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Freston Breakout Session: Advancing FMT research through translational studies Gary D. Wu, MD; Vincent B. Young, MD, PhD. Microbiome research at a cross-road Humans are not mice The scientific value of FMT The future of FMT: Defined microbial consortia

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Freston Breakout Session: Advancing FMT research through translational studies

Gary D. Wu, MD; Vincent B. Young, MD, PhD

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

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?
slide2

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

slide3

Humans are Not Mice: The Effect of Diet on the Gut Microbiota

Human

Mouse

  • 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
  • Daily stool sample collection
slide4

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
slide5

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
slide7

Normon et al. Gastro 2014, in press

Viruses

Enhanced Pathogenicity

Predator-Prey

Relationship

Bacteria

Competition

Syntrophy

Archaea

Fungi

slide8

Robert Baldassano, MD (CHOP)

*James D. Lewis, MD (Penn)

*Frederic D. Bushman, PhD (Penn)

*Gary D. Wu, MD (Penn)

Rob Knight, PhD (U of C, Boulder)

Hongzhe Li, PhD (Penn)

Penn Human Microbiome Project Team

Patient/subject recruitment and phenotyping, dietary assessment, sample collection and processing

DNA sequencing, data analysis, and mathematical modeling

Metabolomics

Gary L. Lichtenstein, MD (Penn)

Michael Bennett, PhD (CHOP)

Charlene Compher, PhD, RD (Penn)

Marc Yudkof, MDf(CHOP)

Anthony Otley, MD (Dalhousie)

Biological Oxymetry

Sergei Vinogradov, PhD

Anne Griffiths, MD (Toronto)

*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

requirements for translational team science
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
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
slide11

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

slide12

“Untargeted”

Analysis

“Targeted”

communication is key
Communication is Key
  • Between investigative teams
  • With patients
  • With regulatory bodies
ethical legal and social issues
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?