The Gut Microbiome In Healthy And Severely Malnourished Humans

Human large intestine is home to tens of trillions of microbes belonging to all three do- mains of life. The functions encoded by the genes in this community: microbiome) include processing and production of macro- and micronutrients. Much remains unknown about the factors that determine the assembly of the gut microbial community starting at birth, and if disruptions in the assembly of this `microbial metabolic organ\u27 early in life result in physiologic and metabolic deficits later in life. The central goal of my thesis was to char- acterize development of the gut microbiome early in life, with a focus on describing the relationship between the microbiome and nutritional status. My thesis consists of three parts. Because the degree of temporal variation in the gut microbiome in children and adults in healthy and diseased state was not well described, I began by using metagenomic methods and a variety of computational and statistical tools to characterize the proportional representation of bacterial phylotypes and gene functions in the fecal communities of seven healthy adult USA monozygotic twin pairs sampled over a four-month period. I found that the fecal microbiota and microbiome are stable within each co-twin even in the face of ecologic invasion with a popular commercial fermented diary product. I then compared the fecal microbiota and microbiome in 524 healthy infants, children and adults living in three different countries with distinct cultural traditions: USA, Malawi and Amazon region of Venezuela). I found that interpersonal variation in babies is significantly greater than between adults, and that the microbiota evolves towards an adult configuration during the first three years of life in all three populations sampled. In addi- tion, distinct patterns of functional maturation were observed which involved microbial genes encoding enzymes that participate in the biosynthesis of several vitamins. Finally, I characterized assembly of gut microbiomes in a cohort of Malawian twins concordant for healthy status and twins discordant for severe forms of malnutrition: kwashiorkor or ma- rasmus). Twins were sampled during their first three years of life, including before, during and after treatment with a peanut butter-based ready-to-use therapeutic food: RUTF). In the case of the discordant twins, both co-twins were treated with RUTF. My comparative metagenomic analyses revealed notable differences in the responses to RUTF in kwashi- orkor versus healthy co-twins