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The impact of gut microbiota manipulation with antibiotics on colon tumorigenesis in a murine model.

ABSTRACT: It has been suggested that manipulation of gut microbiota using antibiotics can inhibit colitis-associated colorectal cancer (CAC) in a mouse model. We investigated whether timing of gut microbial manipulation using antibiotics affects colon tumorigenesis in the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC model. CAC was induced in C57BL/6 mice by injection of 12.5 mg/kg AOM followed by three rounds of 1.7% DSS exposure. There were six groups based on timing of antibiotic administration. Colonic inflammation, proliferation, and tumorigenesis were evaluated after animal sacrifice. High-throughput sequencing of the mice feces was performed to characterize changes in gut microbiota. Full-time antibiotic treatment significantly decreased the number and size of tumors, histological scores, and expression of pro-inflammatory cytokines compared to the AOM/DSS group without antibiotic treatment. The early and late antibiotic groups, antibiotic administration from the first and second rounds of DSS to the end of the study, showed significantly lower histological scores and tumor burden. In contrast, the pretreatment antibiotic group, antibiotic administration from 3 weeks prior to AOM to the first round of DSS, did not exhibit decreased tumorigenesis. Principal coordinate analysis showed similar gut microbial community structures among the full-time, early, and late antibiotic groups, whereas other groups showed distinct gut microbial profiles. There was a positive correlation between number of tumors and number of operational taxonomic units. Colonic tumorigenesis was attenuated by antibiotic administration, except for that only prior to DSS administration, suggesting that gut microbial changes should be maintained throughout the entire period of inflammation to suppress tumorigenesis.

SUBMITTER: Lee JG

PROVIDER: S-EPMC6924659 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The impact of gut microbiota manipulation with antibiotics on colon tumorigenesis in a murine model.

Lee Jae Gon JG Eun Chang Soo CS Jo Su Vin SV Lee A-Reum AR Park Chan Hyuk CH Han Dong Soo DS

PloS one 20191220 12

It has been suggested that manipulation of gut microbiota using antibiotics can inhibit colitis-associated colorectal cancer (CAC) in a mouse model. We investigated whether timing of gut microbial manipulation using antibiotics affects colon tumorigenesis in the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC model. CAC was induced in C57BL/6 mice by injection of 12.5 mg/kg AOM followed by three rounds of 1.7% DSS exposure. There were six groups based on timing of antibiotic administ ...[more]

PMID: 31860645

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Project description: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.

Project description:UnlabelledRecent studies have shown that individuals with colorectal cancer have an altered gut microbiome compared to healthy controls. It remains unclear whether these differences are a response to tumorigenesis or actively drive tumorigenesis. To determine the role of the gut microbiome in the development of colorectal cancer, we characterized the gut microbiome in a murine model of inflammation-associated colorectal cancer that mirrors what is seen in humans. We followed the development of an abnormal microbial community structure associated with inflammation and tumorigenesis in the colon. Tumor-bearing mice showed enrichment in operational taxonomic units (OTUs) affiliated with members of the Bacteroides, Odoribacter, and Akkermansia genera and decreases in OTUs affiliated with members of the Prevotellaceae and Porphyromonadaceae families. Conventionalization of germfree mice with microbiota from tumor-bearing mice significantly increased tumorigenesis in the colon compared to that for animals colonized with a healthy gut microbiome from untreated mice. Furthermore, at the end of the model, germfree mice colonized with microbiota from tumor-bearing mice harbored a higher relative abundance of populations associated with tumor formation in conventional animals. Manipulation of the gut microbiome with antibiotics resulted in a dramatic decrease in both the number and size of tumors. Our results demonstrate that changes in the gut microbiome associated with inflammation and tumorigenesis directly contribute to tumorigenesis and suggest that interventions affecting the composition of the microbiome may be a strategy to prevent the development of colon cancer.ImportanceThe trillions of bacteria that live in the gut, known collectively as the gut microbiome, are important for normal functioning of the intestine. There is now growing evidence that disruptive changes in the gut microbiome are strongly associated with the development colorectal cancer. However, how the gut microbiome changes with time during tumorigenesis and whether these changes directly contribute to disease have not been determined. We demonstrate using a mouse model of inflammation-driven colon cancer that there are dramatic, continual alterations in the microbiome during the development of tumors, which are directly responsible for tumor development. Our results suggest that interventions that target these changes in the microbiome may be an effective strategy for preventing the development of colorectal cancer.

Project description:Ileocecal resection (ICR) is a commonly required surgical intervention in unmanageable Crohn's disease and necrotizing enterocolitis. However, the impact of ICR, and the concomitant doses of antibiotic routinely given with ICR, on the intestinal commensal microbiota has not been determined. In this study, wild-type C57BL6 mice were subjected to ICR and concomitant single intraperitoneal antibiotic injection. Intestinal lumen contents were collected from jejunum and colon at 7, 14, and 28 days after resection and compared to non-ICR controls. Samples were analyzed by 16S rRNA gene pyrosequencing and quantitative PCR. The intestinal microbiota was altered by 7 days after ICR and accompanying antibiotic treatment, with decreased diversity in the colon. Phylogenetic diversity (PD) decreased from 11.8 ± 1.8 in non-ICR controls to 5.9 ± 0.5 in 7-day post-ICR samples. There were also minor effects in the jejunum where PD values decreased from 8.3 ± 0.4 to 7.5 ± 1.4. PCoA analysis indicated that bacterial populations 28 days post-ICR differed significantly from non-ICR controls. Moreover, colon and jejunum bacterial populations were remarkably similar 28 days after resection, whereas the initial communities differed markedly. Firmicutes and Bacteroidetes were the predominant phyla in jejunum and colon before ICR; however, Firmicutes became the vastly predominant phylum in jejunum and colon 28 days after ICR. Although the microbiota returned towards a homeostatic state, with re-establishment of Firmicutes as the predominant phylum, we did not detect Bacteroidetes in the colon 28 days after ICR. In the jejunum Bacteroidetes was detected at a 0.01% abundance after this time period. The changes in jejunal and colonic microbiota induced by ICR and concomitant antibiotic injection may therefore be considered as potential regulators of post-surgical adaptive growth or function, and in a setting of active IBD, potential contributors to post-surgical pathophysiology of disease recurrence.

Dataset Information

The impact of gut microbiota manipulation with antibiotics on colon tumorigenesis in a murine model.

Publications

The impact of gut microbiota manipulation with antibiotics on colon tumorigenesis in a murine model.

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