The gut microbial metabolite formate exacerbates colorectal cancer progression

Dominik Ternes, Mina Tsenkova, Vitaly Igorevich Pozdeev, Marianne Meyers, Eric Koncina, Sura Atatri, Martine Schmitz, Jessica Karta, Maryse Schmoetten, Almut Heinken, Fabien Rodriguez, Catherine Delbrouck, Anthoula Gaigneaux, Aurelien Ginolhac, Tam Thuy Dan Nguyen, Lea Grandmougin, Audrey Frachet-Bour, Camille Martin-Gallausiaux, Maria Pacheco, Lorie Neuberger-CastilloPaulo Miranda, Nikolaus Zuegel, Jean Yves Ferrand, Manon Gantenbein, Thomas Sauter, Daniel Joseph Slade, Ines Thiele, Johannes Meiser, Serge Haan, Paul Wilmes, Elisabeth Letellier*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

The gut microbiome is a key player in the immunomodulatory and protumorigenic microenvironment during colorectal cancer (CRC), as different gut-derived bacteria can induce tumour growth. However, the crosstalk between the gut microbiome and the host in relation to tumour cell metabolism remains largely unexplored. Here we show that formate, a metabolite produced by the CRC-associated bacterium Fusobacterium nucleatum, promotes CRC development. We describe molecular signatures linking CRC phenotypes with Fusobacterium abundance. Cocultures of F. nucleatum with patient-derived CRC cells display protumorigenic effects, along with a metabolic shift towards increased formate secretion and cancer glutamine metabolism. We further show that microbiome-derived formate drives CRC tumour invasion by triggering AhR signalling, while increasing cancer stemness. Finally, F. nucleatum or formate treatment in mice leads to increased tumour incidence or size, and Th17 cell expansion, which can favour proinflammatory profiles. Moving beyond observational studies, we identify formate as a gut-derived oncometabolite that is relevant for CRC progression.

Original languageEnglish
Pages (from-to)458-475
Number of pages18
JournalNature Metabolism
Volume4
Issue number4
DOIs
Publication statusPublished - 18 Apr 2022

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