A Pre-, Peri-, and Post-natal Approach to Understanding the Risk and Mechanisms for Obesity

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Project Summary Although obesity is a serious threat to the nation’s health, little progress has been made in its prevention. Infancy may be an opportune time to prevent its development since the sooner the trajectory towards obesity is halted, the less likely that negative health consequences will arise. Altered early gut bacterial communities may influence offspring obesity through the metabolites they produce. Our overarching working causal model is that pre-, peri- and postnatal exposures alter the microbes that colonize the infant’s gastrointestinal tract, which in turn alters the gastrointestinal metabolites available to the infant host thereby programming that infant for a lifetime of increased energy harvest and adipose deposition. Our preliminary data show that maternal BMI is associated with the infant gut microbiota composition at age 1 month, and that the infant gut microbiota composition and function at 1 month of age is associated with child obesity status at age 2 years, however we have limited knowledge on how these factors may causally influence child growth. Although maternal BMI is a strong determinant of child BMI, not all women with pre-pregnancy obesity will have children that will go on to develop obesity; the converse is true for women who enter pregnancy at normal weight. Different biological mechanisms may be important in the etiology of obesity dependent on prenatal environment. Thus, our overall hypothesis will be tested in a sample stratified by maternal pre-pregnancy BMI category. Our Aims will be completed using two currently established and continually enrolling prospective pregnancy and birth cohorts in Michigan. We expect to enroll 300 dyads from each cohort (600 total) with 200 dyads falling into each of three pre-pregnancy BMI categories (normal weight, overweight and obese; pre-pregnancy underweight is uncommon in Michigan and will not be included). We will obtain data on maternal cardiometabolic health in the pregnancy (blood glucose, blood pressure levels), which may help to differentiate women with a more “pathogenic” body habitus. Prenatal urinary metabolites will be measured to further phenotype the metabolic state. Antimicrobial exposures, assessed by antimicrobial resistance gene abundance, using shotgun metagenomic sequencing and bioinformatics methods, as well as medical record abstraction, will be measured. Additionally, stool metabolites will be assessed prenatally and postnatally to determine transmissible functional aspects of the gut microbiota within each pre-pregnancy BMI strata. The children will undergo body size assessment at ages 1, 2 and 3 years. The research proposed herein will be the first step in a continuum of studies that will generate an important multi- dimensional ‘-omics’ dataset which will identify microbes, metabolites, and pathways which may lead to obesity in later life. These can be targeted with future interventions to reduce the burden of obesity. Our proposal has the capacity to provide evidence and solutions which could allow public health officials to target members of each BMI sub-group with specific recommendations based on the unique microbial and metabolomic interactions that our results reveal.