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Normalization of the microbiota in patients after treatment for colonic lesions

Background. Colorectal cancer is a worldwide health problem. Despite growing evidence that members of the gut microbiota can drive tumorigenesis, little is known about what happens to it after treatment for an adenoma or carcinoma. This study tested the hypothesis that treatment for adenoma or carcinoma alters the abundance of bacterial populations associated with disease to those associated with a normal colon. We tested this hypothesis by sequencing the 16S rRNA genes in the feces of 67 individuals before and after treatment for adenoma (N = 22), advanced adenoma (N = 19), and carcinoma (N = 26).

Results. There were small changes to the bacterial community associated with adenoma or advanced adenoma and large changes associated with carcinoma. The communities from patients with carcinomas changed significantly more than those with adenoma following treatment (P-value < 0.001). Although treatment was associated with intrapersonal changes, the change in the abundance of individual OTUs in response to treatment was not consistent within diagnosis groups (P-value > 0.05). Because the distribution of OTUs across patients and diagnosis groups was irregular, we used the Random Forest machine learning algorithm to identify groups of OTUs that could be used to classify pre and post-treatment samples for each of the diagnosis groups. Although the adenoma and carcinoma models could reliably differentiate between the pre and post-treatment samples (P-value < 0.001), the advanced-adenoma model could not (P-value = 0.61). Furthermore, there was little overlap between the OTUs that were indicative of each treatment. To determine whether individuals who underwent treatment were more likely to have OTUs associated with normal colons we used a larger cohort that contained individuals with normal colons and those with adenomas, advanced adenomas, and carcinomas. We again built Random Forest models and measured the change in the positive probability of having one of the three diagnoses to assess whether the post-treatment samples received the same classification as the pre-treatment samples. Samples from patients who had carcinomas changed towards a microbial milieu that resembles the normal colon after treatment (P-value < 0.001). Finally, we were unable to detect any significant differences in the microbiota of individuals treated with surgery alone and those treated with chemotherapy or chemotherapy and radiation (P-value > 0.05).

Conclusions. By better understanding the response of the microbiota to treatment for adenomas and carcinomas, it is likely that biomarkers will eventually be validated that can be used to quantify the risk of recurrence and the likelihood of survival. Although it was difficult to identify significant differences between pre and post-treatment samples from patients with adenoma and advanced adenoma, this was not the case for carcinomas. Not only were there large changes in pre versus post-treatment samples for those with carcinoma, but these changes were towards a more normal microbiota.


|- README # the top level description of content (this doc) -
|CONTRIBUTING # instructions for how to contribute to your
|project - LICENSE # the license for this project
|- submission/
| |- study.Rmd # executable Rmarkdown for this study, if
| |applicable - # Markdown (GitHub) version of the
| |*.Rmd file - study.tex # TeX version of *.Rmd file -
| |study.pdf # PDF version of *.Rmd file - header.tex # LaTeX
| |header file to format pdf version of manuscript -
| |references.bib # BibTeX formatted references - XXXX.csl # csl
| |file to format references for journal XXX
|- data # raw and primary data, are not changed once created
| |- references/ # reference files to be used in analysis - raw/
| |# raw data, will not be altered
| |- mothur/ # mothur processed data
| +- process/ # cleaned data, will not be altered once created;
|                 # will be committed to repo
|- code/ # any programmatic code
|- results # all output from workflows and analyses
| |- tables/ # text version of tables to be rendered with kable
| |in R - figures/ # graphs, likely designated for manuscript
| |figures
| +- pictures/ # diagrams, images, and other non-graph graphics
|- exploratory/ # exploratory data analysis for study
| |- notebook/ # preliminary analyses
| +- scratch/ # temporary files that can be safely deleted or
| lost
+- Makefile # executable Makefile for this study, if applicable

How to regenerate this repository

Dependencies and locations

  • Gnu Make (v3.81) should be located in the user's PATH
  • mothur (v1.37.5) should be located in the user's PATH
    • Note v1.37.0 causes all sorts of headaches
  • R (v. 3.3.0) should be located in the user's PATH
  • LaTex should be in the user's PATH
  • Pandoc should in the user's PATH
  • PBS job scheduler for server (or something similar)
  • ghostscript libtiff-tools (to convert tiff to pdf)
    • Can check on linux command line by typing which tiff2pdf

Running analysis

git clone
make write.paper