Secondary bile acid production by gut bacteria promotes Western diet-associated colorectal cancer
Year: 2025
Type: article
Abstract: Background Western diet and associated production of secondary bile acids (BAs) have been linked to the development of sporadic colorectal cancer (CRC). Despite observational studies showing that secondary BAs produced by 7α-dehydroxylating (7αDH+) gut bacteria are increased in CRC, a causal proof of their tumour-promoting effects is lacking. Objective Investigate the causal role of BAs produced by 7αDH+ gut bacteria in CRC. Design We performed feeding studies in a porcine model of CRC combined with multi-omics analyses and gnotobiotic mouse models colonised with 7αDH+ bacteria or a genetically modified strain to demonstrate causality. Results Western diet exacerbated the CRC phenotype in APC 1311/+ pigs. This was accompanied by increased levels of the secondary BA deoxycholic acid (DCA) and higher colonic epithelial cell proliferation. The latter was counteracted by the BA-scavenging drug colestyramine. Metagenomic analysis across multiple human cohorts revealed higher occurrence of bai (BA inducible) operons from Clostridium scindens and close relatives in faeces of patients with CRC. Addition of these specific 7αDH+ bacteria ( C. scindens / Extibacter muris ) to defined communities of gut bacteria led to DCA production and increased colon tumour burden in mouse models of chemically or genetically induced CRC. A mutant strain of Faecalicatena contorta lacking 7αDH caused fewer colonic tumours in azoxymethane/dextran sodium sulfate treated mice and triggered less epithelial cell proliferation in human colon organoids compared with wild-type F. contorta . Conclusion This work provides functional evidence for the causal role of secondary BAs produced by gut bacteria through 7αDH in CRC under adverse dietary conditions, opening avenues for future preventive strategies.
Source: Gut
Authors: Annika Osswald, Esther Wortmann, David Wylensek, Stephanie Kuhls, Olivia I Coleman, Kenneth Peuker, Anne Strigli, Quinten R Ducarmon, Martin Larralde, Wei Liang, Nicole S Treichel, Fabian Schumacher, Colin Volet, Silke Matysik, Karin Kleigrewe, Michael Gigl, Sascha Rohn, Chun-Jun Guo, Burkhard Kleuser, Gerhard Liebisch, Angelika Schnieke, Jason M Ridlon, Rizlan Bernier-Latmani, Georg Zeller, Sebastian Zeissig, Dirk Haller, Krzysztof Flisikowski, Thomas Clavel, Soeren Ocvirk
Institutions: German Institute of Human Nutrition, Technical University of Munich, Universitätsklinikum Aachen, RWTH Aachen University, Universitätsmedizin Greifswald, Universität Greifswald, European Molecular Biology Laboratory, Leiden University, Leiden University Medical Center, Freie Universität Berlin, École Polytechnique Fédérale de Lausanne, University Hospital Regensburg, University of Regensburg, Technische Universität Berlin, Weill Cornell Medicine, University of Illinois Urbana-Champaign, University of Bern, University Hospital of Bern
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Awards: G306507530, NFDI4Microbiota Nationale Forschungsdateninfrastruktur für MikrobiotaForschung, Verbund Mi-EOCRC - Mikrobiota-basierte Prävention von Darmkrebs bei jungen Menschen - Standort Aachen, Kausale Rolle des Gallensäuremetabolismus durch das Mikrobiom bei Dickdarmkrebs, Einfluss von BallaststoffSupplementierung auf die Pathogenese kolorektaler Karzinome: Welche Rolle spielt die ButyratProduktion der intestinalen Mikrobiota?, G7710879285, SFB 1371: Microbiome Signatures Funktionelle Relevanz des Mikrobioms im Verdauungstrakt
OpenAlex ID: W4417524175