Microbiome patterns predict colorectal cancer occurrence

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ColorectalGut microbiota can be used to predict the occurrence of colorectal cancer, the second most common type of cancer in women and the third in men, found an international study.

Medical Xpress reports that research by an international team of scientists, including researchers at the University of São Paulo (USP), Brazil, has found a link between colorectal cancer and changes in gut microbiota patterns that do not depend on the dietary habits of the populations studied. The discovery paves the way to the development of non-invasive tests capable of predicting emergence of the disease.

In one of the largest and most varied surveys ever conducted on the topic, the researchers combined metagenomics, bioinformatics and machine learning (with the use of artificial intelligence) to correlate the occurrence of colorectal cancer with gut microbiota data for 969 people in Canada, China, France, Germany, Japan and the US.

The findings identified groups of microorganisms associated with colorectal cancer in all the populations studied, and signatures in the microbial metabolism (patterns of metabolites produced by microorganisms) that can be used to predict the occurrence of the disease. The research had two other important outcomes. One is the discovery in the intestines of colorectal cancer patients of a specific species of bacterium commonly found in the mouth and airways. The other is a correlation between colorectal cancer and the presence of the gene for a microbial enzyme that degrades choline, an essential vitamin B group nutrient.

The study found higher levels of the bacterial species Fusobacterium nucleatum in colorectal cancer patients than in healthy individuals. This bacterium normally inhabits regions of the mouth, and the acidity of other parts of the gastrointestinal tract was thought to be fatal to it.

“Larger numbers of oral bacteria tend to travel to the intestine in colorectal cancer patients. This migration may cause inflammation in the intestine, giving rise to the tumour,” said Dr Andrew Maltez Thomas at the University of São Paulo. “However, we don’t know the actual reason for the migration, only that there’s a link between the presence of these bacteria in the intestine and colorectal cancer, and that the link deserves to be investigated further.”

The other discovery, a significant presence of the gene for the microbial enzyme choline trimethylamine-lyase (cutC) in faecal samples from colorectal cancer patients, reinforces the possibility of a carcinogenic link between gut microbiota and a fatty diet, indicated by previous research. “When the enzyme cleaves choline, which is abundant in diets containing large amounts of red meat and other fatty foods, it releases acetaldehyde, a well-known carcinogen,” Thomas said.

In the study, the researchers used data on the composition and abundance of all bacteria found in 969 faecal samples. To develop a simple method of analysis that can be widely used by clinics and hospitals, they selected the statistically significant bacteria. “Our results from 16 species of bacteria were comparable to those from analyses using all species. This is an important step in the development of a simple diagnostic tool that dispenses with the need to sequence the entire microbiota yet has the necessary precision,” Thomas said.

Research on the links between gut microbiota and human health has grown in the last 10 years, but the new study innovates by conceiving of bacteria as markers of the development of disease.

“Markers are typically looked for directly in association with tumour cells. We use a different concept. Our analysis is based on changes in a relatively small set of bacteria in a spectrum of hundreds of bacteria that live in the gut and may indicate the presence of a disease,” said Emmanuel Dias-Neto, a researcher at AC Camargo Cancer Centre‘s International Research Centre (CIPE) and a co-author.

Sequencing of DNA obtained from gut microbiota enabled the researchers to identify the bacteria present in each faecal sample, to measure the quantity of each bacterium, and to identify variants in their genomes that may be linked to different outcomes, such as a heightened risk of colorectal cancer.

It should be stressed, however, that the study did not show that alterations in gut microbiota cause colorectal cancer. “We detected an association, but that doesn’t necessarily imply a causal link. The question is whether specific bacteria can cause cancer or cancer creates a different environment in the colorectal duct and thereby favours certain bacteria over others. We don’t yet have an answer, which would be fundamental for the results of the research described in the article to develop therapies to treat colorectal cancer,” said Professor João Carlos Setubal of the University of São Paulo’s biochemistry department, a co-author of the article. Setubal and Dias-Neto supervised Thomas’s PhD research.

According to the researchers, this may be the largest-ever study of colorectal cancer based on data from faecal samples and such diverse populations. The group analysed data from five public studies and two other studies by researchers at the University of Trento.

With the data from these seven studies they were able to identify enzymes and bacteria, and to work out how gut microbiota can predict the development of colorectal cancer. They used data from two other studies with 200 samples to validate their findings.
“DNA sequencing of the samples, which required distinguishing between microbiota DNA and human DNA, was a means of identifying and quantifying the species of microorganisms and their genes present in the samples,” Thomas said. “We extracted DNA from the faecal samples and sequenced it. We then used computational methods to analyse the data. As a result, we were able to identify and quantify the species and gene abundance.”

Because the data came from different studies, the researchers used sophisticated statistical methods to analyse them as an ensemble. “We used meta-analytical statistical methods and machine learning techniques to find out how predictive the results were,” Thomas said.

The findings were validated by Nicola Segata, a computational biologist at the University of Trento and supervisor abroad for the project, and reinforced by another study performed at the European Molecular Biology Laboratory (EMBL) in Germany on the links between gut microbiome and cancer.

“While preparing the articles, we exchanged data and information with the other group in a partnership that proved highly important to reinforce our findings. Although we used machine learning techniques and different statistical methods, we arrived at the same conclusion that the gut microbiome can predict the presence of colorectal cancer in different populations and studies,” Thomas said.

Abstract
Association studies have linked microbiome alterations with many human diseases. However, they have not always reported consistent results, thereby necessitating cross-study comparisons. Here, a meta-analysis of eight geographically and technically diverse fecal shotgun metagenomic studies of colorectal cancer (CRC, n = 768), which was controlled for several confounders, identified a core set of 29 species significantly enriched in CRC metagenomes (false discovery rate (FDR) < 1 × 10−5). CRC signatures derived from single studies maintained their accuracy in other studies. By training on multiple studies, we improved detection accuracy and disease specificity for CRC. Functional analysis of CRC metagenomes revealed enriched protein and mucin catabolism genes and depleted carbohydrate degradation genes. Moreover, we inferred elevated production of secondary bile acids from CRC metagenomes, suggesting a metabolic link between cancer-associated gut microbes and a fat- and meat-rich diet. Through extensive validations, this meta-analysis firmly establishes globally generalizable, predictive taxonomic and functional microbiome CRC signatures as a basis for future diagnostics.

Authors
Jakob Wirbel, Paul Theodor Pyl, Ece Kartal, Konrad Zych, Alireza Kashani, Alessio Milanese, Jonas S Fleck, Anita Y Voigt, Albert Palleja, Ruby Ponnudurai, Shinichi Sunagawa, Luis Pedro Coelho, Petra Schrotz-King, Emily Vogtmann, Nina Habermann, Emma Niméus, Andrew M Thomas, Paolo Manghi, Sara Gandini, Davide Serrano, Sayaka Mizutani, Hirotsugu Shiroma, Satoshi Shiba, Tatsuhiro Shibata, Shinichi Yachida, Takuji Yamada, Levi Waldron, Alessio Naccarati, Nicola Segata, Rashmi Sinha, Cornelia M Ulrich, Hermann Brenner, Manimozhiyan Arumugam, Peer Bork, Georg Zeller

Medical Xpress report
Nature Medicine abstract


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