Nebraska Center for the Prevention of Obesity Diseases through Dietary Molecules

University Of Nebraska Lincoln, Lincoln NE

Investigators

Linked publications, trials & patents

Abstract

RESEARCH PLAN: PROJECT SUMMARY GOAL OF THE PARENT AWARD. This administrative supplement is submitted by the Nebraska Center for the Prevention of Obesity Diseases Through Dietary Molecules (NPOD), currently in Phase 2 COBRE funding at the University of Nebraska-Lincoln (UNL). NPOD's mission is to prevent, treat, and cure obesity and co-morbidities by harnessing the power of bioactive food compounds to ameliorate the adverse health effects of obesity. NPOD Phase 2 is guided by four specific aims: 1) Increase NPOD's critical mass of researchers by hiring five early career investigators, recruiting new early stage and senior investigators using pilot and seed grant funding, and continuing to develop strategic alliances with complementary programs; 2) acquire additional equipment for the research core and formalize experimental design services offered through the administrative core; 3) enhance the center's mentoring structure and collaborative, multidisciplinary environment; and 4) implement hiring and recruitment approaches to expand integration of fundamental nutrition and obesity research with clinical, translational, and community research. RESEARCH QUESTION FOR THE SUPPLEMENT AWARD. The proposed research will explore whether the selection of genomic variants in gut bacteria by milk extracellular vesicles (MEVs) alters energy homeostasis in infants. We have pioneered a novel line of discovery by demonstrating that small extracellular vesicles (sEVs) and their regulatory cargo do not originate exclusively in endogenous synthesis but may also be absorbed from milk (milk sEVs, MEVs). Human milk is a rich source of MEVs, and breastfed infants consume approximately 176 trillion MEVs per day. In contrast, formula is essentially free of MEVs and 90% of MEVs are degraded in milk that was frozen in milk banks or at home due to ice crystal formation. The oral bioavailability of MEVs is approximately 50% and the portion of MEVs that escapes absorption interacts with the gut microbiome. MEVs do not only alter bacterial communities, but they also select genomic variants in bacteria where the variants are transcribed into mRNA and clustered in pathways of energy metabolism (purines, glucose). Other studies are consistent with these observations and reveal an up to 120-fold increase in purine metabolites in formula-fed infants and an up to 12.5-fold increase in glucose metabolites in bacteria cultured in media containing a nutritionally relevant concentration of MEVs compared to MEV-free cultures. Motivated by these discoveries, we hypothesize that the dietary intake of MEVs alters energy homeostasis in infants. We will leverage our complementary expertise in bacterial evolution, advanced computational biology, and the development of innovative “energy sensor” mice to complete three specific aims. In Aim 1, we will assess the selection of genomic variants in MEV-defined cultures of infant feces. Specifically, we will assess the selection of genomic variants by MEVs using metagenomics analysis, their transcription using RNA-sequencing analysis, and the effects on pathways implicated in energy homeostasis using metabolomics analysis. In Aim 2, we will assess the effect of MEV selection on a host-adapted infant gut symbiont (Bifidobacterium infantis) in infants. Specifically, we will leverage existing fecal metagenomic data to characterize how MEVs select genetic variants in a host-adapted infant gut symbiont by comparing variants from infants fed frozen pasteurized milk or fresh milk and test the effects of these variants on enteric inflammatory responses. In Aim 3, we will develop NAD(H), NADPH, and ATP sensor mice in collaboration with the University of Arkansas for Medical Sciences' Genetic Models Core and assess if MEV-defined diet consumption alters energy homeostasis in neonate mice. HOW THIS PROJECT BENEFITS FROM A TEAM SCIENCE APPROACH. This research will benefit the IDeA community by supporting three project leaders and four research cores across Nebraska, Nevada, and Arkansas, and two veteran scientist consultants in Kansas and Nevada. A team science approach is essential to project success because the combined expertise required is not currently co-located in one of the participating IDeA states. Only together do we have the necessary expertise and instrumentation to conduct the proposed research. Our team comprises Drs. Qiuming Yao (UNL; NPOD project leader in Phase 2), Steven Frese (University of Nevada, Reno; not supported by NPOD), Jingjie Hao (director of NPOD's Biomedical and Obesity Research Core (BORC)), and leverages the Genomics Core Facility and Mass Spectrometry and Proteomics Core Facilities at the University of Nebraska Medical Center, the Genetic Models Core at the University of Arkansas for Medical Sciences, and UNL's BORC. The parent COBRE grant's principal investigator (PI), Dr. Janos Zempleni, will contribute expertise in milk extracellular vesicles and share archived samples. Ultimately, this project promises to benefit the six million infants annually who consume formula and frozen milk in the United State, e.g., recommending new milk storage protocols that preserve MEVs through economically and technologically feasible approaches that will not raise regulatory agency concerns. This research aligns with NPOD's mission, and we have identified a path to future funding from NIDDK and NCHID (NOT-DK-19-007). NPOD's administrative core will support the team through reciprocal visits by project leaders and an in-person workshop prior to project initiation attended by PI, project leaders and their staff, consultants, and two speakers.