CHARACTERIZATION OF MICROBIOME DIFFERENCES AMONGST PATIENTS WITH COLONIC POLYPOSIS WITH AND WITHOUT A KNOWN GENETIC DRIVER

Background: Colonic polyposis, which is a risk factor for colorectal cancer (CRC), can be driven by a pathogenic variant in a polyposis gene. However, in many cases germline genetic testing is negative, leaving the cause of the polyposis unknown. There has been increasing evidence that specific microbiome and metabolomic signatures may be associated with colon polyp development and CRC. However, at this time it remains uncertain if the microbiome plays a role in the development of colonic polyposis in the absence of a known polyposis gene mutation.

Methods: Subjects undergoing a standard-of-care colonoscopy were recruited via an IRB-approved protocol as either control subjects with 2 or fewer lifetime colon adenomas, or polyposis subjects with ≥10 total colonic adenomas and either negative polyposis multigene panel genetic testing or a known familial adenomatous polyposis (FAP) or MUTYH-associated polyposis (MAP). A stool sample was collected prior to the colonoscopy, and during the procedure mucosal biopsies were obtained from the proximal and distal colon. To measure bacterial community composition, we carried out 16S rRNA marker gene sequencing (hypervariable region V1-V2) on the Illumina MiSeq platform. Analysis was performed using QIIME2 and R.

Results: A total of 30 subjects were recruited, including 17 with polyposis (5 with FAP/MAP [gene-positive] and 12 with negative polyposis genetic testing [gene-negative]) and 13 control subjects. Global analysis of the entire microbial community showed that there is a significant decrease in alpha diversity as measured by richness in the gene-positive polyposis group compared to the gene-negative polyposis and control groups (P= 0.047, P=0.02). Faith’s PD was decreased in the gene-positive polyposis compared to the gene-negative polyposis groups (P=0.031). Bacterial communities in the gene-positive and gene-negative polyposis groups were also different by weighted and unweighted UniFrac distances (PERMANOVA test, P=0.02, P=0.01). Although we could not see any statistically significant differences in individual taxa between the groups through linear models, our analysis was limited by the sample size.

Conclusions: This study provides the first comprehensive microbiome characterization and comparison between individuals with colonic polyposis both with and without a known genetic driver, showing these distinct populations have different microbiome compositions. Elucidating microbiome signatures of the gene-negative polyposis cohort is a critical first step for future studies examining the potential causal role of the microbiome in the development of gene-negative polyposis and for the development of microbiome-targeted therapies to aid in decreasing polyp development and CRC risk.