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Virulence genes are a signature of the microbiome in the colorectal tumor microenvironment.

Burns MB, Lynch J, Starr TK, Knights D, Blekhman R - Genome Med (2015)

Bottom Line: The human gut microbiome is associated with the development of colon cancer, and recent studies have found changes in the microbiome in cancer patients compared to healthy controls.Additionally, we identified a clear, significant enrichment of predicted virulence-associated genes in the colorectal cancer microenvironment, likely dependent upon the genomes of Fusobacterium and Providencia.Our results provide a starting point for future prognostic and therapeutic research with the potential to improve patient outcomes.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN USA ; Department of Ecology, Evolution, and Behavior, University of Minnesota, Minneapolis, MN USA.

ABSTRACT

Background: The human gut microbiome is associated with the development of colon cancer, and recent studies have found changes in the microbiome in cancer patients compared to healthy controls. Studying the microbial communities in the tumor microenvironment may shed light on the role of host-bacteria interactions in colorectal cancer. Here, we highlight the major shifts in the colorectal tumor microbiome relative to that of matched normal colon tissue from the same individual, allowing us to survey the microbial communities in the tumor microenvironment and providing intrinsic control for environmental and host genetic effects on the microbiome.

Methods: We sequenced the microbiome in 44 primary tumor and 44 patient-matched normal colon tissue samples to determine differentially abundant microbial taxa These data were also used to functionally characterize the microbiome of the cancer and normal sample pairs and identify functional pathways enriched in the tumor-associated microbiota.

Results: We find that tumors harbor distinct microbial communities compared to nearby healthy tissue. Our results show increased microbial diversity in the tumor microenvironment, with changes in the abundances of commensal and pathogenic bacterial taxa, including Fusobacterium and Providencia. While Fusobacterium has previously been implicated in colorectal cancer, Providencia is a novel tumor-associated agent which has not been identified in previous studies. Additionally, we identified a clear, significant enrichment of predicted virulence-associated genes in the colorectal cancer microenvironment, likely dependent upon the genomes of Fusobacterium and Providencia.

Conclusions: This work identifies bacterial taxa significantly correlated with colorectal cancer, including a novel finding of an elevated abundance of Providencia in the tumor microenvironment. We also describe the predicted metabolic pathways and enzymes differentially present in the tumor-associated microbiome, and show an enrichment of virulence-associated bacterial genes in the tumor microenvironment. This predicted virulence enrichment supports the hypothesis that the microbiome plays an active role in colorectal cancer development and/or progression. Our results provide a starting point for future prognostic and therapeutic research with the potential to improve patient outcomes.

No MeSH data available.


Related in: MedlinePlus

Differences in metabolic (KEGG) pathways within the normal and colorectal cancer microbiomes. a Stacked bar plots indicating the proportional abundances of metabolic pathways present at ≥1 % in at least one sample. The averages across all normal samples (N) and tumor samples (T) are presented at the left. Rows are arranged as patient-matched tumor (top) and normal (bottom) pairs. Patient ID numbers are appended to the right of the row pairs. b The data from panel (a), presented as the difference in abundance (Tumor – Normal) for each phylum, sorted in the same patient order, where a value of 0 would indicate no difference. Note that the legend at the right is common to panels (a) and (b)
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Fig4: Differences in metabolic (KEGG) pathways within the normal and colorectal cancer microbiomes. a Stacked bar plots indicating the proportional abundances of metabolic pathways present at ≥1 % in at least one sample. The averages across all normal samples (N) and tumor samples (T) are presented at the left. Rows are arranged as patient-matched tumor (top) and normal (bottom) pairs. Patient ID numbers are appended to the right of the row pairs. b The data from panel (a), presented as the difference in abundance (Tumor – Normal) for each phylum, sorted in the same patient order, where a value of 0 would indicate no difference. Note that the legend at the right is common to panels (a) and (b)

Mentions: A recent report presented the validation of a pipeline that leverages knowledge of the human gut reference genomes to predict general microbiome function and enzyme composition from 16S rRNA gene sequencing data [29]. While this approach is not suitable for making conclusive statements regarding single, specific enzymes, it is appropriate for general functional comparisons between groups of samples, as is the case in this report. Using this validated pipeline — Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) — we constructed a virtual metagenome for each of the samples’ microbiomes [29]. The KEGG database was used as a reference to determine the abundances of metabolic pathways and enzymes within the virtual metagenomes [50, 51]. As with the bacterial phyla, we saw significant variation in the predicted functional pathways represented within each of the sampled microbiomes (Fig. 4a), though, as expected from previous studies, we find that the variability in phylum abundances is far greater than the variability in the functional pathways (Fig. 4b) [2, 52]. It is important to note that the results of this analysis are predictions only and not direct measurements of sequences that correspond to pathway member or enzyme genes. Despite the validation of this prediction approach, it is possible that this method biases the predictions toward microbial genomes that are well documented to the exclusion of other, unknown or poorly documented taxa.Fig. 4


Virulence genes are a signature of the microbiome in the colorectal tumor microenvironment.

Burns MB, Lynch J, Starr TK, Knights D, Blekhman R - Genome Med (2015)

Differences in metabolic (KEGG) pathways within the normal and colorectal cancer microbiomes. a Stacked bar plots indicating the proportional abundances of metabolic pathways present at ≥1 % in at least one sample. The averages across all normal samples (N) and tumor samples (T) are presented at the left. Rows are arranged as patient-matched tumor (top) and normal (bottom) pairs. Patient ID numbers are appended to the right of the row pairs. b The data from panel (a), presented as the difference in abundance (Tumor – Normal) for each phylum, sorted in the same patient order, where a value of 0 would indicate no difference. Note that the legend at the right is common to panels (a) and (b)
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4499914&req=5

Fig4: Differences in metabolic (KEGG) pathways within the normal and colorectal cancer microbiomes. a Stacked bar plots indicating the proportional abundances of metabolic pathways present at ≥1 % in at least one sample. The averages across all normal samples (N) and tumor samples (T) are presented at the left. Rows are arranged as patient-matched tumor (top) and normal (bottom) pairs. Patient ID numbers are appended to the right of the row pairs. b The data from panel (a), presented as the difference in abundance (Tumor – Normal) for each phylum, sorted in the same patient order, where a value of 0 would indicate no difference. Note that the legend at the right is common to panels (a) and (b)
Mentions: A recent report presented the validation of a pipeline that leverages knowledge of the human gut reference genomes to predict general microbiome function and enzyme composition from 16S rRNA gene sequencing data [29]. While this approach is not suitable for making conclusive statements regarding single, specific enzymes, it is appropriate for general functional comparisons between groups of samples, as is the case in this report. Using this validated pipeline — Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) — we constructed a virtual metagenome for each of the samples’ microbiomes [29]. The KEGG database was used as a reference to determine the abundances of metabolic pathways and enzymes within the virtual metagenomes [50, 51]. As with the bacterial phyla, we saw significant variation in the predicted functional pathways represented within each of the sampled microbiomes (Fig. 4a), though, as expected from previous studies, we find that the variability in phylum abundances is far greater than the variability in the functional pathways (Fig. 4b) [2, 52]. It is important to note that the results of this analysis are predictions only and not direct measurements of sequences that correspond to pathway member or enzyme genes. Despite the validation of this prediction approach, it is possible that this method biases the predictions toward microbial genomes that are well documented to the exclusion of other, unknown or poorly documented taxa.Fig. 4

Bottom Line: The human gut microbiome is associated with the development of colon cancer, and recent studies have found changes in the microbiome in cancer patients compared to healthy controls.Additionally, we identified a clear, significant enrichment of predicted virulence-associated genes in the colorectal cancer microenvironment, likely dependent upon the genomes of Fusobacterium and Providencia.Our results provide a starting point for future prognostic and therapeutic research with the potential to improve patient outcomes.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN USA ; Department of Ecology, Evolution, and Behavior, University of Minnesota, Minneapolis, MN USA.

ABSTRACT

Background: The human gut microbiome is associated with the development of colon cancer, and recent studies have found changes in the microbiome in cancer patients compared to healthy controls. Studying the microbial communities in the tumor microenvironment may shed light on the role of host-bacteria interactions in colorectal cancer. Here, we highlight the major shifts in the colorectal tumor microbiome relative to that of matched normal colon tissue from the same individual, allowing us to survey the microbial communities in the tumor microenvironment and providing intrinsic control for environmental and host genetic effects on the microbiome.

Methods: We sequenced the microbiome in 44 primary tumor and 44 patient-matched normal colon tissue samples to determine differentially abundant microbial taxa These data were also used to functionally characterize the microbiome of the cancer and normal sample pairs and identify functional pathways enriched in the tumor-associated microbiota.

Results: We find that tumors harbor distinct microbial communities compared to nearby healthy tissue. Our results show increased microbial diversity in the tumor microenvironment, with changes in the abundances of commensal and pathogenic bacterial taxa, including Fusobacterium and Providencia. While Fusobacterium has previously been implicated in colorectal cancer, Providencia is a novel tumor-associated agent which has not been identified in previous studies. Additionally, we identified a clear, significant enrichment of predicted virulence-associated genes in the colorectal cancer microenvironment, likely dependent upon the genomes of Fusobacterium and Providencia.

Conclusions: This work identifies bacterial taxa significantly correlated with colorectal cancer, including a novel finding of an elevated abundance of Providencia in the tumor microenvironment. We also describe the predicted metabolic pathways and enzymes differentially present in the tumor-associated microbiome, and show an enrichment of virulence-associated bacterial genes in the tumor microenvironment. This predicted virulence enrichment supports the hypothesis that the microbiome plays an active role in colorectal cancer development and/or progression. Our results provide a starting point for future prognostic and therapeutic research with the potential to improve patient outcomes.

No MeSH data available.


Related in: MedlinePlus