Microbial, immune, metabolic perturbations by antibiotics (MIME study)

Project Summary
Over 250 million courses of antibiotics are prescribed annually to out-patients in the United States. The perception that
antibiotic use has minimal adverse side effects contributes to their over-use. Since deploying antibiotics seems to be
relatively free of toxicity, there are few disincentives to their use even when perceived benefits are marginal. Recent
understanding of the human microbiome suggests the relevance of antibiotic exposures to health, with the emerging
view that our microbiota are central to human physiology. In animal models, perturbing the microbiota affects
metabolic, immune, and cognitive physiology. Antibiotics diffuse into all body compartments, selecting for resistance.
We propose to examine the effects of two commonly used antibiotics, a beta-lactam (amoxicillin)and a macrolide
(azithromycin) on microbial populations and on metabolic and immune physiology, in healthy volunteers in a
prospective randomized clinical trial conducted at the NIH Clinical Center (CC). We hypothesize that in addition to
acutely perturbing the human microbiome, these agents will have measurable metabolic and immunologic effects, with
effects continuing over the following weeks and months. To test this hypothesis, in Aim 1, we assess the effects of a
brief therapeutic antibiotic course on microbiota and metagenome composition. After initial evaluation, antibiotics are
given for 5-7 days, with a prolonged post-treatment evaluation. Specimens are obtained from multiple sites at each of
10 time-points and used to estimate bacterial and fungal composition and gene content. In Aim 2, we assess the effects
of the antibiotic course on immune physiology. At multiple time points, blood is obtained and used to determine
plasma and cellular levels of markers of both innate and adaptive immunity. In Aim 3, we assess the effects of the
antibiotic course on metabolic physiology. The specimens obtained are assessed for markers of metabolic and
hormonal physiology. A subset of subjects enter the unique CC Metabolic Chamber to quantify 24-hour energy
expenditure and carbohydrate and fat utilization. In addition to the primary data analyses, we will build an informatic
model integrating the temporal data to provide insight into the complex interdependent physiology between
microbiome and host. This project is an opportunity to perform comprehensive and integrated evaluations of two
pharmacologic agents prescribed >90 million times annually in the USA. Careful analysis and development of an
integrated model to understand the pathophysiology of the perturbations may identify problems below the radar in
clinical medicine. The purpose of this renewal is to recruit sufficient numbers of subjects to complete the study after the
interruption caused by COVID-19 and the subsequent COVID studies in the Clinical Center. Increasing the number of
subjects to ~20 per group will permit robust analyses of the extent and duration of microbiome changes due to the
antibiotic perturbations, and their consequent effects on host metabolic and immune functionalities, and their
interactions; the present limitations in numbers of participants constrain a thorough analysis.

Grant Number: 5U01AI122285-08
NIH Institute/Center: NIH
Principal Investigator: MARTIN BLASER