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Microbiome Study of Colorectal Cancer Uncovers Signature of Virulence Genes

NEW YORK (GenomeWeb) – The microbial communities living near tumors in the colon differ from the communities associated with normal colon tissue, according to researchers from the University of Minnesota.

As they reported in Genome Medicine, researchers led by Minnesota's Ran Blekhman compared the microbiomes of 44 primary colon tumors and matched normal colon tissues, finding increased microbial diversity in the tumor environments. In particular, they found increased levels of Fusobacterium and Providencia as well as an enrichment of predicted virulence-associated genes in the colorectal cancer microenvironments.

"It was surprising that the results were so clear," first author Michael Burns from Minnesota said in a statement. "We were able to clearly identify the presence of two virulent strains of bacteria, including the discovery of a new potential culprit, Providencia."

The researchers gathered 44 patient-matched tumor and normal tissue samples for 16S rRNA sequencing and generated some 21.4 million reads for analysis.

Though Firmicutes, Bacteroides, and Proteobacteria dominated both the tumor and normal samples at the phyla level, the researchers noted that the tumor samples had them in a different ratio — they harbored higher levels of Proteobacteria and lower levels of Bacteroides and Proteobacteria than the control samples. The tumor samples also showed an increase in bacteria from the phylum Fusobacteria, which they noted is consistent with previous studies.

There were also noticeable differences between the tumor and control sample microbiomes at the operational taxonomic unit (OTU)-level, the researchers reported, as 19 different taxa exhibited significant differences in abundance. Tumor-associated microbiomes had decreased abundance levels of order Clostridiales taxa like Lachnospiraceae, Ruminococcaceae, and Faecalibacterium prausnitzii, and of order Bacteroidales taxa like Bacteroides, Rikenellaceae, and Bacteroides uniformis.

At the same time, tumor-associated microbiomes were enriched for Fusobacterium and Proteobacteria genera like Candidatus Portiera and Providencia.

Both Fusobacterium and Providencia, Blekhman and his colleagues noted, are known pathogens. Fusobacterium, which has previously been linked to colorectal cancer, is an obligate anaerobe that can infect the oral cavity and the gastrointestinal tract, and Providencia has been linked to urinary tract infections, ocular infections, and gastroenteritis.

A correlation network analysis indicated that changes in abundance of other bacteria in the microbiome were a function of the presence of Fusobacterium and Providencia.

Using the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) pipeline, the researchers developed virtual metagenomes for each of the sample microbiomes, and then, by drawing on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, they came up with the abundance of metabolic pathways and enzymes within these virtual metagenomes.

In this, they saw significant variations in the predicted functional pathways within each of the sample microbiomes.

Still, they noted that 20 predicted pathways were differentially abundant between tumor and normal tissue. Among the depleted pathways in the tumor microbiomes were alanine, aspartate, and glutamate metabolism, DNA replication proteins, and starch and sucrose metabolism pathways, and among the enriched pathways were secretion system, two-component system, and bacterial motility protein pathways.

In addition, by folding in virulence data from the MVirDB database, the researchers found that the tumor-associated microbiome is enriched for genes that encode general virulence proteins.

This enrichment of virulence proteins is dependent upon the presence of Fusobacterium and Providencia in the tumor microbiome, the researchers further reported, as they noted substantial overlap among the virulence-associated genes found in the tumor microenvironment with those associated with Providencia and with those associated with Fusobacterium.

"This has obvious implications for colon cancer patients, and by analyzing the similarities among these pathogens, we have uncovered a single signature of colon cancer when analyzing the gut microbiome that might help researchers identify these cancers in the future," Burns added.

The researchers noted, though, that whether these bacteria cause oncogenesis or become enriched as a result of it is not clear, though the enrichment of virulence proteins in tumor-associated microbiomes suggests to them that the microbiome is an active contributor to colorectal cancer.