A microbial perspective of human development provides opportunities to both expand and refine our definitions of healthy postnatal growth. A corollary is that ensuring healthy microbiota development likely has long-term beneficial effects on host physiology, metabolism, and immunity. Little is known about the mechanisms that drive microbiota assembly (succession). Our central hypothesis is that the nutrient requirements of members of different stages of community development, and that changes in nutrient availability in the diet/gut, are key drivers of succession. Based on our previous studies, we postulate that (i) succession can be modeled in gnotobiotic mice, (ii) the nutrient requirements of community members can be deduced from in silico metabolic reconstructions based on their genome sequences; (iii) predictions from (ii) can be directly tested and refined through analyses of young gnotobiotic mice colonized with defined consortia of human gut bacterial strains representing different stages of community assembly. Based on our birth-cohort studies of healthy USA twins, we will model succession using a collection of sequenced bacterial stains cultured from a single (?formula-fed?) cohort member. Strains have been grouped into consortia representing 3 stages of community development [Stage 1 (S1; months 1-2; when ?weedy organisms? are able to rapidly occupy a previously empty gut ecosystem), Stage 2 (S2, months 3-6; when organisms are rapidly acquired through dispersal from various environmental reservoirs as infants consume a milk-dominated diet), Stage 3 (S3, months 7-24; a period where fruits, vegetables and cereals become a more prominent part of the diet]. Our approach, described in 2 aims, involves multi-omic analyses of succession as a function of the availability of specified dietary nutrients [amino acids, B-vitamins (precursors of essential cofactors for myriad metabolic reactions), and carbohydrates (primary source of carbon/energy). Young GF mice colonized with the different stage consortia, introduced alone, together in various combinations, or in various sequences will be fed an ?unmodified? defined infant formula (IF) diet or IF derivatives where the representation of 4 different amino acids, or 4 different B vitamins, and several carbohydrates represented in fruits and vegetables are varied. The effects on consortium members will be characterized by measurements of their relative and absolute abundances (to assess competitiveness/fitness) in jejunum, cecum, colon, and feces and the results correlated with (i) amino acid, B vitamin, carbohydrate concentrations in these different gut compartments (targeted mass spectrometry), (ii) expression of genes involved in various metabolic pathways (microbial RNA-Seq), and (iii) our in silico subsystems-based approach for predicting metabolic phenotypes/nutrient requirements. Our approach, based on the ability to manipulate which organisms are introduced and when, under specified nutrient conditions, offers the promise of providing new insights about the determinants of cooperation and competition between microbes, and the design of strategies that treat and ultimately help prevent aberrant community development.
Studies of children with undernutrition are providing evidence that disrupted development of their gut microbiota and persistence of microbiota immaturity are causally related to their disease, and contributes to the failure of current therapy to overcome the long-term sequelae associated with this pressing global health problem (stunting, neurodevelopmental abnormalities, immune dysfunction). A corollary hypothesis is that normal development of the gut microbiota is important for the healthy growth of infants and children and likely has long-term effects on an individual?s physiologic, metabolic, immune and perhaps neurological features. Thus, identifying which factors shape normal gut community development and how they operate has broad implications ranging from fundamental insights about the determinants of co-operation and competition between microbes, to the design of therapeutic strategies that prevent, mitigate and/or repair aberrant gut community assembly, to new approaches for reducing risk for pathogen invasion, to learning how to preserve our microbial community diversity against threats posed by Western lifestyles.
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