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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

Differentially abundant pathways and enzyme classes between matched normal and colorectal tissue microbiomes. a Boxplots with corresponding paired dotplots indicating the relative abundances of several pathways showing differential abundance between tumor and normal samples. Lines connect the abundance in the normal (left) and tumor sample (right). Line colors indicate the directionality of the abundance change (blue and red for decreased and increased abundance in the tumor relative to the normal, respectively). Below we plot the difference between the tumor and normal abundance as grey dots, with the purple line representing the 95 % confidence interval (95 % CI) and the mean. Values at 0 (grey dotted lines) represent no change between normal and tumor. b Barchart showing the p values (−log10 transformed) obtained from Fisher’s exact test used to determine virulence category enrichment in the tumor-associated microbiome on the x-axis with the gene categories labeled on the y-axis. Red bars indicate significance by Fisher’s exact test (p < 0.005) and gray bars indicate no statistical significance. The blue dashed line indicates the standard significance cutoff of p = 0.05. c Barchart from the analysis in panel (b), demonstrating the fold-enrichment of virulence protein-encoding genes in the tumor-associated microbiome. The x-axis is the fold enrichment of the different virulence enzyme classes within the tumor microbiome relative to the normal microbiome. The vertical blue dotted line placed at 1 indicates the point where there is no difference between the normal and tumor microbiomes. d Venn diagram indicating the numbers of shared virulence-associated genes among Providencia, Fusobacterium, and the set of statistically significantly increased abundance genes at the tumor
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Fig5: Differentially abundant pathways and enzyme classes between matched normal and colorectal tissue microbiomes. a Boxplots with corresponding paired dotplots indicating the relative abundances of several pathways showing differential abundance between tumor and normal samples. Lines connect the abundance in the normal (left) and tumor sample (right). Line colors indicate the directionality of the abundance change (blue and red for decreased and increased abundance in the tumor relative to the normal, respectively). Below we plot the difference between the tumor and normal abundance as grey dots, with the purple line representing the 95 % confidence interval (95 % CI) and the mean. Values at 0 (grey dotted lines) represent no change between normal and tumor. b Barchart showing the p values (−log10 transformed) obtained from Fisher’s exact test used to determine virulence category enrichment in the tumor-associated microbiome on the x-axis with the gene categories labeled on the y-axis. Red bars indicate significance by Fisher’s exact test (p < 0.005) and gray bars indicate no statistical significance. The blue dashed line indicates the standard significance cutoff of p = 0.05. c Barchart from the analysis in panel (b), demonstrating the fold-enrichment of virulence protein-encoding genes in the tumor-associated microbiome. The x-axis is the fold enrichment of the different virulence enzyme classes within the tumor microbiome relative to the normal microbiome. The vertical blue dotted line placed at 1 indicates the point where there is no difference between the normal and tumor microbiomes. d Venn diagram indicating the numbers of shared virulence-associated genes among Providencia, Fusobacterium, and the set of statistically significantly increased abundance genes at the tumor

Mentions: Twenty pathways (as defined by KEGG, level 3) were found to be differentially abundant between the tumor and normal tissue. Alanine, aspartate, and glutamate metabolism, DNA replication proteins, and starch and sucrose metabolism were significantly depleted in the tumor microbiome (q ≤ 0.01 for each pathway by two-sided Wilcoxon signed rank test after FDR correction; Fig. 5a). Conversely, secretion system, two-component system, and bacterial motility protein pathways were significantly enriched in the tumor microbiome (q ≤ 0.04 for each pathway by two-sided Wilcoxon signed rank test after FDR correction; Fig. 5a).Fig. 5


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)

Differentially abundant pathways and enzyme classes between matched normal and colorectal tissue microbiomes. a Boxplots with corresponding paired dotplots indicating the relative abundances of several pathways showing differential abundance between tumor and normal samples. Lines connect the abundance in the normal (left) and tumor sample (right). Line colors indicate the directionality of the abundance change (blue and red for decreased and increased abundance in the tumor relative to the normal, respectively). Below we plot the difference between the tumor and normal abundance as grey dots, with the purple line representing the 95 % confidence interval (95 % CI) and the mean. Values at 0 (grey dotted lines) represent no change between normal and tumor. b Barchart showing the p values (−log10 transformed) obtained from Fisher’s exact test used to determine virulence category enrichment in the tumor-associated microbiome on the x-axis with the gene categories labeled on the y-axis. Red bars indicate significance by Fisher’s exact test (p < 0.005) and gray bars indicate no statistical significance. The blue dashed line indicates the standard significance cutoff of p = 0.05. c Barchart from the analysis in panel (b), demonstrating the fold-enrichment of virulence protein-encoding genes in the tumor-associated microbiome. The x-axis is the fold enrichment of the different virulence enzyme classes within the tumor microbiome relative to the normal microbiome. The vertical blue dotted line placed at 1 indicates the point where there is no difference between the normal and tumor microbiomes. d Venn diagram indicating the numbers of shared virulence-associated genes among Providencia, Fusobacterium, and the set of statistically significantly increased abundance genes at the tumor
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Related In: Results  -  Collection

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Fig5: Differentially abundant pathways and enzyme classes between matched normal and colorectal tissue microbiomes. a Boxplots with corresponding paired dotplots indicating the relative abundances of several pathways showing differential abundance between tumor and normal samples. Lines connect the abundance in the normal (left) and tumor sample (right). Line colors indicate the directionality of the abundance change (blue and red for decreased and increased abundance in the tumor relative to the normal, respectively). Below we plot the difference between the tumor and normal abundance as grey dots, with the purple line representing the 95 % confidence interval (95 % CI) and the mean. Values at 0 (grey dotted lines) represent no change between normal and tumor. b Barchart showing the p values (−log10 transformed) obtained from Fisher’s exact test used to determine virulence category enrichment in the tumor-associated microbiome on the x-axis with the gene categories labeled on the y-axis. Red bars indicate significance by Fisher’s exact test (p < 0.005) and gray bars indicate no statistical significance. The blue dashed line indicates the standard significance cutoff of p = 0.05. c Barchart from the analysis in panel (b), demonstrating the fold-enrichment of virulence protein-encoding genes in the tumor-associated microbiome. The x-axis is the fold enrichment of the different virulence enzyme classes within the tumor microbiome relative to the normal microbiome. The vertical blue dotted line placed at 1 indicates the point where there is no difference between the normal and tumor microbiomes. d Venn diagram indicating the numbers of shared virulence-associated genes among Providencia, Fusobacterium, and the set of statistically significantly increased abundance genes at the tumor
Mentions: Twenty pathways (as defined by KEGG, level 3) were found to be differentially abundant between the tumor and normal tissue. Alanine, aspartate, and glutamate metabolism, DNA replication proteins, and starch and sucrose metabolism were significantly depleted in the tumor microbiome (q ≤ 0.01 for each pathway by two-sided Wilcoxon signed rank test after FDR correction; Fig. 5a). Conversely, secretion system, two-component system, and bacterial motility protein pathways were significantly enriched in the tumor microbiome (q ≤ 0.04 for each pathway by two-sided Wilcoxon signed rank test after FDR correction; Fig. 5a).Fig. 5

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