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Title: Gut microbiomes of Malawian twin pairs discordant for kwashiorkor

item SMITH, MICHELLE - Washington University
item YATSUNENKO, TANYA - Washington University
item MANARY, MARK - Children'S Nutrition Research Center (CNRC)
item TREHAN, INDI - Washington University
item MKAKOSYA, RAJHAB - University Of Malawi
item CHENG, JIYE - University Of Virginia
item KAU, ANDREW - Washington University
item RICH, STEPHEN - University Of Virginia
item CONCANNON, PATRICK - University Of Virginia
item MYCHALECKYJ, JOSYF - University Of Virginia
item LIU, JIE - University Of Virginia
item HOUPT, ERIC - University Of Virginia
item LI, JIA - Imperial College
item HOLMES, ELAINE - Imperial College
item NICHOLSON, JEREMY - Imperial College
item KNIGHTS, DAN - University Of Colorado
item URSELL, LUKE - University Of Colorado
item KNIGHT, ROB - University Of Colorado
item GORDON, JEFFREY - Washington University

Submitted to: Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/10/2012
Publication Date: 2/1/2013
Citation: Smith, M.I., Yatsunenko, T., Manary, M.J., Trehan, I., Mkakosya, R., Cheng, J., Kau, A.L., Rich, S.S., Concannon, P., Mychaleckyj, J.C., Liu, J., Houpt, E., Li, J.V., Holmes, E., Nicholson, J., Knights, D., Ursell, L.K., Knight, R., Gordon, J.I. 2013. Gut microbiomes of Malawian twin pairs discordant for kwashiorkor. Science. 339(6119):548-554.

Interpretive Summary: Kwashiorkor, a form of severe malnutrition, is caused by inadequate nutrition and environmental stresses present in the gut. This project sought to explore the bowel bacteria of twins with and without kwashiorkor in order to identify any key differences. We found that the pathogens, proteins, metabolic products, and other waste present in the gut play a key role in kwashiorkor. We also proved that the Malawian diet plays a direct role in the onset of malnutrition and that the effects of a kwashiorkor on the gut bacteria cannot immediately be reversed by therapeutic food. Within the bounds of this study, we developed a novel way to explore conditions of the bowel: collecting stool samples from patients, implanting them in mouse models, then observing clinical interventions. This study implicates the role of the gut bacteria as a causal factor of kwashiorkor; it also developed a new way to study the human bowel, by replicating a human donor's gut community in recipient mice, we mimicked a clinical intervention and have observed taxonomic and metabolic responses to therapeutic food in our models.

Technical Abstract: Kwashiorkor, an enigmatic form of severe acute malnutrition, is the consequence of inadequate nutrient intake plus additional environmental insults. To investigate the role of the gut microbiome, we studied 317 Malawian twin pairs during the first 3 years of life. During this time, half of the twin pairs remained well nourished, whereas 43% became discordant, and 7% manifested concordance for acute malnutrition. Both children in twin pairs discordant for kwashiorkor were treated with a peanut-based, ready-to-use therapeutic food (RUTF). Time-series metagenomic studies revealed that RUTF produced a transient maturation of metabolic functions in kwashiorkor gut microbiomes that regressed when administration of RUTF was stopped. Previously frozen fecal communities from several discordant pairs were each transplanted into gnotobiotic mice. The combination of Malawian diet and kwashiorkor microbiome produced marked weight loss in recipient mice, accompanied by perturbations in amino acid, carbohydrate, and intermediary metabolism that were only transiently ameliorated with RUTF. These findings implicate the gut microbiome as a causal factor in kwashiorkor.