Fecal microbiota transplant from common variable immunodeficiency patients to germ-free mice recapitulates gut dysbiosis

Patients with non-infectious complications (NIC) have worse clinical outcomes in common variable immunodeficiency (CVID) than those with infections-only (INF). NIC are associated with gut microbiome aberrations, but there are no reductionist animal models that emulate CVID, to examine the microbiome’s role in NIC-CVID development. To uncover potential microbiome roles in NIC-CVID development, we examined fecal whole genome shotgun sequencing (mWGS) from patients with NIC-CVID, INF-CVID, and their household controls. Potentially pathogenic microbes Streptococcus parasanguinis and Erysipelatoclostridium ramosum were enriched in the gut microbiomes of NIC-CVID patients. In contrast, Fusicatenibacter saccharivorans and Anaerostipes hadrus, known to suppress inflammation and promote healthy metabolism, were enriched in the gut microbiomes of INF-CVID patients. Fecal microbiota transplant (FMT) from NIC-CVID patients, INF-CVID patients, and their household controls into germ-free (GF) mice treated with anti-CD20 revealed gut dysbiosis patterns in NIC-FMT recipients but not INF-FMT and control-FMT recipients. Similar to what we observed in CVID patients, NIC-FMT recipients had a higher relative abundance of microbes that can potentially cause opportunistic infections in immunocompromised individuals, including Dysgonomonas mossii and Negativebacillus massiliensis. Further, INF-FMT recipients had a higher relative abundance of potentially beneficial microbes, including Clostridium symbiosum, a short-chain fatty acid producer associated with immunomodulatory and anti-inflammatory effects. And Parabacteroides distasonis, a succinate and secondary bile acid producer, can promote gut barrier integrity and reduce inflammation in the gut of obese mice. Inter-group analysis in gut microbiota composition identified dissimilarities between NIC-CVID and their household controls, and between NIC-CVID and INF-CVD. In mice, we noted dissimilarities between FMT recipients, most notably between CVID-FMTand control-FMT recipients.