R01AI155893

Impact of Early-Life Perturbations on Pediatric Microbiome Maturation - Abstract

During the first 3 years of life (YOL), the infant gut microbiome (GM) rapidly diversifies both in structure and function, concomitant with dietary and environmental transitions. Critically, the GM response to specific external stimuli is patient-specific, complicating individualized risk predictions. Healthy GM maturation includes accruing multiple strains of the same species, which frequently differ in key functions. These functional differences, accentuated by horizontal gene transfer (HGT) and de novo mutations, could resolve conflicting associations of the same species with both health and disease.

The rationale behind our proposal is that strain- and species-level variation in bacterial functions drives heterogeneous GM responses to early-life (EL) dietary and antibiotic perturbations, which explains, in part, individualized developmental trajectories. This proposal pursues two highly complementary aims: 1) define strain-resolved functional maturation of the pediatric gut microbiome and 2) investigate the acute effects of EL antibiotic (ELA) perturbation on strain dynamics, HGT, and microbiome maturation in preterm neonates and microbiota-humanized mice.

Aim 1 will test the hypothesis that EL environmental exposures shape genomic diversification of gut species, causing lasting changes in GM community structure and microbial functions. We will leverage our unique set of 2,436 stools collected over the first 9 YOL from infants variably exposed to dietary and environmental stimuli. By combining culture-enriched metagenomics, metatranscriptomics, and metabolomics, we will determine taxa-function relationships at the sub-species level and power statistical models that predict the impact of EL exposures on strain diversification, microbe-function associations, and transcriptional activity.

Aim 2 will test the hypothesis that ELA acutely alter strain dynamics and stimulate HGT and that the GM response to ELA can be predicted from baseline composition and function. Here, we will interrogate 160 stools flanking variable ELA exposure in 80 preterm neonates in the first 4 months of life, combining culture-enriched metagenomics with selective culture and isolate sequencing to characterize the preterm 'plasmidome' and profile post-ELA strain dynamics and HGT. To identify microbiome-intrinsic responses to ELA, we will utilize an innovative transgenerational mouse model where germ-free dams receive human, preterm, microbiota that is vertically transferred to their pups, which are treated with parenteral antibiotics. We will use the resulting data to predict individual GM responses to specific antibiotics based on composition, resistance gene content, and bacterial functions.

Our proposal is innovative because our interdisciplinary research team will characterize strain-level bacterial functions to understand the heterogeneity of GM responses to EL perturbations on two pre-existing sets of human specimens; it is significant because it will identify features that predict species-resolved GM-specific responses to EL selection. Our work will advance pediatric microbiome research by comprehensively characterizing strain-resolved functional maturation and GM disruption to understand individual variation leading towards a future of personalized, microbiome medicine.

Washington University

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Saint Louis, Missouri 63130 United States

Single Zip Code

Generating New insights and Mechanistic Understanding of Antibiotic Resistance Development (R01 Clinical Trial Not Allowed) (PA-18-725)

Amendment Since initial award the total obligations have increased 306% from $753,774 to $3,059,443.