Gut Microbial Dysbiosis Underlies Immune Dysregulation in Common Variable Immunodeficiency

Common Variable Immunodeficiency (CVID) is a primary antibody deficiency characterised by hypogammaglobulinemia and recurrent infections. Most morbidity and mortality is caused by immune dysregulation complications (CVIDid), which affect around one-third of CVID patients and are of poorly understood etiology. Here, we investigate the hypothesis that gut microbial dysbiosis contributes to the inflammation underlying CVIDid. In this cross-sectional multicentre study, bacterial localization and crypt architecture were analyzed in gut biopsies of 15 CVID patients, 3 patients with X-linked agammaglobulinemia (XLA), and 9 healthy controls (HC). Next, bacterial load and microbiota composition were characterized using 16S rRNA-targeted qPCR and next-generation sequencing in stool samples of 42 CVIDid patients, 51 CVID patients with infections only (CVIDio), 48 HC and 11 XLA patients. The CVID gut microbiota was characterized by expansion of Enterobacteriaceae and bacterial invasion of colonic crypts in CVID and XLA colon biopsies. Increased fecal bacterial load, decreased alpha diversity were observed in CVIDid compared to HC, as well as a distinct beta diversity in CVIDid. Metagenomic shotgun sequencing followed by selective culturing and qPCR revealed a higher prevalence of Enterococcus gallinarum in CVIDid relative to CVIDio. Presence of E. gallinarum in stool correlated with increased serum IL-17A, IL-10, LILRB4 and Flt3L. When exposed to E. gallinarum supernatants, CVID and HC monocytes showed increased production of IL-6 and IL-6/IL-10 ratio.This study further supports the hypothesis that a dysregulated gut microbiota contributes to systemic inflammation in primary antibody deficiency, and introduces E.gallinarum as a potential pathobiont in CVID with immune dysregulation.