Manipulation of the Gut Microbiota Reveals Role in Colon Tumorigenesis
ABSTRACT There is growing evidence that individuals with colonic adenomas and carcinomas harbor a distinct microbiota. Alterations to the gut microbiota may allow the outgrowth of bacterial populations that induce genomic mutations or exacerbate tumor-promoting inflammation. In addition, it is likel...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2016-02-01
|
| Series: | mSphere |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mSphere.00001-15 |
| _version_ | 1818398502747635712 |
|---|---|
| author | Joseph P. Zackular Nielson T. Baxter Grace Y. Chen Patrick D. Schloss |
| author_facet | Joseph P. Zackular Nielson T. Baxter Grace Y. Chen Patrick D. Schloss |
| author_sort | Joseph P. Zackular |
| collection | DOAJ |
| description | ABSTRACT There is growing evidence that individuals with colonic adenomas and carcinomas harbor a distinct microbiota. Alterations to the gut microbiota may allow the outgrowth of bacterial populations that induce genomic mutations or exacerbate tumor-promoting inflammation. In addition, it is likely that the loss of key bacterial populations may result in the loss of protective functions that are normally provided by the microbiota. We explored the role of the gut microbiota in colon tumorigenesis by using an inflammation-based murine model. We observed that perturbing the microbiota with different combinations of antibiotics reduced the number of tumors at the end of the model. Using the random forest machine learning algorithm, we successfully modeled the number of tumors that developed over the course of the model on the basis of the initial composition of the microbiota. The timing of antibiotic treatment was an important determinant of tumor outcome, as colon tumorigenesis was arrested by the use of antibiotics during the early inflammation period of the murine model. Together, these results indicate that it is possible to predict colon tumorigenesis on the basis of the composition of the microbiota and that altering the gut microbiota can alter the course of tumorigenesis. IMPORTANCE Mounting evidence indicates that alterations to the gut microbiota, the complex community of bacteria that inhabits the gastrointestinal tract, are strongly associated with the development of colorectal cancer. We used antibiotic perturbations to a murine model of inflammation-driven colon cancer to generate eight starting communities that resulted in various severities of tumorigenesis. Furthermore, we were able to quantitatively predict the final number of tumors on the basis of the initial composition of the gut microbiota. These results further bolster the evidence that the gut microbiota is involved in mediating the development of colorectal cancer. As a final proof of principle, we showed that perturbing the gut microbiota in the midst of tumorigenesis could halt the formation of additional tumors. Together, alteration of the gut microbiota may be a useful therapeutic approach to preventing and altering the trajectory of colorectal cancer. |
| first_indexed | 2024-12-14T07:05:49Z |
| format | Article |
| id | doaj.art-24f782e4dd9546a3965146a8d0295374 |
| institution | Directory Open Access Journal |
| issn | 2379-5042 |
| language | English |
| last_indexed | 2024-12-14T07:05:49Z |
| publishDate | 2016-02-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mSphere |
| spelling | doaj.art-24f782e4dd9546a3965146a8d02953742022-12-21T23:12:12ZengAmerican Society for MicrobiologymSphere2379-50422016-02-011110.1128/mSphere.00001-15Manipulation of the Gut Microbiota Reveals Role in Colon TumorigenesisJoseph P. Zackular0Nielson T. Baxter1Grace Y. Chen2Patrick D. Schloss3Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USADepartment of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USADepartment of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan, USADepartment of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USAABSTRACT There is growing evidence that individuals with colonic adenomas and carcinomas harbor a distinct microbiota. Alterations to the gut microbiota may allow the outgrowth of bacterial populations that induce genomic mutations or exacerbate tumor-promoting inflammation. In addition, it is likely that the loss of key bacterial populations may result in the loss of protective functions that are normally provided by the microbiota. We explored the role of the gut microbiota in colon tumorigenesis by using an inflammation-based murine model. We observed that perturbing the microbiota with different combinations of antibiotics reduced the number of tumors at the end of the model. Using the random forest machine learning algorithm, we successfully modeled the number of tumors that developed over the course of the model on the basis of the initial composition of the microbiota. The timing of antibiotic treatment was an important determinant of tumor outcome, as colon tumorigenesis was arrested by the use of antibiotics during the early inflammation period of the murine model. Together, these results indicate that it is possible to predict colon tumorigenesis on the basis of the composition of the microbiota and that altering the gut microbiota can alter the course of tumorigenesis. IMPORTANCE Mounting evidence indicates that alterations to the gut microbiota, the complex community of bacteria that inhabits the gastrointestinal tract, are strongly associated with the development of colorectal cancer. We used antibiotic perturbations to a murine model of inflammation-driven colon cancer to generate eight starting communities that resulted in various severities of tumorigenesis. Furthermore, we were able to quantitatively predict the final number of tumors on the basis of the initial composition of the gut microbiota. These results further bolster the evidence that the gut microbiota is involved in mediating the development of colorectal cancer. As a final proof of principle, we showed that perturbing the gut microbiota in the midst of tumorigenesis could halt the formation of additional tumors. Together, alteration of the gut microbiota may be a useful therapeutic approach to preventing and altering the trajectory of colorectal cancer.https://journals.asm.org/doi/10.1128/mSphere.00001-1516S rRNA gene sequencingazoxymethanecolorectal cancerdextran sodium sulfatemicrobial ecologymicrobiome |
| spellingShingle | Joseph P. Zackular Nielson T. Baxter Grace Y. Chen Patrick D. Schloss Manipulation of the Gut Microbiota Reveals Role in Colon Tumorigenesis mSphere 16S rRNA gene sequencing azoxymethane colorectal cancer dextran sodium sulfate microbial ecology microbiome |
| title | Manipulation of the Gut Microbiota Reveals Role in Colon Tumorigenesis |
| title_full | Manipulation of the Gut Microbiota Reveals Role in Colon Tumorigenesis |
| title_fullStr | Manipulation of the Gut Microbiota Reveals Role in Colon Tumorigenesis |
| title_full_unstemmed | Manipulation of the Gut Microbiota Reveals Role in Colon Tumorigenesis |
| title_short | Manipulation of the Gut Microbiota Reveals Role in Colon Tumorigenesis |
| title_sort | manipulation of the gut microbiota reveals role in colon tumorigenesis |
| topic | 16S rRNA gene sequencing azoxymethane colorectal cancer dextran sodium sulfate microbial ecology microbiome |
| url | https://journals.asm.org/doi/10.1128/mSphere.00001-15 |
| work_keys_str_mv | AT josephpzackular manipulationofthegutmicrobiotarevealsroleincolontumorigenesis AT nielsontbaxter manipulationofthegutmicrobiotarevealsroleincolontumorigenesis AT graceychen manipulationofthegutmicrobiotarevealsroleincolontumorigenesis AT patrickdschloss manipulationofthegutmicrobiotarevealsroleincolontumorigenesis |