Disease signatures in the gut metagenome of a prospective family cohort of inflammatory bowel disease

Inflammatory bowel disease (IBD) is associated with dysbiotic microbiomes. However, whether microbiomes of family members of IBD patients harbour microbial disease signatures of IBD is unknown. Here, we generate shotgun metagenomic data of an IBD family cohort and treatment-naive IBD cases, which we combine with published IBD metagenomes, to perform a meta-analysis of IBD-microbiome associations. Our study reveals microbial shifts that are specific to IBD or IBD subtypes (Crohn’s disease and ulcerative colitis). We find that IBD cohorts share signatures of association with disease irrespective of geography, and we report novel species-level identifications of microbial taxa that are universal markers of Crohn’s disease. We further demonstrate that the microbiome of healthy family members at high risk for IBD represent transitional states between the microbiome of unrelated healthy controls and IBD cases, and harbor diversity, compositional and ecological features that are also observed among IBD microbiomes. Overall, our study provides valuable insights into the intricate relationship between the gut microbiome and IBD, with implications for better predicting disease onset among individuals with high susceptibility for IBD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was financed through the EU Horizon miGut-Health project (Personalised blueprint of chronic inflammation in health-to-disease transition; Grant agreement ID: 101095470, AF, MG) and the DFG-sequencing grant Identification of early fine-scale microbial signatures in inflammatory bowel disease (project 433152305, CB, AF, WL). Microbiome sequencing and data analysis received infrastructure support from the DFG Excellence Cluster 2167 (Precision Medicine in Chronic Inflammation (PMI)) and the DFG Research Unit 5042 miTarget. MR was supported by the Bruhn foundation for the advancement of medical research. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the Medical Faculty of Kiel University gave ethical approval for this work (AZ A117/13 & AZ A103/14) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data and material of the IBD-FC cohort are available upon the submission of a research proposal to https://portal.popgen.de/. Data of the ITM cohort will be uploaded to ENA upon acceptance of this manuscript at a peer-reviewed journal.