Fusobacterium nucleatum , a reproducible microbial marker for CRC prescreening

Abstract

Background Fusobacterium nucleatumis well known as an important pathogenic gut bacterium associated with colorectal cancer (CRC) and the distribution of F. nucleatum and other Fusobacterium species displayed a strong biogeography-specific pattern. However, their capabilities for diagnosing CRC across multi-populations remains unclear. Here we assessed the potential of these Fusobacterium species for CRC diagnosis using whole metagenomic sequencing (WMS) and 16S rRNA data. Design Included in this study were published raw sequencing data, containing WMS data of 1202 subjects from seven countries and 16S rRNA sequencing data of 556 subjects from four countries. MetaPhlAn2 was used to obtain the Fusobacterium species abundance profiles of WMS data. 16S rRNA data were processed with QIIME2 platform. Random forest models were constructed to evaluate the efficiency of Fusobacterium species for CRC diagnosis. Results Compared to western populations, we found that non-nucleatum Fusobacterium species (F. mortiferum, F. ulcerans andF. varium) were more prevalent and abundant in Chinese populations. F. nucleatum was commonly detected in all cohorts across regional and ethnic variations. After adjustment for potential confounding factors, both WMS and 16S data showed that only F.nucleatum was significantly elevated in CRC patients in most populations. The diagnostic models constructed with all Fusobacterium taxa achieved an average area under the receiver operating characteristic curve (AUROC) score of 0.70 with the study cohorts. Similarly, the average AUROC based on 16S rRNA data was 0.74. Then we analyzed the contributions of each Fusobacterium species to the classification models. As expected, F. nucleatumcontributed most in all but the Italy cohort.F.nucleatumwas also the most important feature in models built with 16S rRNA data. Consequently, the models constructed withF. nucleatumperformed better than those with other single non-nucleatum Fusobacterium species with an average AUROC of 0.64 (WMS) and 0.66 (16S rRNA). Conclusion Our study validated that F. nucleatumcould act as the universal and reproducible microbial marker for CRC. It has been universally detected in different populations albeit being less abundant than other Fusobacterium species, and is likely one of the “keystone” species in the CRC pathogenesis. In contrast, non-nucleatum Fusobacterium species were region-specific and with relatively lower capability for diagnosing CRC. Keyworks CRC, Fusobacterium nucleatum, prescreening, keystone