title: Altered Interactions between the Gut Microbiome and Colonic Mucosa Precede Polyposis in APCMin/+ Mice.
abstract: Mutation of the adenomatous polyposis coli (APC gene), an early event in the adenoma-carcinoma sequence, is present in 70-80% of sporadic human colorectal adenomas and carcinomas. To test the hypothesis that mutation of the APC gene alters microbial interactions with host intestinal mucosa prior to the development of polyposis, culture-independent methods (targeted qPCR assays and Illumina sequencing of the 16S rRNA gene V1V2 hypervariable region) were used to compare the intestinal microbial composition of 30 six-week old C57BL/6 APCMin/+ and 30 congenic wild type (WT) mice. The results demonstrate that similar to 12-14 week old APCMin/+ mice with intestinal neoplasia, 6 week old APCMin/+ mice with no detectable neoplasia, exhibit an increased relative abundance of Bacteroidetes spp in the colon. Parallel mouse RNA sequence analysis, conducted on a subset of proximal colonic RNA samples (6 APCMin/+, 6 WT) revealed 130 differentially expressed genes (DEGs, fold change ≥ 2, FDR <0.05). Hierarchical clustering of the DEGs was carried out by using 1-r dissimilarity measurement, where r stands for the Pearson correlation, and Ward minimum variance linkage, in order to reduce the number of input variables. When the cluster centroids (medians) were included along with APC genotype as input variables in a negative binomial (NB) regression model, four of seven mouse gene clusters, in addition to APC genotype, were significantly associated with the increased relative abundance of Bacteroidetes spp. Three of the four clusters include several downregulated genes encoding immunoglobulin variable regions and non-protein coding RNAs. These results support the concept that mutation of the APC gene alters colonic-microbial interactions prior to polyposis. It remains to be determined whether interventions directed at ameliorating dysbiosis in APCMin/+mice, such as through probiotics, prebiotics or antibiotics, could reduce tumor formation.
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, United States of America.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Son
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, United States of America.
authors.forename: Shanawaj
authors.initials: S
authors.lastname: Khair
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, United States of America.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Pettet
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, United States of America.
authors.forename: Nengtai
authors.initials: N
authors.lastname: Ouyang
authors.affiliation: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, United States of America.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Tian
authors.affiliation: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, United States of America.
authors.forename: Yuanhao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Preventive Medicine, Stony Brook University, Stony Brook, NY, United States of America.
authors.forename: Gerardo G
authors.initials: GG
authors.lastname: Mackenzie
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Robertson
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America.
authors.forename: Diana
authors.initials: D
authors.lastname: Ir
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America.
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Frank
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, United States of America.
authors.forename: Basil
authors.initials: B
authors.lastname: Rigas
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, United States of America.
authors.forename: Ellen
authors.initials: E
authors.lastname: Li
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000382:microbiology* / Q000473:pathology*; D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000818:Animals; D041963:Bacteroidetes / Q000502:physiology; D001483:Base Sequence; D016000:Cluster Analysis; D005260:Female; D000069196:Gastrointestinal Microbiome; D020869:Gene Expression Profiling; D005838:Genotype; D007413:Intestinal Mucosa / Q000382:microbiology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D025341:Principal Component Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012336:RNA, Ribosomal, 16S / Q000235:genetics
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D012333:RNA, Messenger; D012336:RNA, Ribosomal, 16S