Freston Breakout Session: Advancing FMT research through translational studies

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

1) Microbiome research at a cross-road2) Humans are not mice3) The scientific value of FMT4) The future of FMT: Defined microbial consortia5) Technologies available to characterize complex microbial communities.6) The gut microbiota is a complex consortia of microbes that have been

incompletely characterized7) 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?

Functional Studies in Animal Models Association Studies in Humans

Functional Studies in Humans

Therapeutic Advances in the Treatment of Disease

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

• 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

MouseHuman

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

•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

FMT and the Treatment of Type 2 Diabetes

The Scientific Value of FMT

•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.

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

Normon et al. Gastro 2014, in press

Bacteria

Viruses

FungiArchaea

CompetitionSyntro

phy

Enhanced Pathogenicity

Predator-PreyRelationship

*Co-Principal Investigators

DNA sequencing, data analysis, and mathematical modeling

*Frederic D. Bushman, PhD (Penn)

Hongzhe Li, PhD (Penn)Rob Knight, PhD (U of C, Boulder)

Penn Human Microbiome Project Team

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

*Gary D. Wu, MD (Penn)*James D. Lewis, MD (Penn)Robert Baldassano, MD (CHOP)

The Joint Penn-CHOP Center for Digestive, Liver, and Pancreatic Medicine

Center for Molecular Studies in Digestive and Liver Diseases (P30 DK050306)

NIH instrument grant S10RR024525 and NIH CTSA grant UL1RR024134

Demonstration Project UH2/3DK083981 (Wu, Bushman, Lewis, Co-PIs)

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

Gary L. Lichtenstein, MD (Penn) Charlene Compher, PhD, RD (Penn)

Anthony Otley, MD (Dalhousie)Anne Griffiths, MD (Toronto)

MetabolomicsMichael Bennett, PhD (CHOP)

Biological OxymetrySergei Vinogradov, PhD

Marc Yudkof, MDf (CHOP)

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

Folker MeyerEugene ChangDionysios Antonopoulos, Jennifer Brulc,Yunwei Wang, Laura Harrell,Andreas Wilke

Vincent YoungGary Huffnagle Pat Schloss

James Tiedje Thomas SchmidtJames Cole, Ryan Penton

Mitchell SoginSusan Huse Hilary Morrison

Analysis“Targeted”

“Untargeted”

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?