R01AI194497

DIETARY FIBER-MICROBIOME INTERACTIONS: ELUCIDATING MECHANISMS TO SUPPRESS MULTI-DRUG RESISTANT ORGANISMS IN THE HUMAN GUT - ASYMPTOMATIC CARRIAGE OF MDROS INCREASES THE RISK OF INFECTION FOR THE CARRIER AND MEMBERS OF THE COMMUNITY TO WHOM THEY MAY TRANSMIT THE ORGANISM. DUE TO THE INCREASED INCIDENCE OF COMMUNITY-ACQUIRED MDRO INFECTIONS, THERE IS A PRESSING NEED TO IDENTIFY FACTORS INFLUENCING MDRO COLONIZATION. WHILE DIET HAS BEEN SHOWN TO MODULATE THE DYNAMICS AND METABOLITE PROFILES OF HUMAN GUT MICROBIOTA, WE LACK A DETAILED AND QUANTITATIVE UNDERSTANDING OF HOW SPECIFIC DIETARY FACTORS AND HUMAN GUT MICROBIOME IMPACT MDRO CARRIAGE. BY INTEGRATING A LONGITUDINAL HUMAN STUDY COUPLED TO A NOVEL SEQUENCING-BASED APPROACH TO ELUCIDATE DIETARY SPECIES, ADVANCED COMPUTATIONAL MODELING, HIGH-THROUGHPUT CONSTRUCTION OF HUMAN GUT COMMUNITIES AND GERM-FREE MOUSE EXPERIMENTS, WILL REVOLUTIONIZE OUR UNDERSTANDING OF THE MULTI-SCALE FIBER-DEPENDENT INTERACTION NETWORKS SHAPING MDRO (CLOSTRIDIOIDES DIFFICILE, VANCOMYCIN-RESISTANT ENTEROCOCCI, THIRD GENERATION CEPHALOSPORIN- RESISTANT ENTEROBACTERIACEAE, AND CARBAPENEM-RESISTANT ENTEROBACTERALES) FITNESS AND COLONIZATION OF THE MAMMALIAN GUT. IN AIM 1, WE WILL PERFORM A PROSPECTIVE, LONGITUDINAL STUDY OF COMMUNITY-BASED PARTICIPANTS TO ELUCIDATE THE MAPPINGS BETWEEN DIET, HUMAN GUT MICROBIOME TAXA, MICROBIAL PATHWAYS AND MDRO CARRIAGE. WE WILL GO BEYOND FOOD INTAKE SELF-REPORTING WHICH IS LIMITED BY SYSTEMATIC BIASES, TO TRACK HUMAN DIET USING A DNA SEQUENCING METHODOLOGY REFERRED TO AS FOODSEQ. LEVERAGING THE LONGITUDINAL DATA, DYNAMIC COMPUTATIONAL MODELING WILL REVEAL MICROBE-MICROBE INTERACTION NETWORKS ACROSS INDIVIDUALS. TO IDENTIFY THE KEY DIETARY FIBERS AND HUMAN GUT SPECIES SHAPING MDRO COLONIZATION, WE WILL USE A HIGH-THROUGHPUT AND AUTOMATED HUMAN GUT COMMUNITY CULTURING PIPELINE. THE SPECIES IDENTITIES AS WELL AS THE SPECIFIC COMBINATIONS OF THESE SPECIES WILL BE SELECTED USING A NOVEL MICROBIAL GENOME-TO-FUNCTION DEEP MACHINE LEARNING MODEL (DATA-DRIVEN COMMUNITY GENOTYPE-FUNCTION OR DCGF) THAT PREDICTS MDRO ABUNDANCE AS A FUNCTION OF DIETARY FIBERS AND THE GENETIC FEATURES OF CONSTITUENT COMMUNITY MEMBERS. USING THIS EXPANDED DESIGN-TEST-LEARN (E-DTL) APPROACH, WE WILL IDENTIFY COMBINATIONS OF SPECIES AND DIETARY FIBERS THAT SIGNIFICANTLY INFLUENCE MDROS FITNESS IN HUMAN GUT COMMUNITIES. ANALYSIS OF THE MODEL USING EXPLAINABLE ARTIFICIAL INTELLIGENCE TECHNIQUES WILL REVEAL GENES/PATHWAYS WITHIN CONSTITUENT COMMUNITY MEMBERS THAT IMPACT MDRO FITNESS, PROVIDING MECHANISTIC INSIGHTS BEYOND THE TAXONOMIC LEVEL. IN AIM 3, WE WILL USE DCGF TO DESIGN ROBUST AND MAXIMALLY INHIBITORY OR ENHANCING SPECIES- FIBER COMBINATIONS FOR CHARACTERIZATION IN A MURINE C. DIFFICILE MODEL. WE WILL EVALUATE THE ABILITY OF THESE DESIGNED SPECIES-FIBER COMBINATIONS TO DECOLONIZE C. DIFFICILE FROM THE MURINE GUT. OVERALL, THIS PROPOSED RESEARCH WILL PROVIDE CRITICAL DATA AND MODELS ACROSS MULTIPLE SCALES TO UNDERSTAND THE INTERPLAY BETWEEN DIET, THE GUT MICROBIOME, AND MDRO CARRIAGE. OUR RESULTS WILL INFORM FUTURE INTERVENTIONS AIMED AT REDUCING MDRO CARRIAGE, TRANSMISSION, AND INFECTIONS IN THE COMMUNITY. FINALLY, THIS SYSTEMS BIOLOGY FRAMEWORK WILL BE GENERALIZABLE TO STUDY OTHER BACTERIAL PATHOGENS, ENVIRONMENTAL FACTORS, AND MICROBIOME FUNCTIONS.

Duke 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]

North Carolina United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)