# Antimicrobial Resistance and Horizontal Gene Transfer in the Human Gut Microbiome in Response to an Antibiotic

> **NIH NIH R01** · PALO ALTO VETERANS INSTIT FOR RESEARCH · 2023 · $715,118

## Abstract

PROJECT SUMMARY
 Antimicrobial resistance (AMR) is an increasingly prevalent and serious problem worldwide. Most often,
AMR arises from horizontal gene transfer (HGT), involving mobile genetic elements (MGE) such as plasmids
and phages. The human gut is a hotspot for both the evolution and spread of AMR; commensals serve as a
source of AMR for pathogens via HGT. Slowing the evolution and spread of AMR is both possible and necessary.
Knowledge about the evolutionary history of AMR development and dissemination in vivo is essential to facilitate
effective stewardship. Yet, this knowledge remains limited. Important aspects of AMR evolution become evident
only in complex environments and in the setting of diverse communities. We will study responses to antibiotic
exposure in the human gut microbiota in vivo, as well as in complex stool-derived subject-specific communities
in vitro, at high temporal resolution and using innovative approaches. We will link AMR and other MGE-
associated genes to their host core genomes using high throughput chromosome conformation capture (Hi-C)
and monitor these genes and elements in bacterial hosts before, during and after antibiotic exposure. The short
term-objectives of the proposed work are to characterize and assess the contributions of de novo mutations and
HGT to the spread and development of AMR in the human gut microbiota during antibiotic exposure. The long-
term objectives are to improve antibiotic stewardship by identifying critical events or transitions in the evolution
and dissemination of AMR in vivo, and the factors and conditions that make those events less likely.
Aim 1. Determine the distribution of antimicrobial resistance genes in the gut microbiota of healthy
humans. We will use Hi-C and metagenomic sequencing to resolve strain-level microbial genomes from stool
samples of 60 healthy adults collected over an 8-week antibiotic-free interval, prior to a ciprofloxacin exposure.
We will identify potential AMR genes and determine their distribution within core and accessory genomes, and
in association with mobile genetic elements.
Aim 2. Characterize the effects of ciprofloxacin on the abundance and mobilization of AMR genes in the
human gut microbiota in vivo. We will use Hi-C and metagenomic sequencing to assay stool samples collected
from the same 60 subjects during and after the ciprofloxacin exposure, and to characterize the composition and
dynamics of selective sweeps that affect the emergence of AMR.
Aim 3. Characterize the effects of ciprofloxacin on the mobilization of AMR genes in synthetic, human
gut-derived microbial communities in vitro. We will propagate pre-exposure fecal communities ex vivo from
all 60 subjects, as well as generate complex, synthetic communities from pre-exposure samples of 5 subjects,
and then passage both bulk and synthetic communities anaerobically under multiple ciprofloxacin regimes. We
will identify factors and conditions that affect emergence of AMR through HGT a...

## Key facts

- **NIH application ID:** 10624323
- **Project number:** 5R01AI147023-04
- **Recipient organization:** PALO ALTO VETERANS INSTIT FOR RESEARCH
- **Principal Investigator:** DAVID A. RELMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $715,118
- **Award type:** 5
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10624323

## Citation

> US National Institutes of Health, RePORTER application 10624323, Antimicrobial Resistance and Horizontal Gene Transfer in the Human Gut Microbiome in Response to an Antibiotic (5R01AI147023-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10624323. Licensed CC0.

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