Mestivier, D. | Search bioRxiv

bioRxiv2025

Poor prognosis in IBD-complicated colon cancer through gut dysbiosis-related immune response failure

BackgroundColorectal cancer (CRC) results from the accumulation of mutations and epigenetic changes in gut epithelial cells likely due to gut microbiota dysbiosis. However, limited research has been done to explore the link between host tumour dysbiosis and disease outcome. MethodsThe mechanisms influencing outcomes of 97 colorectal cancer (CRC) patients, including 13 with Lynch syndrome, 20 with inflammatory bowel disease (IBD), and 64 sporadic cases, were analyzed using a multiomics approach. These patients were categorized into two groups: "disease-free/stable disease" and "progression disease" survival outcomes. The analysis included tumor adherent microbiota composition (16S rRNA), somatic gene mutations (WES), gene expression (RNAseq), immune markers (RNAscope), and immune infiltrate cells (immunohistochemistry). ResultsIBD-CRC patients had worse outcomes than those with Lynch or sporadic CRC, regardless of TNM staging or treatment. Symbiotic bacteria like Lactococcus lactis were significantly reduced in IBD-CRC tissues. Patient outcomes were influenced by the abundance of virulent (Escherichia coli) relative to beneficial bacteria (Lactococcus lactis). Although no significant increase in deleterious somatic mutations was found in IBD-CRC. 16sRNA revealed increased virulent- and decreased anti-inflammatory symbiotic-bacteria correlating with the upregulation of oncogenes and downregulation of anti-oncogenes like PHLPP1. The multiplex in situ hybridization of CD8, IFN{gamma} and PHLPP1 an anti-oncogene revealed significant decrease of immune cells with detectable PHLPP1 expression in IBD-CRC tumour tissues as compared to sporadic CRCs. ConclusionThe poor outcomes in IBD-CRC patients are likely due to gut dysbiosis and immune cell alterations, possibly triggered by microbiota-related epigenetic pathways. What You Need to KnowO_ST_ABSBACKGROUND AND CONTEXTC_ST_ABSColorectal cancer (CRC) is associated with gut microbiota dysbiosis. Inflammatory bowel disease-related CRC (IBD-CRC) is classified as an environment-related condition. NEW FINDINGSIn relation with patient outcomes, tumour tissues from three types of CRC (Sporadic-, IBD-, and Lynch syndrome-CRC) were analyzed using a multiomic approach. This included examining tissue adherent virulent bacteria, gene analyses, and quantifying immune cell infiltration in the mucosa. IBD-CRC patients had the worst outcomes, associated with the down regulation of PHLPP1 gene, virulent/symbiotic imbalance, and immune response failure. LIMITATIONSLack of animal experiments using FMT of fresh stool from IBD-CRC patients. CLINICAL AND TRANSLATIONAL RESEARCH RELEVANCEAmong the different types of CRC, IBD-CRC patients showed a greater imbalance between harmful and beneficial bacteria, along with immune response failure. Lay summaryThis study compares the pathological and clinical characteristics of patients with colorectal cancer (CRC) across three distinct etiologies: sporadic CRC, inflammatory bowel disease (IBD)-associated CRC, and Lynch syndrome-associated CRC (LS-CRC). Distinct differences in tumor-adherent microbiota, gene expression and immune response profiles were observed. Notably, IBD-CRC patients demonstrated the poorest prognosis depending on microbe-host gene interaction highlighting potential biomarkers for disease prognosis and treatment strategies.

immunology↗

bioRxiv2023

Spatially-resolved metabolomic identifies colibactin-specific principles of reprogrammed lipid metabolism to promote cancer progression.

Intratumoral bacteria locally contribute to cellular and molecular tumor heterogeneity that support cancer stemness through poorly understood mechanisms. This study aims to explore how Colibactin-producing Escherichia coli (CoPEC) flexibly alters the tumor microenvironment in right-sided colorectal cancer (CRC). Metabolomic and transcriptomic spatial profiling uncovered that CoPEC colonization establishes a high-glycerophospholipid microenvironment within the tumor that is conducive to exhaustion of infiltrated CD8+ T cell and has a lowered prognostic value in right-sided CRC. Mechanistically, the accumulation of lipid droplets in infected cancer cells relied on the production of colibactin as a measure to limit genotoxic stress and supply with sufficient energy for sustaining cell survival and lowering tumor immunogenicity. Specifically, a heightened phosphatidylcholine remodeling of CoPEC-infected cancer cells by the enzyme of the Lands cycle coincided with a lowered accumulation of proapoptotic ceramide and lysophosphatidylcholine. Consequently, a reduced infiltration of CD8+ T lymphocytes that produce the cytotoxic cytokines IFN-{gamma} was found where invading bacteria have been geolocated. By contrast, such an immunosuppressive dysmetabolic process was not observed when human colon cancer cells were infected with the mutant strain that did not produce colibactin (11G5{delta}ClbQ). This work revealed an unexpected property of CoPEC on lipid overload within tumors that could locally provide an inflammatory environment leading to immunosuppressive mechanisms and tumor expansion. This may pave the way for improving chemoresistance and subsequently outcome of CRC patients who are colonized by CoPEC.

cancer biology↗

bioRxiv2022

Parvimonas micra, an oral pathobiont associated with colorectal cancer, epigenetically reprograms human primary intestinal epithelial cells

Recently, an intestinal dysbiotic microbiota with enrichment in oral cavity bacteria has been described in colorectal cancer (CRC) patients. Here we characterized and investigated one of these oral pathobionts, the Gram-positive anaerobic coccus Parvimonas micra. We identified two phylotypes (A and B) exhibiting different phenotypes and adhesion capabilities. We observed a strong association of phylotype A with CRC, with its higher abundance in feces and in tumoral tissue compared with the normal homologous colonic mucosa, which was associated with a distinct methylation status of patients. By developing an in vitro hypoxic co-culture system of human primary colonic cells with anaerobic bacteria, we showed that P. micra phylotype A alters the DNA methylation profile promoters of key tumor-suppressor genes, oncogenes, and genes involved in epithelial-mesenchymal transition. In colonic mucosa of CRC patients carrying P. micra phylotype A, we found similar DNA methylations alterations, together with significant enrichment of differentially expressed genes in pathways involved in inflammation, cell adhesion, and regulation of actin cytoskeleton, providing evidence of P. micra possible role in the carcinogenic process.

microbiology↗