How Long to Read Commensals Complexed with Secretory IgA as Novel Prevention for Enteropathogenic Infections

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Background: Despite continued advances in medicine, diarrheal disease remains a leading cause of morbidity and mortality in infants globally, but limitations in antibiotic effectiveness and availability make treatment difficult. The gut microbiome plays important roles in infant health and disease, and microbial dysbiosis increases susceptibility to enteric infections. Novel strategies are thus needed to both reshape the infant gut microbiome and target enteric pathogens. Secretory IgA (SIgA), a major breastmilk protein known to provide pathogen defense in the breast-fed infant, holds potential in shaping microbial communities in the infant gut, but little is known about its interactions with infant commensal bacteria. Furthermore, the delivery of pathogen-targeted SIgA as an oral prophylactic into the gut has shown to be a challenge, as peristaltic motility prevents retention at inhibitory concentrations. Objectives: This project investigated the hypotheses that milk-derived or recombinant SIgA (MSIgA or rSIgA, respectively) protects and improves colonization of infant commensal bacteria, and that oral administration of recombinant SIgA complexed to commensals can provided pathogen-targeted defense from enteric pathogens. Methods: Infant commensal Bifidobacterium or Lactobacillus species were first incubated with MSIgA or rSIgA, then subjected to infant digestion conditions and binding assays with human colonocytes in vitro and orally administered to BALBc mice to determine viability post-administration and persistence in the mouse gut in vivo. SIgA association was determined through flow cytometry, and viability and adherence to colonocytes assayed through plating. Strain-specific quantitative PCR (qPCR) was used for fecal or gut bacterial detection and quantification. Human colonocyte cell cultures and mouse intestines were assayed for gene expression changes with the presence of bacteria alone or bacteria-SIgA complexes. To determine pathogen prevention, rSIgA-commensal complexes were either used as pre-treatment for human colonocytes in vitro or orally administered to BALBc mice in vivo followed by Salmonella challenge. A gentamycin protection assay determined invasion of the pathogen into the human colonocytes, and plating of Peyer's patches 24 h post-challenge showed invasion of the pathogen into the mouse gut. Results: SIgA formed concentration-dependent complexes with all Bifidobacterium and Lactobacillus species investigated, and the association increased when the human infant commensals were first grown on the human milk oligosaccharide (HMO) 2'fucosyllactose (2'FL) or lacto-n-neotetraose (LNnT) (Fig 1a). Most Bifidobacterium species were protected from in vitro digestion conditions when bound to MSIgA (Fig 1b), and some showed increased adherence to human colonocytes when associated to MSIgA (Fig 1c). In the mouse, SIgA-complexed commensals were detected 10-fold higher than un-coupled commensals one day after oral administration, confirming the protective capacity of SIgA (Fig 1e). rSIgA-complexed commensals were detected one log-fold higher than un-complexed commensals in the mouse intestines 5 days post-administration, indicating improved persistence of the bacteria when introduced through the immune complex (Fig 1f). SIgA complexes normalized the expression of barrier function and immune response genes of human colonocytes during bacterial exposure (Fig 1d). Pretreatment of human colonocytes in vitro with commensals complexed to pathogen-targeted rSIgA reduced invasion of Salmonella 70% (Fig 2a), and reduced the expression of the pro-inflammatory cytokine IL-8 by 8-fold. In 8-week old female BALBc mice, oral administration of the commensal-rSIgA complex reduced invasion of Salmonella 32% (Fig 2b). The specificity of the prevention in vitro and in vivo indicates the successful use of commensals in retaining pathogen-targeted SIgA. Conclusions: These findings offer insight into the complex dynamics of human SIgA and infant commensal bacteria, and offer a unique mode of delivery for orally administered commensals for the manipulation of gut microbial communities. In addition, the pathogen-targeted defense provided by a recombinant SIgA-commensal complex after oral administration shows a novel prevention strategy for enteric pathogenic infections. With secretory IgA nearing commercial availability, these findings may lead to new products that can promote microbial manipulation of dysbiotic conditions that underlie inflammatory disorders with potential to help stabilize the preterm infant gut.

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