Colorectal cancer: towards a diagnostic test

Researchers have been working toward using the gut microbiome as a clinical target for screening for colorectal cancer. This would ideally allow simple stool tests to be used for early detection of the disease in place of expensive procedures such as colonoscopies. An international study that has just been published in Nature Medicine focused precisely on this subject. The research is coordinated by the University of Trento. The paper was first-authored by Gianmarco Piccinno, with Nicola Segata as head of project and scientific coordinator, both of the Department of Cellular, Computational and Integrative Biology-Cibio. Segata is also principal investigator at the European Institute of Oncology (IEO) in Milan. 

About the study. The team of researchers has identified a "microbial signature", that is, a group of about a dozen bacteria that tend to be much more present and abundant in the intestines of people with colorectal cancer. Among them, Fusobacterium nucleatum has already been extensively studied, but this study has highlighted others such as Parvimonas micra, Gemella morbillorum, Peptostreptococcus stomatis, to name a few.
Nicola Segata explains: "We think that probably, for reasons not fully known yet, these species are able to colonize the so-called ‘tumor microenvironment’ in the guts of patients with colorectal cancer. These bacteria,” he continues, “are normally found in the mouth of healthy individuals, but we find them in sequenced stool samples (that reflect the composition of the gut microbiome) almost only belonging to individuals with colorectal cancer."
The identification of this microbial signature could allow the development of accurate disease screening approaches based exclusively on gut metagenomics, which is an entirely non-invasive method. According to the two scholars, the accuracy of this approach is close to 90 percent. But there’s more to it. The microbial signature they have identified is also correlated with the clinical stage of colorectal cancer, i.e., its severity and anatomical location. In particular, they have seen how some bacteria of the microbial signature increase with tumor development and could therefore provide interesting hypotheses on the mechanisms of the disease and possibly on its clinical development.

The contribution of machine learning. The researchers achieved these results thanks to a methodology based on machine learning that they developed and used. "This technology, applied to the metagenomic analysis approaches that we use in our laboratory,” underlines Segata, “provides a predictive model that says if there is a high probability or not that a person has colorectal cancer."
The question that remains open and which others are trying to answer is whether and which of these microbial species and strains contribute to the onset of the cancer itself. "Whether or not the microbiome in the tumor is a cause of the tumor is almost indifferent if the primary objective is to develop a screening approach for individuals in the general population," clarifies Gianmarco Piccinno. In fact, the study focuses on the potential use as a non-invasive screening tool, so that diseases are identified as early as possible. Nevertheless, the definitive clinical and preventive value of this metagenomic test remains to be verified via future registered clinical trials. 
However, according to Piccinno and Segata, the results achieved, once validated, could contain enough information to be used as an important additional form of screening. This would therefore allow a more targeted use of colonoscopy, which remains the necessary examination for a final diagnosis.

The link between the gut microbiome and colorectal cancer. The first connection was established years ago: some specific bacteria in the microbiota have the ability to disrupt our own cellular biology and are thought to contribute to cancer over time. In some cases, this is due to the production of toxins that can damage our DNA leading to mutations- which are one of the factors that lead to cancer – thus allowing the gut microbiota to perhaps generate an environment that could facilitate the development of the disease. But this is only one of the potential ways through which the microbiome is linked with colorectal cancer, which is the third most frequent type of cancer and the second most lethal in the world, and only 40 percent of patients are diagnosed before metastasis.

This study was primarily funded by the European Commission with the collaboration "ONCOBIOME" led by prof. Laurence Zitvogel which has the overall aim of finding links not only between the human microbiome and colorectal cancer, but also the role of the microbiome in supporting cancer treatment, especially the latest development in immunotherapy approaches for cancer such as metastatic melanoma, small cell lung cancer, and metastatic breast cancer.
What prompted the researchers to investigate this connection further was the increase in incidence of the disease in young adults, particularly in individuals under 50 years of age. Early onset cancers were one of the challenges put to the research community in 2023 by Cancer Grand Challenges, the research initiative co-founded by Cancer Research UK and the National Cancer Institute, with team PROSPECT, led by Andy Chan of Massachusetts General Hospital and Yin Cao of Washington University in St. Louis, subsequently awarded up to $25m funding in 2024 to unravel the mechanisms behind the rise in early onset colorectal cancer. 

Segata and Piccinno also joined the multidisciplinary international PROSPECT team together with Professor Curtis Huttenhower of the Harvard T.H. Chan School of Public Health. Segata, Piccinno, Huttenhower, Chan, and Zitvogel are all co-authors of the study together with several members of their laboratories. Many questions remain regarding the role of the microbiome in cancer, including the full range of mechanisms involved and which microbial species play a causal role, if any.

A worldwide network. The study is part of major international projects involving research partners from all over the world: ONCOBIOME, funded by the European Commission, as well as two Cancer Grand Challenges teams (team PROSPECT, funded by Cancer Research UK, the National Cancer Institute, The Bowelbabe Fund for Cancer Research UK and The French National Cancer Institute, and team OPTIMISTICC, funded by Cancer Research UK). Thanks to this collaboration network, the research group of UniTrento was able to access more than 3,700 samples, collected and sequenced from 18 different studies and from almost all continents (excluding Africa, South America and Oceania). 
The ultimate objective of these studies is to verify whether there is an association between colorectal cancer and the microbiome compared to external factors such as pollution, diet, lifestyle, and to understand which are the most effective treatments given the unique composition of each patient's microbiome.

“Cross-stage, strain-level, pooled analysis of the gut microbiome in 3,741 individuals from 18 colorectal cancer cohorts” was published in Nature Medicine and is available at: https://www.nature.com/articles/s41591-025-03693-9  (DOI: https://doi.org/10.1038/s41591-025-03693-9)