Mucosal IgA responses to members of the gut microbiota in healthy vs. malnourished Malawian children

Abstract Text: Childhood malnutrition is a major contributor to childhood morbidity and mortality worldwide. While inflammatory conditions, such as recurrent infection and environmental enteropathy, have been implicated in pathogenesis, the role of the interaction between the host immune system and the gut microbiota in shaping the outcomes remains poorly understood. In order to identify microbes that were targeted by the host gut mucosal immune response, we developed a flow cytometry-based method to recover and characterize viable gut microbes based on their binding to immunoglobulin A (IgA). Fecal microbiota from Malawian twins discordant for a form of severe acute malnutrition (Kwashiorkor) were transplanted into different groups of adult germ-free C57BL/6J mice that were fed a representative Malawian diet deficient in macro- and micronutrients. IgA-targeted microbes in the fecal microbiota of these ‘kwashiorkor-Malawian diet–fed’ (KM) mice were purified by FACS and transferred to a second group of germ-free mice, also fed the Malawian diet. KM-IgA+ consortia produced (i) dramatic weight loss; (ii) pronounced gut barrier dysfunction manifest by sepsis, and histopathologic changes that were most severe in the colon but also manifest in the small intestine where disruption of the intracellular pattern of epithelial cell adhesion molecule (EpCAM) staining and evidence of extrusion of cells along the length of villi rather than just at the apical region was evident, and (iii) high mortality phenotype in recipient animals. This phenotype was both diet-dependent and microbiota dependent: we did not observe it in mice fed a macro- and micronutrient replete diet or those receiving IgA targeted taxa from mice harboring the healthy co-twin’s microbiota. The barrier dysfunction and mortality phenotypes transmitted by the IgA+ consortium could be mitigated through the administration of IgA-targeted microbes from a mouse colonized with a healthy microbiota, including Akkermansia muciniphila and Clostridium scindens. Applying this FACS-based approach directly to the fecal microbiota of two cohorts of Malawian children, we found that members of Enterobacteriaceae are prominent targets of IgA responses in individuals with severe acute malnutrition. Targeting to other bacterial taxa, including members of Veillonellaceae and Lactobacillaceae, were correlated with the degree of stunting.  These findings indicate that this approach for identifying and quantifying mucosal immune responses to members of the fecal microbiota has potential diagnostic and therapeutic applications to childhood malnutrition, and perhaps other diseases affecting the gut mucosal immune system.

Keywords: gut microbiota, gut immunity, nutritional immunology