Mutually beneficial relationships between microbes and animals are a pervasive feature of life in our microbe-dominated planet. We are no exception: the total number of microbes that colonize our body surfaces exceeds our total number of H. sapiens cells, while the total number of microbial genes in our body’s microbial communities is at least 100-fold greater than the number of genes in our human genome. The vast majority of these microbes live in our gut (tens of trillions, belonging to all three domains of life plus their viruses) where they provide us with traits we have not had to evolve on our own. Thus, we should view ourselves as a composite of microbial and human cells and genes, and our biological features as an amalgamation of human and microbial attributes.
We are interested in the following general questions: What are the genomic and metabolic foundations of our relationships with beneficial gut microbes? What mechanisms govern assembly of gut microbial strains into a community after birth; does this microbial ‘organ’ undergo an identifiable program of functional maturation in infancy and childhood that is shared across biologically unrelated individuals living in different parts of the world? How is this developmental program influenced by breast milk and the types and order of presentation of complementary /weaning foods? What are the consequences of disruption of this postnatal program of development to the health status (physiologic, metabolic, and immunologic phenotypes) of children and adults? Can we intentionally and durably change the properties of our gut microbial communities (microbiota) to improve health?
Our specific focus is on the role of the gut microbiota in defining our nutritional status. This focus is based on the following considerations. First, dramatic changes in socioeconomic status, cultural traditions, population growth, and issues related to sustainable agriculture are affecting diets worldwide, placing great pressure to develop food systems that produce affordable more nutritious foods and to understand the factors that define the nutritional value of food. Second, diet has a great effect on the structural and functional configuration of the gut microbiota; the gut microbiota, in turn, serves as an adaptive microbial ‘metabolic’ organ to transform components of our diets in ways that determine their biologic effects on myriad cell populations. Third, undernutrition in infants and children, and obesity in children and adults are two pervasive and vexing global health challenges.
We are developing gut microbial community-targeted therapeutics to treat undernutrition in infants and children living in low-income countries, and obesity in Westernized countries. In one approach, we transplant intact gut microbial communities directly from human donors sharing characteristics of interest into germ-free mice that harbor no microbes of their own. The resulting `humanized` gnotobiotic mice are then fed the diets consumed by their corresponding human microbiome donors, or systematically manipulated derivatives of those diets. Our ability to replicate an individual’s gut microbial community in recipient mice that are reared under highly controlled environmental conditions allows us to (i) define the degree to which features of the donor’s phenotype can be transmitted to the recipient via the community, (ii) identify the metabolic and signaling networks that link various community members to one another through their syntropic (nutrient sharing) relationships, and to their host, and (iii) determine how dietary context affects these interactions. In cases where a transmissible phenotype is identified, we subsequently generate sequenced collections of cultured gut bacteria that represent the majority of diversity present in the donor`s microbiota. His or her `personal culture collection` is then transplanted into germ-free mice and/or germ-free piglets to ascertain whether it too can transmit features of the donor’s phenotypes. If so, the contributions of the individual components or defined subsets of these culture collections are characterized in an effort to unravel the mechanisms involved in phenotypic transmission.
We apply and integrate a variety of experimental, computational and statistical methods to study human populations, notably twins concordant for undernutrition or obesity, as well as members of birth cohorts from several low-income countries (i.e., infants enrolled at birth and followed serially during their first several years of life). We generate gnotobiotic animal models using gut microbiota of selected members of these human populations. Our experimental approaches include (i) sequencing of gut microbial community DNA as well as the genomes of cultured microbial (primarily bacterial) members of the human gut community, (ii) whole genome transposon mutagenesis of cultured human gut bacterial strains to identify fitness determinants in vitro and in gnotobiotic animal models, (iii) RNA-Seq and targeted mass spectrometry-based analyses of the responses of members of the microbiota to dietary and other perturbations applied to our gnotobiotic animal models, and (iv) assays of metabolic flux, energy balance, innate and adaptive immune responses, bone biology, and CNS metabolism/functional connectivity in our preclinical models. The results are used to guide targeted analyses of biospecimens and clinical/laboratory datasets obtained from the individuals and populations from whom microbial communities were obtained to create these gnotobiotic animal models.
These preclinical models are providing new therapeutic candidates; notably (i) microbiota-directed foods (MDFs) and human gut-derived microbial strains (next generation probiotics) designed to repair developmental abnormalities we have documented in the gut communities of children with undernutrition, and (ii) diet ingredients (including those recovered from otherwise discarded components of current food manufacturing processes) and consortia of human gut-derived microbes to rectify the perturbed functioning of the microbiota in individuals with obesity and its related metabolic abnormalities. With the support of the Bill & Melinda Gates Foundation, we are in the process of advancing our first MDF prototypes into proof of concept clinical trials in children with acute undernutrition in Bangladesh.
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