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DOP008. The absence of the Triggering Receptor Expressed on Myeloid Cells type-2 (TREM-2) induces a transmissible and protective intestinal microbiota for colitis and colitis associated cancer

M. Genua1,2, C. Monico3, S. D'Alessio1, C. Correale1, J. Cibella1, A. Gandelli1, V. Arena4, A. Spinelli5, S. Guglielmetti6, S. Vetrano1, S. Danese1, 1Humanitas Research Hospital, IBD Center, Rozzano, Milan, Italy, 2Humanitas Research Hospital, Medical Biotechnologies and Translational Medicine, Milano, Italy, 3University of Milan, School of Medicine and Surgery, Milan, Italy, 4Catholic University of Sacred Heart, Internal Medicine and Gastroenterology, Rome, Italy, 5Humanitas Research Hospital, IBD Surgery Unit, Milano, Italy, 6University of Milan, DeFENS, Milan, Italy

Background

Intestinal inflammation in inflammatory bowel disease (IBD) promotes colon cancer due to the aberrant recruitment of immune cells and increased release of pro-inflammatory cytokines. 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. TREM-2 expression in healthy and tumor-bearing mice was investigated by confocal microscopy and flow cytometry. To assess the functional role of TREM-2, we analyzed carcinogenesis in TREM-2 knockout (KO) mice evaluating number and grading of tumor lesions. Tumor proliferation was evaluated by BrdU+ cell count. Moreover, TNF, IL-6, IL-23, TGF-β, iNOS and COX-2 mucosal levels were compared between KO and wild-type (WT) littermates. Finally, we explored gut microbiota composition by high-throughput 16S rRNA gene sequencing analyses and assessed the contribution of bacterial communities in CAC pathogenesis through co-housing experiments.

Results

After CAC induction, confocal microscopy and FACS analysis revealed increased TREM-2 expression in CD11c+ dendritic cells surrounding tumor areas. Interestingly, KO mice displayed a decreased number of tumor lesions that also possessed a low-grade, compared to WT littermates. This observation was associated with a reduced inflammation, as assessed by endoscopy and histology. Moreover, tumor dimensions were reduced in KO mice with a decreased number of BrdU+ cells per area. At mucosal level, TREM-2 absence reduced the production of IL-23 and IL-6, and down-regulated tumor promoting proteins such as iNOS and COX-2. Notably, KO mice possessed a unique gut microbiota profile as outlined by microbiomic analyses, with an increased predominance of Firmicutes and a reduced abundance of Bacteroiditeis. Co-housing experiments revealed that microbiota composition might be transmitted horizontally from TREM-2 KO to wild type littermates reducing number and dimension of tumor lesion.

Conclusion

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.