The intestinal microbial – the population of microbes living in our intestine – can be used to predict the occurrence of colorectal cancer, the second most common type of cancer in women and the third in men.
Research by an international team of scientists, including Brazilians, has found a link between colorectal cancer and changes in microbial stomach conditions that do not depend on the eating habits of the studied populations. The discovery opens the way for the development of non-invasive tests that can predict the onset of the disease.
The study was published on Monday, April 1, in the journal Nature Medicine. His first author was Andrew Maltez Thomas, who had a doctorate in bioinformatics at the University of Sao Paulo (USP), Brazil. Thomas is supported by the São Paulo Research Foundation – FAPESP through a research fellowship at the University of Trento in Italy.
In one of the largest and most diverse researches ever conducted on this subject, researchers combined meta-genomics, bioinformatics and machine learning (using artificial intelligence) to connect colorectal cancer with 969 individuals in Canada, China, France, Germany , Japan and the United States.
The findings identified groups of colon cancer-associated microorganisms in all studied populations and signatures in the metabolism of microorganisms (forms of metabolites produced by microorganisms) that can be used to predict the onset of the disease. The research had two more important outcomes. One discovery in the intestine of patients suffering from colon cancer is a specific type of bacteria commonly found in the mouth and respiratory tract. Another correlation is between colorectal cancer and the presence of a microbial enzyme gene that breaks down choline, an essential nutrient of vitamin B.
The study revealed a higher level of bacterial species of Fusobacterium nucleatum in colorectal cancer than in healthy individuals. This bacterium usually resides in the mouth, and the acidity of other parts of the gastrointestinal tract is considered fatal for her.
"A large number of oral bacteria usually travel to the intestine in patients suffering from colon cancer. This migration can cause inflammation in the intestine, leading to a tumor," Thomas said. "However, we do not know the real reason for migration, only there is a link between the presence of these bacteria in the intestines and colon cancer and that this relationship deserves further investigation."
In addition, the presence of a gene for the microbial enzyme choline trimethylamine lysate (cutC) in fecal samples from colorectal cancer patients increases the likelihood of carcinogenic interactions between intestinal microbiotics and fatty food, as indicated in previous studies. "When the enzyme cleans choline, which is abundant in diets that contain large amounts of red meat and other fatty foods, releases acetaldehyde, well-known carcinogen," Thomas said.
In the study, researchers used data on the composition and number of all bacteria found in 969 fecal samples. To develop a simple method of analysis that can be widely used in clinics and hospitals, they selected statistically significant bacteria.
"Our results from 16 different types of bacteria were comparable to those in the analysis using all types of medications. This is an important step in the development of a simple diagnostic tool that relieves the need for sequencing the entire microbial, but requires the necessary precision," said Thomas. .
The association is not a causal relationship
Investigations on intestinal microbiosis and human health have increased in the last ten years, but a new study is initiated by understanding bacteria as a marker of disease development.
"Markers are usually looked for directly in tumor cells, and we use a different concept." Our analysis is based on the changes of a relatively small number of bacteria in the spectrum of hundreds of bacteria living in the intestine and may indicate the presence of the disease, "said Emmanuel Dias-Neto , a researcher at the International Cancer Research Center AC Camargo (CIPE) and co-author of the article.
DNA sequencing obtained from the microbial intestines allowed researchers to identify the bacteria present in each fecal sample, to measure the amount of each bacterium, and to identify variants in their genes that may be related to different outcomes such as an increased risk of colorectal cancer.
It should be noted, however, that the study did not show that changes in intestinal microbiosis cause colon cancer.
The question is whether certain bacteria can cause cancer or cancer creates a different environment in the colorectal canal and thus favors certain bacteria in relation to other responses, which would be of fundamental importance to the results the research described in the article to help develop colon cancer therapy, "said João Carlos Setubal, a full professor at the Department of Biochemistry at the University of São Paulo, coordinator of the University's Graduate Bioinformatics Study as well as a co-author of the article. Setubal and Dias-Neto supervised Thomas's PhD research.
According to researchers, this is perhaps the largest study of colorectal cancer based on data from fecal samples and such diverse populations. The group analyzed data from five public studies and two other researchers from the University of Trento.
Using data from these seven studies, they have been able to identify enzymes and bacteria, and to determine how the intestinal microbial can predict the development of colorectal cancer. They used data from two other studies with 200 samples to confirm their findings.
"DNA sequencing patterns, which required differentiation of DNA from microbial and human DNA, were a means of identifying and quantifying the species of microorganisms and their genes present in the samples," said Thomas. "We extracted DNA from the foliage samples and sequenced it, and then we used computer methods for data analysis. As a result, we were able to identify and quantify the genotype and the number of genes."
Since the data was obtained from different studies, researchers used sophisticated statistical methods to analyze them as a set.
"We used meta-analytical statistical methods and machine learning techniques to find out how much the results were predictive," Thomas said.
These findings are confirmed by Nicola Segata, a computational biologist from the University of Trento and a project supervisor abroad and reinforced by another study conducted in the European Molecular Biology Laboratory (EMBL) in Germany on the connection of intestine and cancer microbes. The article on the EMBL study was published in the same issue of Nature Medicine.
"During the preparation of the articles, we exchanged information and information with the other group in the partnership that proved to be very important for strengthening our findings. Although we used machine learning techniques and various statistical methods, we came to the same conclusion that intestinal microbiology can predict the presence of colorectal cancer in different populations and studies, said Thomas.