Recognition of microbial products occurs via Myd88 (Myeloid differentiation factor 88) a downstream signal transducer for IL1R, IL18R and the majority of TLRs (Toll-like receptors). Previously we reported that IL18R/Myd88 exerts a protective role in colon carcinogenesis induced by AOM-DSS (Azoxymethene-Dextran Sodium Sulfate) treatment. Here we identify myeloid Myd88 and IL18R as the sources of this protection, in that animals with either IL18R or Myd88 deficiency in Cd11b+ cells resemble complete IL18R or Myd88 deficiency. Microbiome sequencing indicated an increase in the abundance of colitogenic species including Escherichia coli serotype H7O7, Blautia sp and Enterococcus faecalis, all of which correlated with polyp multiplicity. Concordantly, expression of Beta-Glucoronidase, PKS (polyketide synthase) and Invasin in these bacterial species account for the pro-carcinogenic effects. Notably, this phenotype was transmissible to wild type animas as detected post- cohousing with mice bearing targeted deletion of Myd88 in myeloid cells and by fecal transplantation. Thus, IL18R/Myd88 signaling in myeloid cells was required for the regulation of microbial composition of the colonic lumen.
Additionally, Myd88 deficient animals harbor a large quantity of viral infectious particles in their colonic mucosa corresponding to EMV2, an ecotropic endogenous retrovirus with low or undetectable levels of expression in wild type C57BL/6 animals. Up to 20% of Myd88 knockouts spontaneously developed T cell lymphomas containing abnormalities in chromosome 17 and 15, with high expression of Mela antigen, and viral particles. Consistently, exposure of the colonic mucosa to DSS increased the frequency of thymic lymphoma 2-fold. DSS treatment also resulted in the induction of other tumor types including liver, intestinal and kidney tumors although to a lower frequency.
Further studies are underway to investigate the contribution of EMV2 in the progression of colonic tumors as well as the effect of the dysbiotic microbiota and their products on spontaneous tumor formation elicited by this endogenous retrovirus.