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

Venkatakrishna R Jala1,2, Paramahamsa Maturu1,2, Sobha R Bodduluri1,2

  • 1James Graham Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY, USA.

Oncoimmunology
|December 7, 2017
PubMed

Insights

Mice lacking leukotriene B4 receptor 1 (BLT1) showed increased colon tumor development due to altered gut microbiota and impaired infection response. Restoring normal microbial sensing mechanisms protected these mice from tumors.

Area of Science:

  • Immunology
  • Microbiology
  • Gastroenterology

Background:

  • Inflammation and infection are known drivers of colon cancer.
  • Leukotriene B4 receptor 1 (BLT1) deficiency protects against inflammatory diseases but its role in colon cancer is unclear.

Purpose of the Study:

  • To investigate the role of BLT1 in colon tumor development and its interplay with microbial sensing pathways.

Main Methods:

  • Utilized BLT1-deficient (BLT1-/-) mice crossed with a spontaneous tumor model (ApcMin/+) and MyD88-deficient mice.
  • Employed germ-free conditions and fecal transplantation experiments.
  • Administered broad-spectrum antibiotics to assess the impact of microbiota manipulation.

Main Results:

  • BLT1-/-ApcMin/+ mice exhibited accelerated intestinal tumor development and mortality, linked to increased inflammation and defective host response to infection.
  • Germ-free BLT1-/-ApcMin/+ mice were tumor-free, with tumors reappearing after fecal transplantation.
  • Microbiota analysis revealed that defective host response in BLT1-/-ApcMin/+ mice reshaped the gut microbiota, promoting colon tumor development.
  • BLT1-/-MyD88-/- mice showed susceptibility to neonatal infections, which was mitigated by antibiotics. Double-deficient BLT1-/-MyD88-/-ApcMin/+ mice were protected from colon tumors.

Conclusions:

  • BLT1 plays a critical role in controlling colon tumor development.
  • A novel interplay exists between Toll-like receptor-mediated microbial sensing and BLT1-mediated host response in colon cancer.
  • Targeting BLT1 and microbial sensing pathways may offer therapeutic strategies for colon cancer.

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