Faecal Microbiota Characterization in Lynch Syndrome (LS) Patients With or Without Colorectal Neoplasia ( AAS-Lynch-Microbiote)

Background and originality of the project with regards to the state of the art :

Colorectal cancer (CRC) is the second leading cause of cancer-related death in western countries and the third most prevalent cancer worlwide. CRC prevention and screening are major public health issues. Better knowledge of colorectal carcinogenesis could lead to better prevention and screening. Recent observational data in human and experimental data in vitro or in rodents showed that gut microbiota could contribute to CRC pathogenesis.

The proposal will allow the evaluation of the role of gut microbiota in CRC carcinogenesis in a cohort of Lynch syndrome (LS) patients at high risk for colorectal neoplasia and with well characterized environmental risk factors particularly dietary factors.

Microbiota and CRC Gut microbiota is a complex community consisting of bacteria, fungi, protozoa, viruses and bacteriophages which live in a symbiotic and epigenetic relationship with the host. Gut microbiota can promote either health or tumor progression through its inflammatory and proliferative effects likely dependent on the context and genetic factors of the host. Specific microorganisms or variability of the microbiome have been associated with CRC over the past years. Fusobacterium nucleatum and Porphyromonas gingivalis sequences are over represented in CRC versus matched normal control tissue, and a positive association with lymph node metastasis has been characterized. In patients with sporadic CRC, Fusobacterium nucleatum overexpression is associated with specific CRC carcinogenesis pathways. Studies have also identified several other bacteria as Escherichia coli, Bacteroides fragilis, and Enterococcus faecalis increase in CRC patients, whereas the Clostridiales, Faecalibacterium, Blautia, Bifidobacterium, or Lactobacillus genus were low or absent. In vitro, Fusobacterium nucleatum promotes CRC cell proliferation; in mice, the presence of F. nucleatum inpatient-derived CRC xenografts (where patient CRC samples are implanted in mice) increases tumor growth rates. A possible mechanism to explain these findings is that the F. nucleatum adhesin, FadA, binds to E-cadherin on the CRC cell surface and activates oncogenic Wnt/β-catenin signaling. F. nucleatum can also alter the function of tumor-infiltrating lymphocytes and natural killer (NK) cells by binding to the inhibitory immune receptor TIGIT (T cell immunoreceptor with Ig and ITI Mdomains) through another adhesin, Fap2. Fap2 also binds a disaccharide sugar motif [galactoseN-acetyl-D-galactosamine (Gal-GalNAc)] which is expressed at high levels on the surface of many tumor cell types, as well as other cell types, and facilitates F. nucleatum binding to CRC cells. Enterotoxigenic Bacteroides fragilis (ETBF) potentiates colorectal carcinogenesis in mice, and ETBF was detected in biofilms coating human CRCs and precancerous colonic lesions. Escherichia coli expressing the genomic island polyketide synthase (pks+) enhance tumorigenesis in preclinical CRC models and are enriched in human CRC tissues. pks+ E. coli produce the genotoxin colibactin, which alkylates DNA, resulting in DNA adducts in colonic epithelial cells.

Bacterial metabolites have also been seen to have an effect. Butyrate which can only be produced by specific members of the Firmicutes phylum through the fermentation of dietary fiber and resistant starches can modulate inflammation, epithelial proliferation, and apoptosis. Hydrogen sulfide is also an important regulatory metabolite.