V. Sethi1, B. Giri1, B. Garg1, M. Tarique1, S. Lavania1, L. Hellmund1, Z. Malchiodi1, S. Kurtom1, A. Farrantella1, S. Banerjee1, S. Ramakrishnan1, S. Roy1, A. Saluja1, V. Dudeja1 1University Of Miami,Department Of Surgery,Miami, FL, USA
Introduction: Microbiome of the gut forms an important ‘hidden organ’ of our body, changing with diet, disease state, use of antibiotics, and even age. While literature abounds with associational studies of changed gut microbiome with disease states like inflammatory bowel disease, diabetes, colitis etc., precious little is known on how, if at all, the gut microbiome modulates cancer and metastases. The aim of this current study was to analyze this obscure cancer-gut microbiome relationship.
Methods: The gut microbiome of C57BL/6 mice was depleted by daily oral administration of broad-spectrum antibiotics having minimal systemic absorption. Various cancers were modelled on antibiotic-given mice as well as control mice and tumor burden was compared between the two groups. These models included subcutaneous implantation of pancreatic cancer cells derived from KPC (Kras LSL.G12D/+; p53 R172H/+ ;Pdx::Cre) mice and melanoma cells derived from Braf-Pten (Tyr::CreER; Braf V600E/+;Ptenlox5/lox5 ) mice . Additionally hepatic metastases were induced by intrasplenic injections of KPC pancreatic cancer cells, B16-F10 melanoma cancer cells and MC38 colon cancer cells. Tumors were immunophenotyped through flow cytometry and immunostained for various antigens. Various ex-vivo cytotoxicity experiments were performed with cancer cells and splenocytes. To confirm the role of adaptive immunity, similar experiments were performed in immunodeficient Rag1 knockout mice having a Rag1tm1Mom mutation.
Results: Depletion of the gut microbiome significantly decreased primary cancer and metastases burden in all the studied murine models. Tumors in antibiotics-gavaged mice showed increased cleaved caspase 3 staining. Ex-vivo, splenocytes from antibiotics-gavaged mice caused a much higher cytotoxicity of cancer cells than control splenocytes. The role of immune system was confirmed when antibiotic administration in immunodeficient Rag1 KO mice failed to show a reduced cancer burden compared to control mice.
Conclusion: Gut microbiome depletion causes reduced cancer burden by modulating the immune system.
