deletion of Tnf in Winnie-ApcMin/+ mice resulted in an initial reduction of dysplastic lesions at disease onset, but facilitated disease progression with a unique molecular footprint. Our results confirm that even a mild, but chronic, inflammation represents a crucial risk factor in individuals genetically-predisposed to CRC, and support a dual role for TNF in the onset vs. progression towards CRC.

2021-12-31 | GSE138722 | GEO

Bacteroides thetaiotaomicron ameliorates colon inflammation in preclinical models of Crohn’s Disease [Bacteroides]

Project description:Analysis of the Bacteroides thetaiotaomicron(BT) transcriptome during co-culture with Caco-2 intestinal epithelial cells To identify potential bacterial protein(s) involved in the anti-inflammatory effect of BT in colitis, BT was incubated with Caco-2 human intestinal epithelial cells for 2 hours, and bacterial gene expression was assessed on a Bacteroides thetaiotaomicron VPI-5482 specific microarray. Forty-three BT genes were up-regulated by five-fold or more and of these, twenty genes encoded hypothetical proteins.

2019-03-06 | GSE118525 | GEO

Deletion of TNF in Winnie-ApcMin/+ mice reveals its dual role in the onset and progression of colitis-associated colorectal cancer

Project description:Colorectal cancer (CRC) is among the best examples depicting the relationship between inflammation and increased cancer risk. The introduction of new therapeutic options targeting the inflammatory mediators has been shown to markedly decrease the overall risk of CRC even though their chemopreventive potential is still under debate [1,2]. Specifically, conflicting reports exist concerning the relationship between Infliximab, a monoclonal antibody that specifically blocks Tumor Necrosis Factor (TNF), and an increased risk of CRC in patients with Inflammatory Bowel Disease (IBD). To address the axis between TNF and CRC development and progression, we depleted the Tnf from our previously established murine model of colitis-associated cancer (CAC), the Winnie-ApcMin/+ line. Surprisingly, a detailed histological characterization, demonstrated that the deletion of Tnf in Winnie-ApcMin/+ mice resulted in an initial reduction of dysplastic lesions incidence in 5-week-old mice, followed by faster disease progression with a unique molecular pattern at 8 weeks. Our results highlight that TNF could exert a dual role in CAC supporting the promotion of neoplastic lesions onset at the early stage of the disease and inducing their reduction during disease progression.

2023-05-01 | E-MTAB-12356 | biostudies-arrayexpress

ERK1/2 controlled genes ANGPT2 and CXCR4 mediate liver metastasis from colon cancer

Project description:Carcinoma development in colorectal cancer (CRC) is driven by genetic alterations in numerous signaling pathways. Alterations in the RAS-ERK1/2 pathway are associated with the shortest overall survival for patients after diagnosis of CRC metastatic disease, but how RAS-ERK signaling regulates CRC metastasis is still unknown. An unbiased screening approach based on selection of highly liver metastatic CRC cells in vivo was used to determine genes associated with metastasis and a ERK1/2-controlled metastatic gene set (EMGS) defined. The ANGPT2 and CXCR4, two genes within the gene set, were subjected to gain and loss of function validation in CRC cells (SW620, SW480, Colo26, HCT116), its downstream mechanism validated, and tested in clinical samples. Here, we identified an EMGS that is associated with increased recurrence and reduced survival for patients with CRC tumors. Higher levels of EMGS expression were detected in the CRC subsets Consensus Molecular Subtype (CMS)1 and CMS4. We show that the RAS-ERK1/2 axis controls the expression of the cytokine ANGPT2 and the cytokine receptor CXCR4 in CRC cells, and that this facilitates the development of liver but not lung metastases, suggesting that ANGPT2 and CXCR4 are essential for metastatic outgrowth in the liver. We also show that CXCR4 also controls the expression of the cytokines IL10 and CXCL1, and provide evidence for a causal role of IL10 in supporting liver colonization. In summary, we demonstrate that amplification of ERK1/2 signaling in KRAS-mutated CRC cells affects the cytokine milieu of the tumors, thus possibly affecting tumor?stroma interactions and favoring liver metastasis formation.

2020-07-31 | GSE142219 | GEO

RNA m6A methylation suppresses insect juvenile hormone degradation to minimize fitness costs in response to a pathogenic attack

Project description:Bioinsecticides and transgenic crops based on the bacterial pathogen Bacillus thuringiensis (Bt) can effectively control diverse agricultural insect pests, nevertheless, insect resistance evolution without causing obvious fitness costs has seriously eroded the sustainable use of these Bt products. Recently, we have discovered that an increased titer of juvenile hormone (JH) favors an insect host (Plutella xylostella) to enhance fitness whilst resisting the Bt pathogen, however, the underlying regulatory mechanisms of the increased JH titer is obscure. Here, we define the involvement of N6-methyladenosine (m6A) RNA modification in modulating the availability of JH in this process. Specifically, we found that two m6A methyltransferase subunit genes, PxMettl3 and PxMettl14, repressed the expression of a key JH-degrading enzyme JH esterase (JHE) to induce an increased JH titer, mitigating the fitness costs associated with a robust defense against the Bt pathogen. This study identifies an as-yet uncharacterized m6A-mediated epigenetic regulator of insect hormones for maintaining fitness during pathogen defense and unveils an emerging Bt resistance-related m6A methylation atlas in insects, which further expands the functional landscape of m6A modification and showcases the pivotal role of epigenetic regulation in host-pathogen interactions.

2023-11-10 | GSE247107 | GEO

Mouse slurry colons 2 weeks

Project description:Defining the complex role of the microbiome in colorectal cancer (CRC) and the discovery of novel, pro-tumorigenic microbes are areas of active investigation. In the present study, culturing and reassociation experiments revealed that toxigenic strains of Clostridioides difficile drove the tumorigenic phenotype of a subset of CRC patient-derived mucosal slurries in germ-free ApcMin/+ mice. Tumorigenesis was dependent on the C. difficile toxin TcdB and was associated with induction of Wnt signaling, reactive oxygen species, and pro-tumorigenic mucosal immune responses marked by infiltration of activated myeloid cells and interleukin-17 (IL-17)-producing lymphoid and innate lymphoid cell subsets. In vitro, purified TcdB directly induced DNA strand breaks at low picomolar concentrations. These findings suggest that chronic colonization with toxigenic C. difficile is a potential driver of CRC in patients. Comparing scRNA-seq from mouse colon tissue 2 weeks after inoculation with different bacterial slurries

2022-05-27 | GSE200969 | GEO

Intestinal tumor expression data from Apcmin/+ mice gavaged by feces from healthy controls or colorectal cancer patients

Project description:Colorectal cancer (CRC) is closely related to gut dysbiosis. We investigated the effects of imbalanced gut microbiota on the progression of intestinal adenoma in Apcmin/+ mice model using fecal microbiota transplantation (FMT). Administration of feces from CRC patients increased tumor proliferation and decreased apoptosis in tumor cells. Abnormal expression of genes related to Wnt-protein binding and lipid metabolic process was observed.

2019-09-16 | GSE136682 | GEO

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