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Apyrase-mediated amplification of secretory IgA promotes intestinal homeostasis

ABSTRACT: Morphogenesis of epithelial tissues relies on the precise developmental control of cell polarity and architecture. In the early Drosophila embryo, the primarSecretory IgA (SIgA) interaction with commensal bacteria regulates the composition and function of the microbiota, contributing to gut ecosystem homeostasis. However, mechanisms regulating the reciprocal control of microbiota and SIgA are not defined. Bacteria-derived ATP limits T follicular helper (Tfh) cells activity in the Peyer’s patches (Pps) of the small intestine via the P2X7 receptor and thereby SIgA generation. Here we show that inhibition of bacteria derived ATP signaling by delivery of the ATP-degrading enzyme apyrase to the intestine results in the amplification of the SIgA repertoire. The enhanced breadth of SIgA in mice colonized with apyrase-releasing E. Coli conditioned topographical distribution of bacteria and expression of genes involved in metabolic versus immune functions in the intestinal epithelium. SIgA mediated conditioning of bacteria and enterocyte function was also reflected by selective differences in nutrients absorption in mice colonized with apyrase expressing bacteria. Hydrolysis of bacteria derived ATP was particularly helpful in restoring intestinal homeostasis via SIgA in antibiotics induced dysbiosis. Administration of apyrase expressing bacteria attenuated intestinal barrier impairment, glucose metabolism perturbation and susceptibility to infection by enteric pathogens induced by antibiotic treatments. Therefore, microbiota derived ATP regulates SIgA, and amplification of SIgA response by apyrase can be leveraged to restore intestinal fitness in dysbiotic conditions.y epithelium forms during cellularisation, following a tightly controlled genetic programme where specific sets of genes are up-regulated. Some of them, for instance, control membrane invagination between the nuclei anchored at the apical surface of the syncytium.

ORGANISM(S): Mus musculus Mus

PROVIDER: GSE203433 | GEO | 2022/07/13

REPOSITORIES: GEO

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Project description:Maintenance of intestinal homeostasis requires a healthy relationship between the commensal gut microbiota and the host immune system. Breast milk supplies the first source of antigen-specific immune protection in the gastrointestinal tract of suckling mammals, in the form of secretory immunoglobulin A (SIgA). SIgA is transported across glandular and mucosal epithelial cells into external secretions by the polymeric immunoglobulin receptor (pIgR). Here, a breeding scheme with pIgR-sufficient and -deficient mice was used to study the effects of breast milk-derived SIgA on development of the gut microbiota and host intestinal immunity. Early exposure to maternal SIgA prevented the translocation of aerobic bacteria from the neonatal gut into draining lymph nodes, including the opportunistic pathogen Ochrobactrum anthropi. By the age of weaning, mice that received maternal SIgA in breast milk had a significantly different gut microbiota from mice that did not receive SIgA, and these differences were magnified when the mice reached adulthood. Early exposure to SIgA in breast milk resulted in a pattern of intestinal epithelial cell gene expression in adult mice that differed from that of mice that were not exposed to passive SIgA, including genes associated with intestinal inflammatory diseases in humans. Maternal SIgA was also found to ameliorate colonic damage caused by the epithelial-disrupting agent dextran sulfate sodium. These findings reveal unique mechanisms through which SIgA in breast milk may promote lifelong intestinal homeostasis, and provide additional evidence for the benefits of breastfeeding. We used microarrays to determine the effects of passive and active secretory IgA, in the presence or absence of the epithelial-disrupting agent dextran sulfate sodium, on gene expression in intestinal epithelial cells of mice A breeding scheme was used that involved crosses between mouse dams and sires that were deficient or sufficient for expression of the polymeric immunoglobulin receptor (Pigr), a protein that is required for transport of secretory IgA (SIgA) into external secretions. Offspring of these crosses were genotyped for Pigr alleles, and littermate offspring were distributed into 4 groups based on early exposure to passive SIgA in mother's milk (P-yes and P-no) and ability to carry out Pigr-mediated endogenous transport of active SIgA (A-yes and A-no). Seventy-day-old gender-matched Pigr+/- and Pigr-/- offspring of Pigr+/- and Pigr-/- dams were left untreated or given 2% dextran sulfate sodium (DSS) in drinking water for 8 days. Colonic epithelial cells were isolated, and total cellular RNA was purified. RNA was pooled from 3 mice for each of 2 biological replicates for microarray analysis.

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Apyrase-mediated amplification of secretory IgA promotes intestinal homeostasis

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