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Title: Functional characterization of IgA-targeted bacterial taxa from undernourished Malawian children that produce diet-dependent enteropathy

Author
item KAU, ANDREW - Washington University School Of Medicine
item PLANER, JOSEPH - Washington University School Of Medicine
item LIU, JIE - University Of Virginia School Of Medicine
item RAO, SINDHUJA - Washington University School Of Medicine
item YATSUNENKO, TANYA - Washington University School Of Medicine
item TREHAN, INDI - Washington University School Of Medicine
item MANARY, MARK - Children'S Nutrition Research Center (CNRC)
item LIU, TA-CHIANG - Washington University School Of Medicine
item STAPPENBECK, THADDEUS - Washington University School Of Medicine
item MALETA, KENNETH - University Of Malawi
item ASHORN, PER - University Of Tampere Medical School
item DEWEY, KATHRYN - University Of California
item HOUPT, ERIC - University Of Virginia School Of Medicine
item HSIEH, CHYI-SONG - Washington University School Of Medicine
item GORDON, JEFFREY - Washington University School Of Medicine

Submitted to: Science Translational Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/5/2015
Publication Date: 2/25/2015
Citation: Kau, A.L., Planer, J.D., Liu, J., Rao, S., Yatsunenko, T., Trehan, I., Manary, M.J., Liu, T., Stappenbeck, T.S., Maleta, K.M., Ashorn, P., Dewey, K.G., Houpt, E.R., Hsieh, C., Gordon, J.I. 2015. Functional characterization of IgA-targeted bacterial taxa from undernourished Malawian children that produce diet-dependent enteropathy. Science Translational Medicine. 7(276):276ra24.

Interpretive Summary: The purpose of the work was to understand how the gut bacteria and gut immune/barrier function contributes to childhood undernutrition and childhood vaccine effectiveness. Stool from malnourished Malawian infants was transplanted into mice and the antibodies made by the mice were measured. By measuring antibodies at different time points, normal immune development was understood which may improve treatment of malnutrition and suggest more effective therapeutic measures.

Technical Abstract: To gain insights into the interrelationships among childhood undernutrition, the gut microbiota, and gut mucosal immune/barrier function, we purified bacterial strains targeted by immunoglobulin A (IgA) from the fecal microbiota of two cohorts of Malawian infants and children. IgA responses to several bacterial taxa, including Enterobacteriaceae, correlated with anthropometric measurements of nutritional status in longitudinal studies. The relationship between IgA responses and growth was further explained by enteropathogen burden. Gnotobiotic mouse recipients of an IgA(+) bacterial consortium purified from the gut microbiota of undernourished children exhibited a diet-dependent enteropathy characterized by rapid disruption of the small intestinal and colonic epithelial barrier, weight loss, and sepsis that could be prevented by administering two IgA-targeted bacterial species from a healthy microbiota. Dissection of a culture collection of 11 IgA-targeted strains from an undernourished donor, sufficient to transmit these phenotypes, disclosed that Enterobacteriaceae interacted with other consortium members to produce enteropathy. These findings indicate that bacterial targets of IgA responses have etiologic, diagnostic, and therapeutic implications for childhood undernutrition.