Mutually beneficial relationships between microbes and animals are a key feature of life on our microbe-dominated planet. We are no exception: the total number of microbial genes in our body’s microbial communities is several orders of magnitude greater than the number of genes in our human genome. The vast majority of these microbes live in our gut where they specify traits we have not had to evolve on our own.
We are interested in the following basic questions: What mechanisms govern assembly of gut microbial strains into a community after birth? Does the gut microbial community undergo an identifiable program of functional maturation in healthy infants and children that is shared across biologically unrelated individuals living in different parts of the world? What are the consequences of disruption of normal gut community development on the health status of growing infants and children (i.e., their physiologic, metabolic, immunologic and neurodevelopmental phenotypes)?
The principal focus of the lab is the role of the gut microbiota in defining healthy growth of infants and children and in the pathogenesis of malnutrition. 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 foods for various consumers. Second, diet has a great effect on the structural and functional configuration of the gut community; the community and its genes (microbiome), in turn, operates as an adaptive ‘metabolic organ’ to transform components of our diets in ways that determine their biologic effects on myriad host cell populations. Third, malnutrition represents the leading cause of death in children under 5 years of age worldwide. In addition, malnutrition in women and the ‘intergenerational cycle of malnutrition’ are pressing global health challenges. Fourth, current nutritional interventions have had limited success in overcoming the sequelae of malnutrition (stunting, impaired neurodevelopment, immune and metabolic dysfunction) – underscoring our limited knowledge of disease pathogenesis.
We are pursuing the hypothesis that healthy postnatal development of infants and children is causally linked to healthy co-development of their gut microbial communities. Our studies of healthy members of birth cohorts living in several low- and middle-income countries (LMICs) have identified shared features of gut microbial community assembly – a process that is largely completed by the end of the second postnatal year. We have also found that malnourished children have gut communities that resemble those of chronologically younger children (i.e. are immature). Colonization of gnotobiotic mice with fecal microbiota from chronologically age-matched healthy children and those with acute malnutrition disclosed that immature microbial communities from malnourished children transmit impaired weight gain phenotypes, altered bone growth, plus metabolic and immune abnormalities.
These results provided preclinical evidence of a causal role for the microbiota in the pathogenesis of malnutrition. We subsequently used gnotobiotic mouse and gnotobiotic piglet models to develop microbiota-directed complementary food (MDCF) formulations for repairing the microbial communities of children with moderate acute malnutrition (MAM). Together with our long-standing collaborators in the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), we conducted a 3-month randomized controlled trial (RCT) of 12-18-month-old Bangladeshi children with MAM and demonstrated clinical proof-of-concept (POC) that a lead MDCF formulation (‘MDCF-2’) emanating from our preclinical models produced a significant improvement in the rate of weight gain compared to a commonly administered ready-to-use supplementary food (RUSF) that was not designed to repair the gut microbiota. Follow-up ‘multi-omic’ analyses of biospecimens collected from study participants (i) identified key bacterial strains whose fitness and expression of various metabolic pathways were specifically affected by MDCF-2 and correlate with weight gain (ii) revealed links between these bacterial strains and plasma protein mediators of musculoskeletal and CNS development, as well as metabolic and immune function.
To test the generalizability and durability of the effects of these microbiota-directed interventions, we are conducting clinical studies of infants and children with severe and moderate acute malnutrition, who represent a range of ages and live in various parts of Bangladesh and India, plus several East and West African countries. These studies are being supported by the Bill & Melinda Gates Foundation, the World Health Organization, and UNICEF.
To gain additional mechanistic insights into how gut microbiota repair is linked to host systems biology (gut health, metabolic regulation, immune function, CNS development), we perform ‘reverse translation’ experiments. These experiments involve germ-free female mice (dams) that have just given birth to pups. Dams are sequentially colonized with defined collections of genome-sequenced bacterial strains representing different stages of human gut community development; they are cultured from the gut communities of children from the same area where the clinical trials have been performed. The clinical trial is then reenacted in these developing mice and a variety of computational and experimental methods are applied to dissect host and microbial responses to treatment (e.g., microbial RNA-Seq to define transcriptional responses of bacterial taxa; single nuclear RNA-Seq to characterize the responses of metabolic and intercellular signaling pathways in various gut cell lineages to gut microbiota repair; mass spectrometry-based analyses of host and microbial community metabolism).
These mechanistic studies are revealing the bioactive compounds present in the therapeutic food formulations as well as the how these compounds interact with microbiota members to shape host metabolism and physiology. At the same time, they are yielding new prebiotic and probiotic candidates for more precise and effective repair of gut microbial communities of malnourished infants and children, as well as prevention strategies for ensuring healthy microbiota.
We are also characterizing the role of the small intestinal microbiota in the pathogenesis of an enteropathy hypothesized to be a major contributor to malnutrition in children and their mothers. These studies include introduction of defined collections of cultured genome-sequenced small intestinal microbes from malnourished donors into germ-free female mice prior to pregnancy, and characterizing the physiologic, metabolic, and immunologic effects of these consortia on these animals prior to, during and after pregnancy, and on their pups; this includes effects on gut, brain and fetal/placental development.
Together, these interdisciplinary studies are providing new mechanistic insights into how components of the microbiota interact with one another and with various host biological processes to shape healthy growth, as well as new therapeutic candidates designed to treat malnourished infants, children and their mothers. This work also provides us with an opportunity to participate in a multidimensional process whose goal is to scale production of affordable, culturally acceptable microbiota-directed therapeutic agents, and to implement new policies for more effectively treating and preventing malnutrition in LMICs. This includes a capacity building effort where young icddr,b investigators come to our lab so that they can learn the computational and experimental approaches underlying our translational medicine pipeline and then establish these capabilities at icddr,b and reciprocal secondments so that our lab members are exposed to the unique capabilities represented in the iccdr,b related to clinical trial design and execution, obtain deeper knowledge of issues related to maternal-child health in LMICs, and become familiar with the societal, educational, and regulatory issues/challenges encountered when developing/deploying new microbiota-directed therapeutics.
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