Gut microbial dysbiosis, IgA, and Enterococcus in common variable immunodeficiency with immune dysregulation
Roos-Marijn Berbers, Fernanda L. Paganelli, Joris M. van Montfrans, Pauline M. Ellerbroek, Marco C. Viveen, Malbert R. C. Rogers, Moniek Salomons, Jaap Schuurmans, Martine van Stigt Thans, Remi M. M. Vanmaris, Lodewijk A.A. Brosens, Marlot van der Wal, Virgil A. S. H. Dalm, P. Martin van Hagen, Annick A. J. M. van de Ven, Hae‐Won Uh, Femke van Wijk, Rob J. L. Willems, Helen L. Leavis
Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and recurrent infections. Significant morbidity and mortality are caused by immune dysregulation complications (CVIDid), which affect around one-third of CVID patients and have a poorly understood etiology. Here, we investigate the hypothesis that gut microbial dysbiosis contributes to the inflammation underlying CVIDid. RESULTS: Bacterial invasion of colonic crypts was observed in CVID (3/15) and X-linked agammaglobulinemia (XLA, 1/3), but not in healthy control (HC, 0/9) biopsies. Fecal gut microbiota was characterized using 16S rRNA-targeted amplicon sequencing. Increased bacterial load, decreased alpha diversity and distinct beta diversity were observed in CVIDid (n = 42) compared to HC (n = 48), and similar results were seen in CVID with IgA deficiency (n = 40) compared to HC. CVIDid and CVID-IgA showed enrichment of the genus Enterococcus, and in vitro studies confirmed the inflammatory potential of Enterococcus gallinarum and Enterococcus hirae in patient monocytes. CONCLUSIONS: This study further supports the hypothesis that a dysregulated gut microbiota, with IgA deficiency as an important driving factor, contributes to systemic inflammation in primary antibody deficiency, and introduces enterococci as potential pathobionts in CVIDid. Video Abstract.