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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

Relationships among the taxa found in colorectal cancer patients’ microbiomes. a Phylogenetic tree depicting the relatedness of the bacterial taxa present (>0.1 % of total) within 50 % or more of the samples. The bars to the right indicate the –log10(p value) from the Wilcoxon signed rank test to determine differential abundance between the normal and tumor microbiomes. Red bars indicate significance at 10 % FDR, while gray bars indicate that the specific taxon did not reach significance. b Correlation network showing the relationship among the abundances of genera with absolute values of 0.05 or more and statistical significance (pseudo p value <0.05). Edges indicate correlations: the edge thickness represents the magnitude and the color represents the sign (blue is positive correlation, red is negative correlation). Each node is a microbial genus where diamond shaped nodes indicate a higher average abundance and circular nodes indicate a lower average abundance in the tumor microbiome compared with normal
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Fig3: Relationships among the taxa found in colorectal cancer patients’ microbiomes. a Phylogenetic tree depicting the relatedness of the bacterial taxa present (>0.1 % of total) within 50 % or more of the samples. The bars to the right indicate the –log10(p value) from the Wilcoxon signed rank test to determine differential abundance between the normal and tumor microbiomes. Red bars indicate significance at 10 % FDR, while gray bars indicate that the specific taxon did not reach significance. b Correlation network showing the relationship among the abundances of genera with absolute values of 0.05 or more and statistical significance (pseudo p value <0.05). Edges indicate correlations: the edge thickness represents the magnitude and the color represents the sign (blue is positive correlation, red is negative correlation). Each node is a microbial genus where diamond shaped nodes indicate a higher average abundance and circular nodes indicate a lower average abundance in the tumor microbiome compared with normal

Mentions: When we assessed the differences at the level of OTUs we discovered numerous changes between the normal and tumor microbiomes with significant differences in the abundances of 19 different taxa (Wilcoxon signed rank test q ≤ 0.1 after FDR correction; Additional file 5). Of note, the tumors showed decreases in the abundances of several taxa within the order Chlostridales, namely, Lachnospiraceae, Ruminococcaceae, and Faecalibacterium prausnitzii, as well as several members within the order Bacteroidales, including Bacteroides, Rikenellaceae, and Bacteroides uniformis (Figs. 2 and 3a). Taxa that were enriched in the tumor microbiomes included Fusobacterium and several Proteobacteria genera, including Candidatus, Portiera and Providencia (Figs. 2 and 3a; Additional file 6). Both Fusobacterium and Providencia are known pathogens, and when a correlation network is generated, it is clear that there are correlated abundance changes in the microbiome as a function of their presence (Fig. 3b). For instance, Fusobacterium species have been shown to have a mutualistic relationship with some Pseudomonas species at abscesses [49]. This co-occurrence is seen in our data as a positive correlation between the abundances of the two genera (Fig. 3b). Other specific interactions between different bacterial taxa remain speculative. In the case of Lactobacillus in the human microbiome, it has been demonstrated that there can be reciprocal interference between species in this genus and other bacterial species in the form of competition for epithelial cell adhesion. As both Lactobacillus and Providencia utilize cell adhesion in their colonization of the human body, this may explain the negative correlation between the two genera in our dataset (Fig. 3b). While there was not a significant correlation between the relative abundances of Fusobacterium and Providencia in this analysis, we assessed the overlap among patients who showed increased levels of these genera at the tumor sites. Taken individually, Fusobacterium and Providencia were more abundant in the tumor microenvironment of 23 out of 44 and 28 out of 44 patients, respectively. Nineteen out of 44 patients showed increases in both of the genera in their tumor microenvironments with respect to their normal matched tissue microbiomes.Fig. 2


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)

Relationships among the taxa found in colorectal cancer patients’ microbiomes. a Phylogenetic tree depicting the relatedness of the bacterial taxa present (>0.1 % of total) within 50 % or more of the samples. The bars to the right indicate the –log10(p value) from the Wilcoxon signed rank test to determine differential abundance between the normal and tumor microbiomes. Red bars indicate significance at 10 % FDR, while gray bars indicate that the specific taxon did not reach significance. b Correlation network showing the relationship among the abundances of genera with absolute values of 0.05 or more and statistical significance (pseudo p value <0.05). Edges indicate correlations: the edge thickness represents the magnitude and the color represents the sign (blue is positive correlation, red is negative correlation). Each node is a microbial genus where diamond shaped nodes indicate a higher average abundance and circular nodes indicate a lower average abundance in the tumor microbiome compared with normal
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Fig3: Relationships among the taxa found in colorectal cancer patients’ microbiomes. a Phylogenetic tree depicting the relatedness of the bacterial taxa present (>0.1 % of total) within 50 % or more of the samples. The bars to the right indicate the –log10(p value) from the Wilcoxon signed rank test to determine differential abundance between the normal and tumor microbiomes. Red bars indicate significance at 10 % FDR, while gray bars indicate that the specific taxon did not reach significance. b Correlation network showing the relationship among the abundances of genera with absolute values of 0.05 or more and statistical significance (pseudo p value <0.05). Edges indicate correlations: the edge thickness represents the magnitude and the color represents the sign (blue is positive correlation, red is negative correlation). Each node is a microbial genus where diamond shaped nodes indicate a higher average abundance and circular nodes indicate a lower average abundance in the tumor microbiome compared with normal
Mentions: When we assessed the differences at the level of OTUs we discovered numerous changes between the normal and tumor microbiomes with significant differences in the abundances of 19 different taxa (Wilcoxon signed rank test q ≤ 0.1 after FDR correction; Additional file 5). Of note, the tumors showed decreases in the abundances of several taxa within the order Chlostridales, namely, Lachnospiraceae, Ruminococcaceae, and Faecalibacterium prausnitzii, as well as several members within the order Bacteroidales, including Bacteroides, Rikenellaceae, and Bacteroides uniformis (Figs. 2 and 3a). Taxa that were enriched in the tumor microbiomes included Fusobacterium and several Proteobacteria genera, including Candidatus, Portiera and Providencia (Figs. 2 and 3a; Additional file 6). Both Fusobacterium and Providencia are known pathogens, and when a correlation network is generated, it is clear that there are correlated abundance changes in the microbiome as a function of their presence (Fig. 3b). For instance, Fusobacterium species have been shown to have a mutualistic relationship with some Pseudomonas species at abscesses [49]. This co-occurrence is seen in our data as a positive correlation between the abundances of the two genera (Fig. 3b). Other specific interactions between different bacterial taxa remain speculative. In the case of Lactobacillus in the human microbiome, it has been demonstrated that there can be reciprocal interference between species in this genus and other bacterial species in the form of competition for epithelial cell adhesion. As both Lactobacillus and Providencia utilize cell adhesion in their colonization of the human body, this may explain the negative correlation between the two genera in our dataset (Fig. 3b). While there was not a significant correlation between the relative abundances of Fusobacterium and Providencia in this analysis, we assessed the overlap among patients who showed increased levels of these genera at the tumor sites. Taken individually, Fusobacterium and Providencia were more abundant in the tumor microenvironment of 23 out of 44 and 28 out of 44 patients, respectively. Nineteen out of 44 patients showed increases in both of the genera in their tumor microenvironments with respect to their normal matched tissue microbiomes.Fig. 2

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