Microbial, functional, and virulence biomarkers associated with familial risk of Crohn's disease and ulcerative...

First-degree relatives of patients with inflammatory bowel disease (IBD) carry elevated disease risk and offer a unique window into preclinical gut microbiome alterations. We investigated whether familial IBD risk is associated with intermediate, disease-specific, or shared gut microbiome configurations in both Crohn's disease (CD) and ulcerative colitis (UC), the two main form of IBD.

Using shotgun metagenomics, we analysed fecal samples from CD (n = 68) and UC (n = 77) patients, their healthy first-degree relatives (CD-HFDRs, n = 37; UC-HFDRs, n = 30), and unrelated healthy controls (HCs, n = 497), integrated species-level taxonomy, MetaCyc functional pathways, and virulence factor gene (VFG) profiling, with differential abundance analyses adjusted for relevant covariates.

HFDRs exhibited preserved alpha diversity but intermediate dysbiosis relative to patients and HCs. CD-HFDRs shared CD-associated taxonomic alterations, including depletion of Faecalibacterium prausnitzii, and enrichment of adherence- and invasion-associated VFGs, with 16 of 18 HFDR-enriched VFGs also elevated in CD patients. CD-HFDR functional pathway profiles nonetheless closely resembled those of HCs, revealing a dissociation between taxonomic and functional dysbiosis. Random forest classifiers distinguished HFDRs from HCs with strong performance: species- and VFG-based models achieved an AUCs of 0.966 in CD, and 0.946 in UC. Top predictive features were depletion of F. prausnitzii and enrichment of the E. coli adhesin gene fdeC. UC-HFDRs showed subtler alterations but comparable classifier performance.

IBD first-degree relatives harbour a transitional gut microbiome between health and disease, more pronounced in CD, with F. prausnitzii depletion and pathobiont virulence genes emerging as robust microbiome-based risk indicators.