Infant Stool Markers in Satiety Regulation and Obesity


Target Investigator:
Matthew D. Di Guglielmo, MD, PhD


Childhood obesity is increasing with more than one-third of adolescents currently overweight and one in five with obesity. The life-long incidence of obesity-related morbidities has also increased with childhood obesity. It is not yet known how obesity develops in an individual, specifically in early childhood. Further, it is unclear what mechanistic role a child’s earliest nutrition or changing intestinal flora has in the etiology of obesity. Very young children are developing appetite and satiety patterns early in life. Nutrition and gut microbial flora have impact on how these processes unfold, but specific mechanisms are not yet well understood. The intestinal hormone uroguanylin, a short peptide, leaves the gut and travels to the brain where it binds guanylyl cyclase C (GUCY2C), a primarily intestinal enzyme, in the hypothalamus, increasing satiety. The initiation of endoplasmic reticulum stress response disrupts uroguanylin signaling in rodents. Spexin, a novel gut peptide, has a potential role in inducing satiety in humans; it reduces uptake of long-chain fatty acids by adipocytes. Breast-fed infants have lower risk for obesity and a different microbial flora in their gut that affect the metabolism of carbohydrates and contribute to host cellular changes. We hypothesize that formula-fed infants with changes in their microbial flora are more likely to have altered carbohydrate metabolism, evidenced by greater imbalances of fatty acid production, and are more likely to have accelerated growth trajectory due to satiety disruption. We further hypothesize that altered carbohydrate metabolism, e.g., imbalances of short- and long-chain fatty acid levels in the gut, stimulate ER stress and affect Spexin and uroguanylin. We will compare the microbiome of the intestinal microbial flora in two groups of infants, one breast-fed and the other formula-fed, using longitudinally collected fecal samples from both groups. We will apply shotgun metagenomics analysis and simultaneous metabolomics analysis. A bioinformatics approach will elucidate key differences among and between sample groups, and we will further analyze bacterial gene expression on levels related to carbohydrate metabolism. We will compare the expression of human proteins involved in ER stress response and gut peptide signaling by applying quantitative RT-PCR to mRNA isolated from the longitudinally collected samples from both groups. We will monitor the trajectory of growth and feeding over the first two years of life. The project’s focus on the influence of different early feeding types, microbial flora changes, and altered carbohydrate metabolism leading to disruption of gut-brain signaling will provide critical data for host microbiome interactions and translational therapeutic targets.