Intestinal Microbiome and Childhood Feeding
A number of pressing nutritional issues face the US and other nations. Over 20% of children throughout the world are obese with even more children overweight; both associated with diabetes and heart disease. New strategies are critically needed to address this ever-increasing epidemic. Given the recent recognition of the importance of the gut bacteria in our general health and weight control in particular, we propose to test a dietary supplement (prebiotic) that selectively enhances the growth and activity of bacteria associated with leanness. We anticipate that this prebiotic will reduce the risk of overweight and obesity in children. At the opposite end of the nutritional spectrum, severe acute malnutrition directly contributes to deaths of more than a million children under 5 each year globally. Stunting affects about 23% of all children under 5 years of age globally. Most of these children are in Africa and south Asia and the consequences include lower economic productivity, decreased cognition and more diabetes and hypertension. Similar to obesity, the microbiome is implicated as a cause of stunting and new treatments are needed. Researchers will compare four supplementary foods of differing carbohydrate and protein compositions in the treatment of moderate acute malnutrition (MAM) and their effects on gut permeability and intestinal microbiome. These studies will provide novel data as to how dairy and vegetable ingredients affect intestinal permeability, the microbiome configuration and the fecal metaboiome in young children.
Research Faculty: Rob Shulman/ Mark Manary
Microbiome as a Mediator of Host-Genome-Determined Lactation Outcomes
Genetic background is known to influence variation in milk production. However, genetics only explains a fraction of this variation and environmental factors also play a role. Advances in high-throughput DNA sequencing technologies have revolutionized the way in which the microbial world is viewed. This revolution has led to the concept that the microbiome is a major regulator of normal development and health. The microbiome is regulated by diet, but is also under the control of the host genome. In this regard, the full number of host genetic variants associated with lactation-related traits remains to be determined. A premise for this work is that differences in milk production are driven by changes in gene expression within organs important to milk synthesis. A second premise is that the intestinal microbiome is controlled by the host genome, but can directly influence gene expression within the host. The long-term goal is to understand how variations in the maternal genome interact with the microbiome to determine lactation success. Whole genome sequence data from select mouse strains will identify genetic variants that are unique to high or low milk production. These newly identified variants will be functionally linked to milk production and composition, and to lactation-induced intestinal and mammary gene expression through a specific RNA Sequencing test known as allelic imbalance. Strain- and allele-dependent differences in fecal ribosomal 16s sequencing reads will associate the variants with the intestinal microbiome. Lastly, maternal microbiome seeding through neonatal cross-fostering will establish the ability of the intestinal microbiome to over-ride the effects of genetic background lactation-dependent gene expression and milk production.
Research Faculty: Darryl Hadsell
Adipocyte Gap Junction on Milk Production and Milk Quality
Milk production is influenced by both genetic factors and environmental factors. Maternal obesity, characterized as an excess amount of adipose tissue, is an evolutionarily novel condition for the human species. As such, little is known about how hypertrophied adipocytes contribute to breast milk production and milk’s nutritional and non-nutritional components and whether this deviation from the norm contributes to the infants’ metabolic dysfunction in later life. Adipocytes, the primary cell type in the non-lactating breast, display a drastic morphological change during the lactation in rodent studies: lipid-filled cells virtually disappear undergo lipolysis to provide fatty acids for triglyceride synthesis and also as an energy source to support milk production; they come back as lipid-laden cells once the animal is done lactating. Our objective is to assess whether breast-milk composition can be regulated by maternal adipose tissue physiology – more specifically, adipose tissue gap junction. The results of this research can be leveraged to improve milk quantity and quality to benefit infant growth and future metabolic status. The central hypothesis is that adipose tissue responds to metabolic and hormonal cues to support milk production and that the Connexin43 gap junction is required to facilitate this process by coupling a group of adipocytes together. Genetic manipulation of adipose tissue Connexin43 will be used to determine the effects of Connexin43 deletion on milk production and milk composition as well as on the offspring’s metabolic health. This work will guide dietary intervention during lactation, aiming to modulate adipose tissue Connexin43 gap junction and adipose tissue physiology.
Research Faculty: Yi Zhu
The Liver-Gut Axis in Lactation
The American Pediatric Association and the World Health Organization recommend exclusive breastfeeding as the sole source of nutrition for the first 6 months of life. BF is associated with benefits for both the mother and offspring. Although the rates of BF have increased globally, there is much variability in BF initiation and duration rates. Lactation insufficiency, inability to produce enough breast milk to support offspring development, is estimated to be between 40-60%. The underlying mechanisms of lactation insufficiency are not well understood and require more study. The liver and small intestine undergo metabolic changes that support the production of mature milk in the mammary gland in lactating rodents, including significant increases in hepatic and intestinal bile acids. In lactating animal models, key enzymes involved in cholesterol and lipid homeostasis are altered during lactation. Bile acids promote the solubilization of cholesterol and lipid soluble nutrients, which enhance milk lipid nutrient composition. These genes are regulated by a group of transcription factors called nuclear receptors, in particular, the metabolic nuclear receptors farnesoid x receptor (FXR) and peroxisome proliferator activated receptor alpha (PPAR). These nuclear receptors and their target genes represent novel targets for study to address our central hypothesis that manipulation of hepatic and intestinal nuclear receptors alters lipid composition in breast milk. The overall goal of this project is to determine the role of FXR and PPARalpha in the metabolic adaptations of the maternal liver-gut axis. This study will clarify maternal hepatic and intestine metabolic signaling pathways that support milk production, the impact of dietary challenges on the maternal liver-gut axis and nuclear receptor signaling cascades, the long-term protective effects against metabolic disease and fatty liver for the lactating dams.
Research Faculty: Ruth Wooton-Kee
Hypothalamic Regulation on Lactational Hyperphagia
During breast feeding, female mammals dramatically increase their food intake and serum prolactin (PRL) level to support milk production. These increases of food intake and PRL during lactation are called lactational hyperphagia and lactational hyperprolactinemia, respectively. Dysregulation of this process may cause breastfeeding failure or metabolic disorders. The underling neuroendocrine mechanisms are not well understood. Here we will explore how 17β-estradiol (E2) contributes to lactational hyperprolactinemia and hyperphagia. Low E2 actions and high PRL level co-exist during lactation. E2 can activate neurons that express estrogen receptor-α (ERα). We found that virgin female mice developed similar hyperprolactinemia and hyperphagia phenotypes when E2 actions are blocked by deletion of ERα from a group of neurons in the ventrolateral subdivision of the ventromedial hypothalamus (ERαvlVMH). Importantly, we found that ERαvlVMH neurons were inhibited during lactation. We hypothesize that the attenuation of E2 actions on ERαvlVMH neurons is required to increase PRL and food intake in lactating dams. We will develop mouse models to specifically activate or inhibit ERαvlVMH neurons during lactation. We will measure serum PRL levels in lactating dams and monitor the metabolic status of lactating dams and their pups, including daily body weight and food intake of the dams, as well as the survival and body weight of pups. Further, we will also map the ERαvlVMH originated neuron circuits and compare their neuron activities between virgin and lactating female mice. Accomplishment of the studies will identify a novel neuroendocrine mechanism underlying hyperprolactinemia and hyperphagia during lactation, which should have significant impact on both the postpartum metabolic health of breastfeeding moms and the nutrition supply for infants.
Research Faculty: Chunmei Wang