Effects of Milk Secretory Immunoglobulin A on the Commensal Microbiota
Summary
Breast milk contains many components capable of modifying the infant intestinal microbiota, including antimicrobial peptides and bio- active proteins like lactoferrin and lysozyme, oligosaccharides that feed commensal bacteria and provide pathogen decoys, and a high concentration of secretory IgA (SIgA), the primary mucosal antibody responsible for pathogen exclusion at mucosal surfaces. Milk SIgA is derived from a diverse pool of intestinally induced plasma cells homing to the lactating
mammary gland. This antibody repertoire is varied, with evidence of both naturally polyreactive and antigen-specific monoclonal immunoglobulins with capacity to bind to enteric pathogens like Campylobacter, but also to cross-react with general microbial- and self-antigens [1]. This cross-reactivity may be due to both a low-affinity maturation of some milk immunoglobulins or to the glycan heterogeneity on the SIgA glycoprotein. Milk SIgA is heavily glycosylated with O- and N-linked glycans that bind to
select commensals promoting mucosal localization and increasing their
colonization potential in the infant gut (Fig. 1).
Recent data from Nakajima et al. [2] suggest that antigen-independent binding of commensal bacteria can occur while the immunoglobulin is bound to its cognate antigen in a process termed “bystander effect.” Studies provide evidence that nonspecific binding of SIgA promotes colonization of the commensal bacteria in a unique mucosal niche in the intestine, reducing competition within the complex microbiota and providingbenefit to the host. In a mouse model, nonspecific SIgA binding of commensals reduced dextran sulfate sodium-induced colitis whereas both the absence of SIgA in IgA-deficient mice and the absence of polysaccharide
production in commensals responsible for the IgA association failed to protect the mouse from the development of colitis [3]. In vitro, nonspecific SIgA binding to commensals reduced the induction of proinflammatory cytokines and increased the expression of tight junction binding
proteins in mammalian colonocytes when the bacteria were added to the cell culture [4]. Our research group has shown that polymeric milk SIgA binding to select commensals protects them from intestinal proteolysis in vitro. In addition, Moor et al. [5] demonstrated the ability of targeted SIgA to remain bound to the bacterial surface throughout the process of cell division in their model of enchained growth. Taken together, milk SIgA may retain antipathogenic protective functions with Fab-dependent
high-affinity interactions while concurrently maintaining homeostatic commensal colonization in the infant intestinal mucosa through glycan or nonspecific binding that promotes exopolysaccharide production and niche partitioning. These studies and others demonstrate the complex utility of milk SIgA in shaping the intestinal microbiota in the infant, both in the protection from pathogens and in the promotion of commensal
colonization.
References
1 Bunker JJ, Erickson SA, Flynn TM, et al: Natural polyreactive IgA antibodies coat the
intestinal microbiota. Science 2017;358:eaan6619.
2 Nakajima A, Vogelzang A, Maruya M, et al: IgA regulates the composition and met-
abolic function of gut microbiota by promoting symbiosis between bacteria. J Exp Med 2018;215:2019–2034.
3 Donaldson GP, Ladinsky MS, Yu KB, et al: Gut microbiota utilize immunoglobulin A
for mucosal colonization. Science 2018;360:795–800.
4 Mathias A, Duc M, Favre L, et al: Potentiation of polarized intestinal Caco-2
cell responsiveness to probiotics complexed with secretory IgA. J Biol Chem 2010;285:33906–33913.
5 Moor K, Diard M, Sellin ME, et al: High-avidity IgA protects the intestine by enchain-
ing growing bacteria. Nature 2017;544:498–502.
