149 Intestinal Microbiota Defined by the Absence of the Triggering Receptor Expressed on Myeloid Cells Type-2 (TREM-2) Is Transmissible and Protects From Colitis Associated Cancer

Abstract

BACKGROUND. Inflammatory bowel disease (IBD) represents a prototypic example of connection between inflammation and cancer. Severity, extent and duration of the disease represent the major risk factors related to colorectal cancer (CRC) development. Recently we have demonstrated that the absence of the bacterial sensor TREM-2 prevented acute and chronic colitis, reducing the levels of mucosal inflammatory cytokines and T-cell activation. However, whether TREM-2 plays also a role in regulating the composition of microbial communities or in colitis associated cancer (CAC) is unknown. METHODS. The carcinogen azoxymethane (AOM) with 3 cycles of dextran sulfate sodium (DSS) was used as CAC model. Gut microbiota composition was estimated by high-throughput 16S rRNA gene sequencing in fecal samples collected from TREM-2 knockout (KO) and wild-type (WT) littermates. The bacterial communities were assessed in healthy and tumor-bearing mice, evaluating their contribution in CAC development by co-housing experiments. TREM-2 expression was investigated by confocal microscopy and flow cytometry. Carcinogenesis was evaluated counting and grading the tumor lesions. Moreover, tumor proliferation was evaluated by BrdU+ cell count. Finally, TNF, IL-6, IL-23, TGF-β, iNOS and COX-2 mucosal levels were compared between KO and WT littermates. RESULTS. After CAC induction, confocal microscopy and FACS analysis revealed increased TREM-2 expression in CD11c+ dendritic cells surrounding tumor areas. Carcinogenesis was affected in the absence of TREM2, with a reduced number of tumor lesions that also possessed a low-grade and displayed a reduced proliferation. Interesting, co-housing experiments revealed that intestinal microbiota composition might be transmitted horizontally from TREM-2 KO to WT littermates decreasing significantly number (WT = 6±1, WT CH = 3±1, p < 0.05) and dimension (WT = 18.5±2.8 mm2, WT CH = 6.2±1.2 mm2, p < 0.01) of tumor lesions. In particular, both CAC induction and co-housing induced a redistribution of the relative abundance of Prevotellaceae (belonging to the phylum Bacteroidetes), Ruminococcaceae (Firmicutes) and Rikenellaceae (Bacteroidetes). Finally, at mucosal level, TREM-2 absence reduced the production of IL23 and IL-6, and down-regulated tumor promoting proteins such as iNOS and COX-2. CONCLUSIONS. Our findings reveal TREM-2 as a key component involved in controlling colon cancer development. In particular, TREM-2 expression is up-regulated during CAC by CD11c+ dendritic cells and its genetic deletion prevents tumor formation and proliferation. TREM-2 shapes gut microbiota composition and unveils a novel mechanism that could offer a new therapeutic target to prevent or treat intestinal inflammation and carcinogenesis.