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Principal Investigator: Colleen Renee Kelly
Organization: AMERICAN GASTROENTEROLOGICAL ASSN/INST
Fiscal Year: 2024
Award: $673,041
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Fecal microbiota transplantation (FMT) is an established treatment for patients with recurrent Clostridioides difficile
infection (CDI). Although most patients with CDI can be successfully treated, the subset of acutely ill patients with severe
and fulminant CDI is a much greater challenge, with high rates of colectomy and mortality. Furthermore, a variety of
safety concerns remain for FMT. The risk of transmission of harmful microbes is highlighted by recent reports of
transmission of multi-drug resistant organisms and enteropathogenic E. coli (EPEC). In addition, although most work has
focused on bacteria, FMT also transfers non-bacterial microorganisms, and the clinical impact of these microbes may be
important in fully understanding the clinical implications of FMT. Because the gut microbiota also plays a role in the
pathogenesis of chronic medical conditions (e.g., diabetes, cancer, heart disease), FMT has the potential to cause
chronic conditions that might take years to manifest clinically. Finally, the field is rapidly evolving with the development
of commercial products formulated with live microorganisms, known as live biotherapeutic products (LBPs). Thus,
critically important questions regarding the real-world safety and effectiveness of FMT and LBPs remain unanswered.
The FMT National Registry is a uniquely suited resource to study these key issues. The Registry includes 32 North
American sites (and 19 additional centers pending) with an established infrastructure to collect clinical data on FMT
donors and recipients and a separate portal to collect information from FMT recipients. The Registry’s link to an
independent biobank also provides a rich source for studying manipulation of the gut microbiota in humans.
Our first specific aim is to expand knowledge on the long-term safety and effectiveness of FMT by A) continuing
systematic collection of clinical metadata up to 10 years post-FMT to better define safety, including risk of developing
chronic medical conditions, with incidence rates for predefined chronic conditions in Registry participants compared
with a control group of patients from a national database with multiply recurrent CDI not treated with FMT; B)
determining real-world estimates of effectiveness of FMT and LBPs to treat hospitalized patients with severe/fulminant
CDI and identify factors associated with cure; and C) expanding the registry to include new LBPs, assessing effectiveness
for CDI as compared to FMT in real-world populations and examining off-label use of LBPs for indications beyond CDI.
The second specific aim is to characterize the potential value of shotgun metagenomics sequencing (SMS) and data
analytics as a platform technology to identify and characterize potentially harmful microbes transmitted by FMT or LBPs
by first determining the sensitivity and specificity of SMS to identify and characterize bacterial pathogens using the
emerging pathogen, atypical EPEC (aEPEC) as a prototype. Genotype-phenotype analyses will be performed using a
combination of in vitro bioassays and whole genome sequencing. The sensitivity and specificity of SMS to identify these
strains and their virulence genes will then be determined by fecal spiking experiments. Additionally, studies will be
performed to characterize the impact of FMT/LBP therapy on the resistome and transmission of non-bacterial microbes
(virome, mycobiome) with SMS in patients treated for severe/fulminant CDI.
Terms: <Acute><Address><American><Animal Model><Animal Models and Related Studies><Bacteria><Biological Response Modifier Therapy><Biological Therapy><Biometrics><Biometry><Biostatistics><C diff><C difficile><C. diff><C. difficile><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Cancers><Cardiac Diseases><Cardiac Disorders><Case Study><Childhood><Chronic><Clinical><Clinical Data><Clinical effectiveness><Clostridioides difficile><Clostridium difficile><Colectomy><Colitis><Collection><Communicable Diseases><Control Groups><Crohn disease><Crohn's><Crohn's disease><Crohn's disorder><Data><Data Analytics><Data Bases><Databases><Development><Diabetes Mellitus><Donor Screening><Donor Selection><Donor person><E. coli produce shiga toxin><EHEC><EPEC><Effectiveness><Eligibility><Eligibility Determination><Enrollment><Enterohemorrhagic E. coli><Enterohemorrhagic Escherichia coli><Enterohemorrhagic strain of E. coli><Enterohemorrhagic strain of Escherichia coli><Escherichia coli EHEC><Evaluation><Event><FDA approved><Feces><Feedback><Formulation><Foundations><GI microbiota><Gastroenterology><Gastrointestinal microbiota><Genotype><Goals><Granulomatous Enteritis><Heart Diseases><Hepatology><Hospital Admission><Hospitalization><Human><Human Microbiome><Incidence><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Infrastructure><Infusion><Infusion procedures><Investigation><Knowledge><Link><MDR organism><MDR pathogen><Malignant Neoplasms><Malignant Tumor><Marketing><Medical><Metadata><Microbe><Modern Man><Morbidity><Morbidity - disease rate><North America><Obesity><Participant><Pathogenesis><Patients><Phase 2/3 trial><Phase II/III Trial><Phenotype><Population><Practice Guidelines><Protocol Screening><Provider><Randomization trial><Recurrence><Recurrent><Registries><Reporting><Research><Research Resources><Resources><Risk><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Safety><Scientific Advances and Accomplishments><Sensitivity and Specificity><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Shiga toxigenic E. coli><Shiga toxigenic Escherichia coli><Shiga toxin containing E. coli><Shiga toxin containing Escherichia coli><Shiga toxin producing E. coli><Shiga toxin secreting E. coli><Shiga toxin secreting Escherichia coli><Shiga toxin-producing Escherichia coli><Shotguns><Site><Societies><Source><Structure><Techniques><Time><Transmission><Transplant Recipients><Work><adiposity><assess effectiveness><bacteria pathogen><bacterial pathogen><biobank><biological therapeutic><biological treatment><biologically based therapeutics><biorepository><biotherapeutics><biotherapy><case report><clinical practice><comparative effectiveness><comparative safety><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><corpulence><data base><determine effectiveness><developmental><diabetes><effectiveness assessment><effectiveness evaluation><eleocolitis><emerging pathogen><enroll><enteric microbial community><enteric microbiota><enteropathogenic E coli><enteropathogenic E. coli><enteropathogenic E.coli><enteropathogenic Escherichia coli><entire genome><evaluate effectiveness><examine effectiveness><experiment><experimental research><experimental study><experiments><fecal microbial transplantation><fecal microbiome transplantation><fecal microbiota transplant><fecal microbiota transplantation><fecal transplant><fecal transplantation><full genome><fungal microbiome><gastrointestinal microbial flora><genome sequencing><gut commensal><gut community><gut flora><gut microbe community><gut microbes><gut microbial community><gut microbial composition><gut microbial consortia><gut microbial species><gut microbiota><gut microbiotic><gut microflora><heart disorder><high risk group><high risk individual><high risk people><high risk population><human-associated microbiome><in vitro Bioassay><infusions><intestinal flora><intestinal microbes><intestinal microbiota><intestinal microflora><intestinal tract microflora><malignancy><meta data><metagenome sequencing><metagenomic sequencing><microorganism><model of animal><mortality><multi-drug resistant organism><multi-drug resistant pathogen><multidrug resistant organism><multidrug resistant pathogen><multiple drug resistant organism><multiple drug resistant pathogen><mycobiome><neoplasm/cancer><new pathogen><next generation><novel pathogen><nutrition><off-label application><off-label prescribing><off-label use><participant enrollment><pathogenic bacteria><pathogenicity gene><patient enrollment><pediatric><prototype><randomized trial><recurrence prevention><regional enteritis><resistome><scientific accomplishments><scientific advances><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><shot gun><social role><stool><technology platform><technology system><transmission process><transplant donor><transplant patient><viral microbiome><virome><virulence gene><virulent gene><whole genome>