Dissecting roles of microbiome-host interactions in colorectal neoplasia etiology using multi-omics data

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PROJECT SUMMARY Microbiome dysbiosis has been increasingly recognized to be associated with colorectal neoplasia, including colorectal adenoma and colorectal cancer (CRC). Disturbances of the gut microbial community, as well as the presence of specific gut microbes, such as Fusobacterium nucleatum and Bacteroides fragilis, have been linked to the initiation and progression of colorectal neoplasia. Meanwhile, aberrant DNA methylation and gene expression patterns are hallmarks of colorectal neoplasia. Hence, to establish a direct and causal link between the gut microbiome and colorectal neoplasia, it is crucial to determine whether and how the gut microbiome affects the DNA methylome and transcriptome in colon tissues. A well-designed population-based study investigating microbiome-host interplays would shed new light on the etiology of colorectal neoplasia. During the past ~20 years, my mentor's team has established two large population-based studies, the Tennessee Colorectal Polyp Study (TCPS, part of the P50CA95103, PI: Zheng) and the Southern Community Cohort Study (SCCS, U01CA202979, PIs: Blot, Zheng and Shrubsole). Herein, I propose a multi-omics study leveraging the unique resources from these large studies to systematically evaluate the impact of the gut microbiome on DNA methylome and transcriptome in human colorectal neoplasia. In the K99 phase, for Aim 1, I will investigate the associations of microbiome with DNA methylation and gene expression in colorectal adenoma tissues (N=200). For Aim 2, I will evaluate the mediatory roles of microbiome on the associations of known CRC risk factors, such as obesity and unhealthy dietary patterns, in association with DNA methylation and gene expression in colorectal adenoma tissues (N=200). In the R00 phase, for Aim 3, I will further evaluate the findings from the K99 phase in additional colorectal adenoma tissues (N=439) and search for novel associations and mediations through combining all data of colorectal adenoma tissues (N=639). In addition, the findings in colorectal adenoma tissues will be investigated in CRC tumor tissues (N=96). For Aim 4, I will prospectively investigate the relationship of the pre-diagnostic gut microbiome with DNA methylation and gene expression in colorectal adenoma tissues (N=139) and CRC tumor tissues (N=96), as well as with risks of colorectal adenoma (139 cases and 139 matched controls) and CRC (96 cases and 96 matched controls). Finally, these results will be integrated to identify potential pathways through which the microbiome might impact colorectal neoplasia. The findings will improve our understanding of how the microbiome-host interactions impact colorectal neoplasia development and have translational potential to develop new tools for CRC prevention. The proposed career development award will help me gain advanced knowledge of epidemiology, CRC biology, microbiology, advanced bioinformatics and biostatistics, as well as skills in mentoring and educating students and junior fellows, for my transition to a successful independent investigator.