Leukotriene B4-receptor-1 mediated host response shapes gut microbiota and controls colon tumor progression

Inflammation and infection are key promoters of colon cancer but the molecular interplay between these events is largely unknown. Mice deficient in leukotriene B4 receptor1 (BLT1) are protected in inflammatory disease models of arthritis, asthma and atherosclerosis. In this study, we show that BLT1(-/-) mice when bred onto a spontaneous tumor (Apc(Min+)) model displayed an increase in the rate of intestinal tumor development and mortality. A paradoxical increase in inflammation in the tumors from the BLT1(-/-) Apc(Min+) mice is coincidental with defective host response to infection. Germ-free BLT1(-/-) Apc(Min+) mice are free from colon tumors that reappeared upon fecal transplantation. Analysis of microbiota showed defective host response in BLT1(-/-) Apc(Min+) mice reshapes the gut microbiota to promote colon tumor development. The BLT1(-/-) MyD88(-/-) double deficient mice are susceptible to lethal neonatal infections. Broad-spectrum antibiotic treatment eliminated neonatal lethality in BLT1(-/-) MyD88(-/-) mice and the BLT1(-/-) MyD88(-/-) Apc(Min+) mice are protected from colon tumor development. These results identify a novel interplay between the Toll-like receptor mediated microbial sensing mechanisms and BLT1-mediated host response in the control of colon tumor development.