High-fat diet-mediated dysbiosis cooperates with oncogenic K-Ras activation to promote intestinal carcinogenesis independently of obesity.

ABSTRACT: Several aspects of a Western lifestyle such as increased obesity and decreased physical activity are associated with increased risk for gastrointestinal cancers1. Although high-fat diet (HFD) induced low-grade inflammation has been closely linked to tumorigenesis2, however, the microbial shift that occurs due to diet and consequent alterations in host immunity have merely been considered to play a critical role during carcinogenesis. Here we show that HFD promotes tumor progression in the small intestine of genetically susceptible mice, however, independently of obesity and diet-induced chronic inflammation. HFD consumption cooperates with mutant K-Ras to mediate a shift in the composition of microbiota, which is associated with a decrease in Paneth cell antimicrobial host defense that compromises dendritic cell (DC) recruitment and MHCII presentation in the gut-associated lymphoid tissues (GALTs). DC recruitment in GALTs can be normalized and tumor progression attenuated completely when K-Ras mutant mice are supplemented with the short chain fatty acid butyrate, a bacterial fermentation end product, or partially when provided with probiotics. Importantly, Myd88-deficiency completely blocks tumor progression in K-ras mutants, however, rather by substantial changes in the microbiota than host-mediated signaling mechanisms. Strikingly, transfer of fecal samples from diseased donors into healthy adult K-ras mutants is sufficient to enhance tumor progression in the absence of HFD suggesting a pivotal role for distinct microbiota shifts in aggravating disease in the small intestine. Collectively, these data underscore the reciprocal interaction between host and environmental factors for the composition of intestinal microbiota that favors carcinogenesis and suggest tumor progression could potentially be “transmitted” in genetically predisposed individuals. 13 samples; S103_396_GroupA_Arkan and S104_429_GroupA_Arkan represent the controls of the first group, S105_394_GroupB_Arkan and S106_429_GroupB_Arkan represent ViRas (mutated) mice of the first group. S982_groupA_ 1 and S983_groupA_2 represent the cotrols of the second group, S984_groupB_3, S985_groupB_4 and S986_groupB_5 represent ViRas (mutant) mice of the second group, S563_CO1979 represent the control of the third group, S564_KO1_1231, S565_KO2_1984 and S566_KO3_2013 represent the ViRas (mutant) mice of the third group. The first group are mice kept on HFD, second group kept on ND and third group kept on HFD plus treated with butyrate

ORGANISM(S): Mus musculus

SUBMITTER: Olivia Prazeres da Costa 

PROVIDER: E-GEOD-42840 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress