Freston Breakout Session: Advancing FMT research through translational studies
Gary D. Wu, MD; Vincent B. Young, MD, PhD
1) Microbiome research at a cross-road
2) Humans are not mice
3) The scientific value of FMT
4) The future of FMT: Defined microbial consortia
5) Technologies available to characterize complex microbial communities.
6) 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
Mouse
Human
• 10 Healthy volunteers
• Randomized to high fat vs. low fat diet
• 10 day inpatient stay with same meals each day
• Caloric intake adjusted to maintain current weight
•
CaFE%1%Unweighted%Unifrac%
Day%1%is%different%from%all%other%days.%
Unweighted*UniFrac*(p<0.0001)* Weighted*UniFrac*(p=0.002)*

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

ACCEPTED MANUSCRIPT
Normon et al.
Gastro 2014, in press
Archaea
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Viruses
Predator-Prey
Relationship
Enhanced
Pathogenicity
Bacteria
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Fungi
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IP
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Penn Human Microbiome Project Team
Patient/subject recruitment and phenotyping, dietary assessment, sample collection and processing
DNA sequencing, data analysis, and mathematical modeling
*Frederic D. Bushman, PhD (Penn)
Robert Baldassano, MD (CHOP)
Rob Knight, PhD (U of C, Boulder)
*James D. Lewis, MD (Penn)
Hongzhe Li, PhD (Penn)
*Gary D. Wu, MD (Penn)
Metabolomics
Gary L. Lichtenstein, MD (Penn)
Michael Bennett, PhD (CHOP)
Charlene Compher, PhD, RD (Penn)
Marc Yudkof, MDf (CHOP)
Anthony Otley, MD (Dalhousie)
Anne Griffiths, MD (Toronto)
Biological Oxymetry
Sergei Vinogradov, PhD
* Co-Principal Investigators
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

• 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).

• 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”

• Between investigative teams
• With patients
• With regulatory bodies

• 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?