Research Abstract:

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 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 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, epidemiologic studies have shown that malnutrition is not due to food insecurity alone. Moreover, 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 development of their gut microbial communities. Our studies of healthy members of birth cohorts living in several low- and middle-income countries 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. 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). In a 3-month randomized controlled feeding study of 12-18-month-old Bangladeshi children with MAM, we 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 of these children compared to a commonly administered ready-to-use supplementary food (RUSF) that was not designed to repair the gut microbiota. Follow-up analyses (i) identified key bacterial taxa whose fitness and expression of various metabolic pathways were specifically affected by MDCF-2 and (ii) revealed links between these bacterial taxa and plasma protein mediators of musculoskeletal and CNS development, as well as metabolic and immune function.

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 colonization of gnotobiotic mice with intact fecal microbial communities sampled from children enrolled in POC studies prior to treatment (or defined collections of sequenced bacterial strains cultured from their gut communities), followed by re-enactment of the therapeutic intervention. We apply a variety of computational and experimental methods to dissect host and microbial responses to treatment in these studies (e.g., microbial RNA-Seq to define transcriptional responses of bacterial taxa; single nuclear RNA-Seq to characterize the responses of various cell lineages in different host tissues to gut microbiota repair; mass spectrometry-based analyses of host and microbial community metabolism; forward genetic screens to identify key determinants of the fitness/functions of key taxa; introduction of engineered retrievable microscopic artificial food particles that serve as in vivo biosensors of nutrient metabolism by microbial communities and as a way to further establish how microbes cooperate and compete for bioactive components of microbiota-directed therapeutic foods).

Analogous studies are being performed to characterize the role of the small intestinal microbiota in the pathogenesis of malnutrition in children and their mothers - with the goal of understanding mechanisms underlying intergenerational malnutrition. These latter studies include introducing defined collections of cultured small intestinal microbes from malnourished donors into germ-free female mice and characterizing the physiologic, metabolic, immunologic, and neurodevelopmental effects of these consortia on these animals prior to, during and after pregnancy, and on their pups.

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 children who present with malnutrition at various stages of postnatal development. Our plans in the coming year include continuing our studies in Bangladesh, and expanding to sites in India, west Africa as well as the inner city of St. Louis.

Selected Publications:

Last Updated: 8/19/2021 11:54:11 AM