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.
