M2ISH - Microbes, intestine, inflammation and Susceptibility of the Host

Published on June 8, 2021 – Updated on July 21, 2021

The M2iSH unit’ research focuses on the implication of host-pathogen interaction in the etiopathogenesis of digestive diseases, such as colorectal cancer (CRC). The unit has shown that particular Escherichia coli strains, such as colibactin-producing E. coli (CoPEC), play a role in colorectal carcinogenesis and could be a factor of poor prognosis. The carcinogenic effects of these bacteria are under investigation.

Intracellular persistence of CoPEC bacteria in human intestinal epithelial T84 cell at 24 hours post-infection. Observation by transmission electron microscopy (20,000x magnification, at Centre d'Imagerie Cellulaire Santé, Clermont-Ferrand)

Intracellular persistence of CoPEC bacteria in human intestinal epithelial T84 cell at 24 hours post-infection. Observation by transmission electron microscopy (20,000x magnification, at Centre d'Imagerie Cellulaire Santé, Clermont-Ferrand)

The initiation and promotion of tumorigenesis and escape of tumor are not only determined by the genotype of tumor cells, but also by their interactions with the microenvironment. In the context of CRC, the bacterial composition of the gut microbiota appears to play an important role in colorectal carcinogenesis. Several independent studies, including those from M2iSH unit, have shown that the intestinal mucosa of CRC patients is abnormally colonized with particular E. coli strains designated as CoPEC (for "colibactin-producing E. coli"). In different mouse models predisposed to CRC, the pro-carcinogenic role of CoPEC has been demonstrated. These bacteria are able to promote cell proliferation via the induction of cellular senescence, which is accompanied by the production of growth factors, and a pro-carcinogenic microenvironment (an increase in inflammation and neutrophils associated to mucosa, as well as a decrease in anti-tumoral T lymphocytes). We recently showed that autophagy is an important mechanism of host defense to inhibit the pro-tumoral effects of CoPEC. The mechanisms of action of these bacteria, particularly in the early stages of the carcinogenesis, are under investigation, and this could help to identify new therapeutic targets.

Another part of our works suggests that CoPECs could be used as biomarkers of poor prognosis. We were the first to show that the presence of CoPEC is associated with several clinical factors of poor prognosis (TNM stages III/IV, dissemination to lymph nodes, MSS phenotype). Recently, we observed that chronic infection with CoPEC induces resistance to anti-PD-1 treatments in a mouse model of CRC. Based on these results, two clinical studies are currently in progress in collaboration with the Clermont-Ferrand University Hospital (project Metabiote – Prof. Pezet, Drs. Véziant and Gagnière) and the Montpellier Cancer Institute (project Micare – Prof. Rouanet) to assess the prognostic values of CoPEC in the surgical management of CRC patients or in the therapeutic management of patients with rectal cancer.

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