Abstract
Recent studies investigating the human microbiome have identified particular bacterial species that correlate with the presence of colorectal cancer. To evaluate the role of qualitatively different but naturally occurring gut microbiota and the relationship with colorectal cancer development, genetically identical embryos from the Polyposis in Rat Colon (Pirc) rat model of colorectal cancer were transferred into recipients of three different genetic backgrounds (F344/NHsd, LEW/SsNHsd, and Crl:SD). Tumor development in the pups was tracked longitudinally via colonoscopy, and end-stage tumor burden was determined. To confirm vertical transmission and identify associations between the gut microbiota and disease phenotype, the fecal microbiota was characterized in recipient dams 24 hours pre-partum, and in Pirc rat offspring prior to and during disease progression. Our data show that the gut microbiota varies between rat strains, with LEW/SsNHsd having a greater relative abundance of the bacteria Prevotella copri. The mature gut microbiota of pups resembled the profile of their dams, indicating that the dam is the primary determinant of the developing microbiota. Both male and female F344-Pirc rats harboring the Lewis microbiota had decreased tumor burden relative to genetically identical rats harboring F344 or SD microbiota. Significant negative correlations were detected between tumor burden and the relative abundance of specific taxa from samples taken at weaning and shortly thereafter, prior to observable adenoma development. Notably, this naturally occurring variation in the gut microbiota is associated with a significant difference in severity of colorectal cancer, and the abundance of certain taxa is associated with decreased tumor burden.
Highlights
Colorectal cancer (CRC) is a multifactorial disease induced via multiple genetic factors such as the mutations associated with Familial Adenomatous Polyposis (FAP)and Hereditary Non-Polyposis Colorectal Cancer (HNPCC), and a wide range of other factors such as intestinal inflammation, age, diet, alcohol and tobacco consumption, stress, obesity, and activity level, among others
To characterize the gut microbiota (GM) present in each genetic background, fecal DNA was extracted, the microbial V4 region was amplified via PCR, and 16S rRNA amplicon sequencing was performed
Resolved to the level of operational taxonomic unit (OTU), there was considerable variability among the GM of Lewis dams, while the GM of F344 and SD dams was fairly consistent between rats (Figure 1B)
Summary
Hereditary Non-Polyposis Colorectal Cancer (HNPCC), and a wide range of other factors such as intestinal inflammation, age, diet, alcohol and tobacco consumption, stress, obesity, and activity level, among others. Many of these factors influence the composition of the resident gut microbiota (GM) [1,2,3,4,5], raising the www.impactjournals.com/oncotarget question of whether the GM may serve as a common mediator in pathways through which these factors exert their influence. The relatively strong evidence for heritability of CRC and paucity of loci identified in genome-wide association studies of CRC [6] may be a reflection of the variation in contribution of non-host, i.e., microbial, factors. Considering the extended time course over which CRC develops in humans, such studies necessitate the use of animal models
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