DOP02 Supplementation with butyrate producing bacteria reduces tumour load in a mouse model of colitis-associated cancer. (25th January 2019)

• Record Type: Journal Article
• Authors: Montalban Arques, A; Olivares Rivas, I; Atrott, K; Gottier, C; Lang, S; Leventhal, G; DeWouters, T; Scharl, M; Spalinger, M
• Is Part Of: Journal of Crohn's and colitis. Volume 13(2019)Supplement 1
• Page Start: S028
• Page End: S029
• Publication Date: 2019-01-25
• Subjects: Inflammatory bowel diseases -- Periodicals; 616.344005
• DOI: 10.1093/ecco-jcc/jjy222.037
• Languages: English
• ISSNs: 1873-9946

Abstract

Abstract: Background: Colorectal carcinoma is still a severe complication in patients with long-standing and severe ulcerative colitis. Current guidelines suggest that surgical total proctocolectomy must be considered in patients with high-grade dysplasia. Pharmacologic treatments that could prevent the onset of carcinoma in UC patients would be a milestone in the therapy of these patients. Here, we studied how the intestinal microbiota contributes to the onset/prevention of inflammation-induced colorectal carcinoma. Methods: Colitis associated tumours were induced in wild-type (WT) and RAG2−/− C57BL/6 mice via administration of three cycles of DSS in the drinking water (7 days DSS, 10 days recovery, each) + AOM injections at Day 1 and 8 of each DSS cycle. Peptostreptococcus stomatis or a mix of 4 butyrate-producing strains ( A. caccae, E. hallii, F. prausnitzii, and R. intestinalis ) was supplemented via daily oral gavage on Days 8–10 of each AOM/DSS cycle. Results: We found that tumour burden in the DSS/AOM model was associated with increased levels of faecal P. stomatis, but overall reduced levels of butyrate producers. In DSS/AOM-treated WT mice, supplementation with P. stomatis significantly enhanced tumour load when compared with PBS-treated controls ( p < 0.01, n = 10, each). In contrast, only a small fraction of WT mice supplemented with butyrate producers developed tumours ( n = 10; p < 0.05 vs. PBS group). Supplementation with P. stomatis was associated with increased intestinal inflammation as assessed in endoscopy and histology ( p < 0.05, each) after each AOM/DSS cycle. As causative mechanisms, we found elevated numbers of PD-L1+/PD-L2+ tumour-associated macrophages ( p < 0.05) in P. stomatis supplemented mice, while numbers of regulatory T cells were not affected. In mice receiving butyrate producers, DSS-induced intestinal inflammation was similar to DSS/AOM-treated control mice; however, we observed increased numbers of IFNγ+ CD8+ cytotoxic T cells and IFNγ+ NK cells specifically within the tumour tissue, indicating that supplementation with butyrate producers promoted increased anti-tumour immune responses. Furthermore, the increase in PD-L1+/PD-L2+ tumour-associated macrophages was absent in those mice. Of interest, the protective effect of supplementation with butyrate producers was completely abrogated in RAG−/− mice, indicating that T cells are crucially involved in mediating the anti-tumour effect. Conclusions: Our results indicate that oral supplementation with selected butyrate producers protects from colitis-associated tumour development via promoting anti-tumour T-cell responses in vivo . Our findings suggest that manipulation of the intestinal microbiota might be a promising novel approach to promote anti-cancer immune responses.