Periodic Reporting for period 5 - ONCOBIOME (Gut OncoMicrobiome Signatures (GOMS) associated with cancer incidence, prognosis and prediction of treatment response.)
Berichtszeitraum: 2024-08-01 bis 2025-06-30
The ONCOBIOME consortium was launched in January 2019 to explore in depth the role of the microbiota in cancer development, progression and response to therapy, with the goal of developing clinically usable biomarkers, tests and therapeutic interventions. The primary research endpoints were to define Gut OncoMicrobiome Signatures (GOMS) characterizing the composition and structure of the intestinal microbiome before and after cancer diagnosis, as well as their role on the response and toxicity of chemo- and immunotherapy in 4 major malignancies (breast cancer, lung cancer, colon cancer and melanoma). The project aimed at assessing the diagnostic and prognostic values of such GOMS and the extent to which they can be generalized and embedded in the clinical practice. The secondary objectives were to map functional microbial entities associated with metabolic and/or immune properties and to leverage them into innovative microbiota-centered interventions (MCI).
The ONCOBIOME network has spurred an international effort to identify and validate relevant gut microbiota-related biomarkers in oncology, generating a unique and publicly available microbiome resource. It has built new diagnostic tools to define and measure dysbiosis by analysis of the fecal microbiota and blood biomarkers, classified intestinal microorganisms according to their effect on cancer immunosurveillance, identified clinical interventions modulating the microbiota and engaged in community building and practice-changing actions.
The ONCOBIOME network has spurred an international effort to identify and validate relevant gut microbiota-related biomarkers in oncology, generating a unique and publicly available microbiome resource. It has built new diagnostic tools to define and measure dysbiosis by analysis of the fecal microbiota and blood biomarkers, classified intestinal microorganisms according to their effect on cancer immunosurveillance, identified clinical interventions modulating the microbiota and engaged in community building and practice-changing actions.
Gathering more than 100 physicians and scientists with trans-disciplinary assets, ONCOBIOME achieved most of its goals while exploiting prospective trials and two national registries. More than 30 cohorts of patients with stage III/IV cancer, either observational or interventional studies based on chemo+/-immuno-therapy, diet, fecal microbiota transplantation (FMT), or live biotherapeutics were investigated prospectively using various omics technologies (including primarily metagenomics and metabolomics). In total, 5,339 cancer patients and 4,535 healthy controls were enrolled allowing stool sequencing of up to 12,059 stool specimens within the ONCOBIOME network. Methods for the diagnosis of gut dysbiosis have been developed based on onco-microbiome signatures associated with the diagnosis, prognosis, and treatment responses in patients with cancer. The mechanisms explaining how dysbiosis compromises natural or therapy-induced immunosurveillance have been explored. We showed that broad spectrum antibiotics are associated with immunoresistance, through a mechanism involving the downregulation of the intestinal mucosal addressin MADCAM-1. Hence, serum soluble MAdCAM-1 is a reliable and robust biomarker of dismal prognosis during immune checkpoint inhibitors and other therapies. The network also identified immunogenic and tolerogenic bacteria and archaea that directly activate or suppress systemic immune functions respectively. This allowed to define a personalized score of dysbiosis, defined as the TOPOSCORE, that can be calculated using shot gun metagenomics or PCR. Circulating metabolites, in particular distinct bile acids, can characterize antibiotics-associated gut dysbiosis and immunosuppression. This consortium developed several microbiota-centered interventions to circumvent primary resistance to immunotherapy due to gut dysbiosis, in particular the prebiotic castalagin, fecal microbial transplantation and launched the first Phase I trial using Akkermansia massiliensis as a live biotherapeutics against metastatic cancer in individuals devoid of Akkermansia species. Oncobiome EU will transform into the ONCOBIOME ATLAS through the support of a philantropy, SEERAVE Foundation, to pursue stool metagenomics diving into not only bacteria and archaea but also fungi and allowing the identification of drugs and medicinal compounds causing gut dysbiosis within the polypharmacy received by patients.
Through its integrative approach of leveraging multiple cohorts across populations, cancer types and stages, ONCOBIOME has laid the theoretical and practical foundations for the recognition of microbiota alterations as a hallmark of cancer influencing therapy outcome. ONCOBIOME has launched microbiota-centered interventions and lobbies in favour of official guidelines for avoiding diet-induced or iatrogenic (e.g. antibiotic- or proton pump inhibitor-induced) dysbiosis. We conclude why gut dysbiosis is a risk factor in oncology and how intestinal biomarkers should become the scaffold for future microbiota-centered measures in our ONCOBIOME article recently published in Nature Medicine (volume 31, pages 1085–1098 (2025)). Biotechnological companies were emerging from this network, either to exploit diagnosis tools (such as the toposcore) or live biotherapeutics (EVERIMMUNE for Akkermansia massiliensis), or castalagin.