Gut dysbiosis patterns in CVID patients with noninfectious complications observed in a germ-free mouse model through fecal microbiota transplantation

Patients with common variable immunodeficiency (CVID) who develop noninfectious complications (NIC) have worse clinical outcomes than those with infections only (INF). While gut microbiome aberrations have been linked to NIC, reductionist animal models that accurately recapitulate CVID are lacking. Our aim in this study was to uncover potential microbiome roles in the development of NIC in CVID. We performed whole-genome shotgun sequencing on fecal samples from CVID patients with NIC, INF, and their household controls. We also performed fecal microbiota transplants from CVID patients to germ-free mice. We found potentially pathogenic microbes <i>Streptococcus parasanguinis</i> and <i>Erysipelatoclostridium ramosum</i> were enriched in gut microbiomes of CVID patients with NIC. In contrast, <i>Fusicatenibacter saccharivorans</i> and <i>Anaerostipes hadrus</i>, known to suppress inflammation and promote healthy metabolism, were enriched in gut microbiomes of INF CVID patients. Fecal microbiota transplant from NIC, INF, and their household controls into germ-free mice revealed gut dysbiosis patterns only in recipients from CVID patients with NIC, but not in those from INF CVID or household controls recipients. Our findings provide a proof of concept that fecal microbiota transplant from CVID patients with NIC to germ-free mice recapitulates microbiome alterations observed in the donors.