Abstract Introduction: Inflammatory responses play a decisive role in colorectal cancer etiology, yet specific causes remain unclear. Our hypothesis is that gut microbial alterations promote colorectal carcinogenesis, possibly through inflammation. To test this hypothesis, we conducted a case-control study of the gut microbiome in 47 histologically confirmed colorectal cancer cases and 94 non-cancer controls (matched by gender and body mass index) who were previously recruited (Schiffman et al, 1989). Demographic and clinical information was assessed by questionnaire and medical chart review, and lyophilized fecal biospecimens for gut microbiome analysis were obtained before initiation of any treatment. Methods: Ribosomal 16S rRNA genes in fecal DNA were amplified by universal primers, bar coded and sequenced by 454 FLX technology. 16S rRNA bacterial gene sequences were binned into operational taxonomic units (OTUs) with 97% identity and aligned to fully sequenced microbial genomes (IMG/GG GreenGenes) in the QIIME pipeline. We performed t-tests and nonparametric Wilcoxon signed-rank tests to compare differences between colorectal cancer cases than controls on alpha diversity (Shannon's diversity index) and relative abundance of specific taxa, respectively, unadjusted for multiple comparisons. Results: From 141 fecal samples, we have obtained 794,217 16S rRNA gene sequence reads. Shannon's diversity index was significantly lower in cases (p=0.02; 7.86 for cases; 8.33 for controls). In taxonomy-based analyses, Fusobacterium genus was significantly enriched in the colorectal cancer cases compared with control group (p=0.003). Relative abundance of Fusobacterium sequences ranged from 0-28.9% in cases (median 0.072%) compared to 0-1.3% in controls (median 0.027%). We also noted a relative decrease in abundance of Clostridia (p=0.01, class) and Actinobacteria (p=0.03, phylum) in the colorectal cancer group compared with controls. Conclusion: This first study of the gut microbiome in colorectal cancer patients compared with non-cancer controls suggests that the differential abundances in stool of Fusobacteria, and possibly Clostridia and Actinobacteria, are associated with risk of colorectal cancer. Consistent with our results, two recent studies reported that Fusobacterium sequences were enriched in human colorectal tumor tissue compared to adjacent normal tissue (Kostic et al, 2012 and Castellarin et al, 2012). Fusobacterium is an anaerobic, Gram-negative bacteria, with invasive and proinflammatory characteristics through lipopolysaccharides. Further study is needed to define its role in colorectal carcinogenesis. Citation Format: Jiyoung Ahn, Rashmi Sinha, Zhiheng Pei, Christine Dominianni, James J. Goedert, Richard B. Hayes, Liying Yang. Human gut microbiome and risk of colorectal cancer, a case-control study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2290. doi:10.1158/1538-7445.AM2013-2290