Transcript The Future of FMT

Freston Breakout Session: Advancing FMT research
through translational studies
Gary D. Wu, MD; Vincent B. Young, MD, PhD
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Microbiome research at a cross-road
Humans are not mice
The scientific value of FMT
The future of FMT: Defined microbial consortia
Technologies available to characterize complex microbial communities.
The gut microbiota is a complex consortia of microbes that have been
incompletely characterized
7) An example of a human gut microbiome research team
• What are the short- and long-term bacterial taxonomic effects of FMT?
• What are the short- and long-term non-bacterial microbial taxonomic effects of
FMT?
• What are the fecal metabolomic consequences of FMT?
• Is there an effect of host preparation on the effectiveness of FMT inoculation?
• Do any of the above associations have clinical relevance in the care of patients?
• Are there taxonomic characteristics of the gut microbiota that are predictive of
response to FMT?
Despite major advances in gut microbiome research showing its impact
on disease, there is still a lot to be done to realize its full potential
Functional Studies in Animal Models
Association Studies in Humans
Functional Studies in Humans
Therapeutic Advances in the Treatment of Disease
Humans are Not Mice: The Effect of Diet on the
Gut Microbiota
Human
• 10 Healthy volunteers
Mouse
• Randomized to high fat vs. low fat diet
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10 day inpatient stay with same meals each day
Caloric intake adjusted to maintain current weight
Daily stool sample collection
CaFE%1%Unweighted%Unifrac%
The Scientific Value of FMT
FMT and the Treatment of Type 2 Diabetes
•The success of FMT in the treatment of CDI is “proof of principle” that
the dysbiotic human microbiota can be modified to treat disease.
•Emphasizes the importance of using a resilient microbial community
to modify dysbiosis.
•FMT is a window into the biology of the gut microbiome in humans:
• Translation of findings in animal models into human biology.
• Understand the long term consequences of manipulating the gut microbiota in humans
The Future of FMT: Transplantation of Defined
Microbial Communities
•Customization of consortium membership of bacteria with
specific biological properties to produce predictable responses
and reduce both short- and long-term adverse outcomes
•Laboratory defined conditions prevent pathogen transmission
•Development of standardized conditions for the transplantation
(inoculation) and maintenance of the community
•Durable communities that are resilient to change
RI
PT
Viruses
M
AN
US
C
Normon et al.
Gastro 2014, in
press
Predator-Prey
Enhanced
Relationship Pathogenicity
Archaea
D
Bacteria
Fungi
Penn Human Microbiome Project Team
Patient/subject recruitment and
phenotyping, dietary assessment,
sample collection and processing
Robert Baldassano, MD (CHOP)
*James D. Lewis, MD (Penn)
DNA sequencing, data analysis, and
mathematical modeling
*Frederic D. Bushman, PhD (Penn)
Rob Knight, PhD (U of C, Boulder)
Hongzhe Li, PhD (Penn)
*Gary D. Wu, MD (Penn)
Metabolomics
Michael Bennett, PhD (CHOP)
Marc Yudkof, MDf (CHOP)
Gary L. Lichtenstein, MD (Penn)
Charlene Compher, PhD, RD (Penn)
Anthony Otley, MD (Dalhousie)
Anne Griffiths, MD (Toronto)
*Co-Principal
Investigators
Biological Oxymetry
Sergei Vinogradov, PhD
Jun Chen, Sam Minot, Serena Dollive, Eric Chen, Meenakshi Bewtra, Christian Hoffmann, Ying-Yu Chen, Sue
A. Keilbaugh, Kyle Bittinger, Jennifer Hwang, Erin Gilroy, Kernika Gupta, Lisa Nessel, Lindsey Albenberg,
Judith Kelsen, Colleen Judge, Christel Chahoud, David Shen, Rohini Sinha, David Metz, Tatiana Esipova
Demonstration Project UH2/3DK083981 (Wu, Bushman, Lewis, Co-PIs)
Center for Molecular Studies in Digestive and Liver Diseases (P30 DK050306)
The Joint Penn-CHOP Center for Digestive, Liver, and Pancreatic Medicine
NIH instrument grant S10RR024525 and NIH CTSA grant UL1RR024134
Requirements for Translational Team
Science
• Teams composed of investigators with varied
interests and expertise.
• Communication and coordination of teams is
essential and sometimes difficult.
• Standardization of procedures and techniques
needed if multicenter group (common).
Example HMP UH2/3
• Human microbiome
project: Role of the gut
microbiota in the
pathogenesis of
pouchitis
• About 30% of patients
with ulcerative colitis
(UC) undergo
colectomy after 15y
• Ileal pouch anal
anastomosis (IPAA) is
surgical treatment of
choice
Mitchell Sogin
Susan Huse
Hilary Morrison
Eugene Chang
Folker Meyer
Dionysios Antonopoulos, Jennifer Brulc,
Yunwei Wang, Laura Harrell,
Andreas Wilke
James Tiedje Thomas Schmidt
James Cole, Ryan Penton
Vincent Young
Gary Huffnagle Pat Schloss
“Untargeted”
“Targeted”
Analysis
Communication is Key
• Between investigative teams
• With patients
• With regulatory bodies
Ethical, Legal and Social Issues
• Similar to issues in Human Genome Project
– Informed consent
• Much is still “unknown”
– Data sharing
• Deposit data rapidly (identification?)
– Return of results
• If we don’t know what the microbiome “causes” how
do we advise study subjects/patients?