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Study shows microbiome-derived formate promotes colorectal cancer

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Published on Monday, 20 June 2022

Colorectal cancer (CRC) is one of the most common and lethal malignancies in Western countries. It is the second most commonly diagnosed cancer and the second most common cause of death from cancer in Europe (World Cancer Research Fund). In recent years, an increased morbidity in young adults has been observed in several parts of the word most probably due to lifestyle, body fatness and dietary patterns.

The microbiome (the bacteria which inhabit the gut) is now recognized as a metabolically active ecosystem which interacts with the surrounding cells influencing the general health status. Evidence suggests a clear relationship between alterations in the gut microbiota composition and diverse human pathologies such as CRC. Several studies have identified specific bacteria species that are highly enriched in CRC patient tissues, stool and saliva. Thus, the gut microbiome may play an important role in CRC development and therapy resistance. However, regarding host-microbial interactions, few CRC-associated microbes have been studied, hence the role of bacteria in the etiology of the disease remains unknown.

About the study

The Molecular Disease Mechanisms Group at the Department of Life Sciences and Medicine at the University of Luxembourg in close collaboration with the Systems Ecology Group at the Luxembourg Center for Systems Biomedicine and with the doctors at the Centre Hospitalier Emile Mayrisch recently published an article on Nature Metabolism about the crosstalk between the gut microbiome and the host.

They used novel experimental approaches such as the gut-on-chip model HuMiX and patient-derived gut organoids in combination with in silico metabolic models and various mouse models to go beyond the observational microbiome studies described so far in literature. “We specifically focus on Fusobacterium Nucleatum, a bacterium species often found in CRC patients. We describe molecular signatures linking CRC phenotypes with Fusobacterium abundance,” said Dr. Elisabeth Letellier, head of the Molecular Disease Mechanisms group.

By focusing on the metabolic crosstalk between Fusobacterium and tumor cells, the researchers identified the metabolic product formate to promote CRC development. “Our gut on the chip model HuMiX allowed us to specifically study the metabolic cross-talk between a bacterium and host tumor cells”, added Prof. Paul Wilmes.  The findings were confirmed in in vivo studies: Fusobacterium nucleatum or formate treatment in mice led to increased tumor incidence, size, and expansion of a subset of pathogenic T cells, which can favor pro-inflammatory profiles. 

This kind of study design is very timely – as microbiome-cancer research is an emerging and rapidly developing field, a wide variety of techniques and approaches are used. They are often not easy to compare. This article seeks to build upon the currently used strategies in the field and proposes a novel integrative approach. The approach aspires to unify and link omics technologies and bioinformatics with culture/isolate-based microbiology and clinical research, as well as in vitro and in vivo experimental research on host-microbiome interactions, particularly focusing on the metabolic cross-talk between the microbiota and the host. Altogether, “our study uncovers formate as a microbiome-derived oncometabolite in colorectal cancer and opens upon new therapeutic strategies for CRC patients,” concluded Dr. Letellier.