UC San Diego

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.