Project Grant K43TW012864

BIFIDOBACTERIUM INFANTIS SUPPLEMENTATION IN EARLY LIFE TO IMPROVE NEURODEVELOPMENT IN INFANTS EXPOSED TO HIV - HIGHER RISK OF NEURODEVELOPMENTAL DELAY DURING EARLY CHILDHOOD HAS BEEN REPORTED AMONG INFANTS WHO ARE HIV EXPOSED IN UTERO BUT UNINFECTED (IHEU) COMPARED TO THEIR HIV UNEXPOSED COUNTERPARTS, TO WHICH BOTH HIV AND ANTIRETROVIRAL REGIMENS MAY CONTRIBUTE. SIMILARLY, IHEU HAVE FOUND TO HAVE ALTERED GUT MICROBIOME COMPOSITION, WITH DECREASES IN BIFIDOBACTERIA ABUNDANCE, PARTICULARLY B. INFANTIS, AND INCREASED SYSTEMIC INFLAMMATION DURING THE FIRST YEAR OF LIFE. RECENT STUDIES FOUND THAT LOW ABUNDANCE OF GUT BIFIDOBACTERIA DURING EARLY LIFE IS ASSOCIATED WITH INCREASED RISK OF NEURODEVELOPMENTAL DELAY DURING EARLY CHILDHOOD IN AT-RISK INFANTS. AS EARLY LIFE GUT MICROBIOME IS ALSO CRUCIAL FOR IMMUNE MATURATION AND DEVELOPMENT OF COGNITIVE FUNCTION, THE QUESTION ARISES WHETHER OPTIMIZATION OF THE GUT MICROBIOME DURING EARLY LIFE WOULD BE SUFFICIENT TO DECREASE SYSTEMIC INFLAMMATION AND IMPROVE NEURODEVELOPMENT AMONG IHEU. DR HAPPEL, A SENIOR RESEARCH OFFICER AT THE UNIVERSITY OF CAPE TOWN WITH EXPERTISE IN MOLECULAR BIOLOGY, MICROBIOLOGY AND IMMUNOLOGY AND CAREER DEVELOPMENT NEEDS IN COMPUTATIONAL BIOLOGY, BIOSTATISTICS AND EPIDEMIOLOGY, WILL LEVERAGE AN ONGOING RANDOMIZED, DOUBLE-BLINDED TRIAL OF ORAL B. INFANTIS VS. PLACEBO GIVEN DURING THE FIRST MONTH OF LIFE TO 200 IHEU (R01HD109089). THE TRIAL PROVIDES RIGOROUSLY COLLECTED CLINICAL AND BIOLOGICAL DATA, A SAMPLE REPOSITORY, AND THE INFRASTRUCTURE TO ASSESS NEURODEVELOPMENT AND SYSTEMIC INFLAMMATION IN THESE IHEU TO ADDRESS THIS HYPOTHESIS. SPECIFIC AIM 1: TO COMPARE NEURODEVELOPMENT LONGITUDINALLY IN IHEU RANDOMIZED TO RECEIVE B. INFANTIS VERSUS PLACEBO IN EARLY LIFE USING THE CULTURALLY ADAPTABLE BAYLEY SCALES OF INFANT AND TODDLER DEVELOPMENT, 4TH EDITION, AT 9 AND 24 MONTHS OF AGE. SPECIFIC AIM 2: TO COMPARE SYSTEMIC INFLAMMATION LONGITUDINALLY IN IHEU RANDOMIZED TO RECEIVE B. INFANTIS VERSUS PLACEBO IN EARLY LIFE BY MEASURING LEVELS OF CIRCULATING CYTOKINES PREVIOUSLY ASSOCIATED WITH HIV EXPOSURE AND NEURODEVELOPMENT AT 1 AND 9 MONTHS OF LIFE BY LUMINEX. SPECIFIC AIM 3: TO IDENTIFY MICROBIAL AND SYSTEMIC PREDICTORS OF NEURODEVELOPMENT IN SOUTH AFRICAN INFANTS BY INTEGRATING BACTERIAL SHOTGUN METAGENOMICS, STOOL METABOLOMICS, T CELL PHENOTYPES, SYSTEMIC MICROBIAL TRANSLOCATION (GENERATED AS PART OF THE PARENT TRIAL) AND PLASMA CYTOKINE DATA WITH NEURODEVELOPMENTAL OUTCOME DATA (GENERATED HERE) USING MULTIPLE DATA DRIVEN APPROACHES. THE PROPOSED PROJECT WILL PROVIDE CRITICAL DATA TO DESIGN FURTHER INTERVENTIONS OF MODIFIABLE BIOLOGICAL DOMAINS AMONG IHEU THAT MAY IMPROVE NEURODEVELOPMENTAL HEALTH OF THIS GROWING POPULATION. FINDINGS WILL PROVIDE INSIGHT INTO THE USE OF EARLY-LIFE BIOMARKERS AS PREDICTORS OF NEURODEVELOPMENT DURING INFANCY THAT COULD SUBSEQUENTLY BE EXPLOITED FOR DIAGNOSTIC TOOL DEVELOPMENT TO IDENTIFY AT-RISK INFANTS. TOGETHER, THIS MIGHT ULTIMATELY RESULT IN DECREASED MORBIDITY OF IHEU, OR OF OTHER INFANTS WHOSE GUT MICROBIOME WAS DISTURBED DURING EARLY LIFE. THIS PROPOSAL IS HIGHLY RELEVANT FOR SUB-SAHARAN AFRICA, WHERE >25% OF INFANTS ARE HIV-EXPOSED.