Gut microbiomes of Malawian twin pairs discordant for kwashiorkor

Epidemiologic studies have emphasized that food insecurity is not the sole cause of malnutrition. To investigate the role of the gut microbiome, we studied 317 Malawian twins during the first 3 years of life. Discordance for moderate or severe malnutrition was 43%, and not affected by zygosity or gender. Both co-twins in a discordant pair with kwashiorkor were treated with a peanut based, ready-to-use therapeutic food (RUTF). Time-series metagenomic studies of 9 same-gender pairs who remained healthy and 13 who became discordant for kwashiorkor revealed that RUTF produced a transient maturation in the representation of metabolic functions in kwashiorkor microbiomes that regressed shortly after cessation of RUTF. Previously frozen fecal communities from several discordant pairs were transplanted into gnotobiotic mice who were given a representative, nutrient-deficient Malawi diet followed by RUTF and then the Malawi diet. Metagenomic, mass spectrometric and NMR studies revealed that the combination of a Malawi diet and a kwashiorkor microbiome produced marked weight loss in the gnotobiotic mice, accompanied by substantial perturbations in amino acid and carbohydrate metabolism that were only transiently ameliorated with RUTF. These findings implicate the gut microbiome as a causal factor in a severe form of undernutrition and suggest that long-term nutritional support may be required to correct persistent metabolic defects arising from microbiome dysfunction in undernourished children.