Gut Microbiomes of Malawian Twin Pairs Discordant for Kwashiorkor

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, while 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 microbiomes that regressed when 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.

Exploring host–microbiota interactions in animal models and humans

“…The laboratory mouse has been instrumental for establishing roles for the gut microbiota in many aspects of mammalian physiology: angiogenesis (Stappenbeck et al 2002;Reinhardt et al 2012), bone mineral density (Cho et al 2012;Sjö gren et al 2012), brain development and behavior (Sudo et al 2004;Bravo et al 2011;Diaz Heijtz et al 2011;Ezenwa et al 2012), obesity and malnutrition Smith et al 2013), hepatic function (Dapito et al 2012;Henao-Mejia et al 2012), intestinal response to injury and repair (Rakoff-Nahoum et al 2004; Swanson et al 2011), and innate and adaptive immune function (for reviews, see Garrett et al 2010b;Littman and Pamer 2011;Hooper et al 2012). Ninety-nine percent of mouse genes are shared with humans at the host genetic level, and they share key similarities with the human gut microbiome at the phylum through family levels ( Fig.…”

“…In contrast to prior studies of obesity and Western dietary patterns, a study of the microbiota of malnutrition was recently published. Smith et al (2013) performed fecal surveys of the microbiota in a Malawian twin cohort study of severe malnutrition and generated HMM from afflicted children. These HMM mice lost a substantial amount of weight and also provided important data on how the microbiota responds to dietary interventions used to treat malnutrition.…”

Breast milk, microbiota, and intestinal immune homeostasis

“…The intestinal microbiota was implicated in this disease, because a transfer of the microbiome from TLR-5 knockout mouse to a genetically identical, but germ-free mouse, resulted in the same expression of disease. Accordingly, it has been proposed that the microbiome in numerous disease states (inflammatory bowel disease (IBD), type 1 diabetes, and necrotizing enterocolitis) may function as an intermediary determinant of the phenotypic disease expression (27).…”

Symbiosis as a General Principle in Eukaryotic Evolution

“…Transplant studies suggest that the altered microbial community likely contributes to the altered host phenotype. When introduced to germ-free control mice (reared on the standard diet/of wild-type genotype), the recipients display similar deleterious phenotypic traits (Vijay-Kumar et al 2010;Smith et al 2013). These various data sets reinforce the growing appreciation that the composition and activities of the resident microbiota are important for host health, such that perturbation of the microbiota can contribute to chronic ill health, a condition known as "dysbiosis."…”