Paradoxically, loss of immunoglobulin A (IgA), one of the most abundant antibodies, does not irrevocably lead to severe infections in humans but rather is associated with relatively mild respiratory infections, atopy, and auto immunity. IgA might therefore also play covert roles, not uniquely associated with control of pathogens. We show that human IgA deficiency is not associated with massive quantitative perturbations of gut microbial ecology. Metagenomic analysis highlights an expected pathobiont expansion but a less expected depletion in some typi cally beneficial symbionts. Gut colonization by species usually present in the oropharynx is also reminiscent of spatial microbiota disorganization. IgM only partially rescues IgA deficiency because not all typical IgA targets are efficiently bound by IgM in the intestinal lumen. Together, IgA appears to play a nonredundant role at the fore front of the immune/microbial interface, away from the intestinal barrier, ranging from pathobiont control and regulation of systemic inflammation to preservation of commensal diversity and community networks.

Background: Besides intestinal barrier function, the host tolerates gut commensals through both innate and adaptive immune mechanisms. It is now clear that gut commensals induce local immunoglobulin A (IgA) responses, but it remains unclear whether anti-microbiota responses remain confined to the gut. Objective: The aim of this study was to investigate systemic and intestinal responses against the whole microbiota under homeostatic conditions, and in the absence of IgA. Methods: We analyzed blood and feces from healthy donors, patients with selective IgA deficiency (SIgAd) and common variable immunodeficiency (CVID). Immunoglobulincoated bacterial repertoires were analyzed by combined bacterial fluorescence-activated cell sorting and 16S rRNA sequencing, and bacterial lysates were probed by western blot analysis with healthy donors serums. Results: Although absent from the healthy gut, serum anti-microbiota IgG are present in healthy individuals, and increased in SIgAd patients. IgG converge with non-overlapping secretory IgA repertoires to target the same bacteria. Each individual targets a diverse, microbiota repertoire whose proportion inversely correlates with systemic inflammation. Finally, Intravenous Immunoglobulin preparations (IVIG) target much less efficiently CVID gut microbiota than healthy microbiota. Conclusion: Secretory IgA is pivotal for induction of tolerance to gut microbiota. SIgAdassociated inflammation is inversely correlated with systemic anti-commensal IgG responses, which may thus serve as a second line of defense. We speculate that SIgAd patients could benefit from oral IgA supplementation. Our data also suggest that IVIG preparations might be supplemented with IgG from IgA deficient patients pools in order to offer a better protection against gut bacterial translocations in CVID. Key Messages:-Systemic IgG and secretory IgA bind a common spectrum of commensals.-Increased proportions of IgG+ microbiota and inflammatory markers in SIgAd.-IVIG poorly target CVID and SIgAd gut microbiota.