Secretory immunoglobulin A (IgA) is the most abundant antibody in mucosal secretions and has been recognized as a first line of defense in protecting the intestinal epithelium from enteric pathogens. Despite its important role in mucosal immunity and intestinal homeostasis, IgA deficiency—defined by undetectable seric IgA titers (<0.07 mg/ml) with normal IgG concentration—is related to a very mild phenotype in humans, while it may also have clinical consequences such an increased incidence of respiratory infections, allergy and autoimmunity. However, little is known about how the absence of IgA affects the composition of human gut microbiota.
A new study, led by Dr. Guy Gorochov from Sorbonne Université and Assistance Publique-Hôpitaux de Paris (France), has shown that human IgA deficiency is not associated with extensive perturbations of gut commensal communities.
The researchers compared the gut microbial communities in the feces of patients with IgA deficiency (n = 21) with those of age- and sex-matched healthy control patients (n = 34) using a metagenomics approach.
Both patients with selective IgA deficiency (SIgAd) and controls had similar fecal microbiota diversities, which were found to be relatively stable over time. Although overall microbiome diversity was preserved in SIgAd patients, the relative compositions were different. IgA deficiency led to pathobiont expansion and a depletion in some typically beneficial symbionts. Specifically, proportions of 17 microbial species within the Firmicutes, Bacteroidetes and Proteobacteria (exclusively Gammaproteobacteria) phyla (including species usually present in the oropharynx such as Streptococcus sanguinis, Veillonella parvula and Haemophilus parainfluenzae) were higher in the IgA-deficient subjects, while the proportions of 14 other species were reduced.
The lack of IgA also induced perturbations in host systemic inflammatory versus regulatory responses, which was assessed by measuring cytokine-secreting circulating CD4+ T cells. However, the researchers did not find correlations between clinical status and any of the elevated immunological and translocation markers. Furthermore, an association analysis was able to infer interactions between individual taxa and how such networks were disrupted in the absence of IgA, revealing that IgA deficiency was associated with a disturbed bacterial dependency association network.
Beyond studying the impact of IgA deficiency on gut microbiota composition, SIgAd patients exhibited IgM on the surface of intestinal microbes, which supports the potential argument that secretory immunoglobulins from different isotypes can replace each other. This would also explain the mild phenotype observed in SIgAd patients. However, some taxa, including members from the Enterobacteriaceae family, were shown not to be well bound by IgM. All together, these data show that the compensation host mechanisms of IgA deficiency are driven in different ways. Further research is needed to explore whether IgA deficiency may also affect the small intestine and not only the microbiota of fecal samples.
This is the first study that has explored how IgA deficiency affects the composition of gut microbiota in humans, providing insight into how secretory IgA shapes microbiota composition. IgA deficiency may lead to mild dysbiosis and altered immunoglobulin-binding profiles, and understanding these mechanisms could provide better insight regarding not only the behavior and function of IgA, but also its consequences for the host.
This study is not the only one that has recently explored mechanisms involved in facilitating the establishment and stability of the gut microbiota in the context of IgA responses. Another study, led by Dr. Sarkis K. Mazmanian from the California Institute of Technology in Pasadena (California, USA), has found that IgA responses improved mucosal colonization of the gut commensal Bacteroides fragilis in mice.
The researchers found that the genetic locus, called commensal colonization factors (ccf)—previously reported by the same research group to be essential for B. fragilis for colonization of colonic crypts—regulated capsule expression of B. fragilis to allow its binding with IgA, which ultimately helps bacteria colonizing the mucus lining of the gut. However, microscopy revealed that B. fragilis was not capable of aggregating along the intestinal lining in IgA-deficient mice. These data support the role of IgA in allowing gut commensal species to colonize specific niches in the gut (named “single-strain stability”), beyond its role in enteric pathogen clearance.
These results show that IgA has a role in promoting specific bacteria colonization in the gut in addition to its role in pathogen clearance. This new finding sheds light on why the host immune system has evolved to invest a considerable amount of energy in producing several grams of IgA daily, even though the consequences of its deficiency are mild.
Donaldson GP, Ladinsky MS, Yu KB, et al. Gut microbiota utilize immunoglobulin A for mucosal colonization. Science. 2018; doi: 10.1126/science.aaq0926.
Fadlallah J, El Kafsi H, Sterlin D, et al. Microbial ecology perturbation in human IgA deficiency. Sci Transl Med. 2018; 10(439). doi: 10.1126/scitranslmed.aan1217.