The California Institute for Telecommunications and Information Technology

Stability in Health vs. Abrupt Changes in Disease in the Human Gut Microbiome EcologyPresentationArivaleSeattle, WAApril 21, 2016Dr. Larry SmarrDirector, California Institute for Telecommunications and Information TechnologyHarry E. Gruber Professor, Dept. of Computer Science and EngineeringJacobs School of Engineering, UCSDhttp://lsmarr.calit2.net1

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The Knight Lab Uses the Unifrac Metricto Quantitatively Compare Different Microbiome Ecologies

This method, UniFrac, measures the phylogenetic distance between sets of taxa in a phylogenetic tree as the fraction of the branch length of the tree that leads to descendants from either one environment or the other, but not both. UniFrac can be used to determine whether communities are significantly different

A Healthy Persons MicrobiomeIs in a Stable Equilbrium Over TimeBackground is Human Microbiome Project Data

Using Unifrac in Principle Coordinate AnalysisMap Microbiome Ecologies of Individuals to PointsSamples From Multiple Body Sites

Overlay Longitudinal Time Series of Male and Female SubjectDuration 60 DaysTime Points Separated by One DaySampled Oral, Skin, Stool Microbiomes16S Sequencing

MouthStoolVaginaSkinSource: Knight Lab, UCSD

Source: Knight Lab, UCSD

An Unhealthy Persons MicrobiomeCan Abruptly Shift Between Two States With External Influence

Example: Clostridium difficile and Fecal Transplant

Multiple C. diff Patients With a Single Donor

Dramatic Shift Back to Healthy Microbiome in Days

Fecal TransplantsFrom Healthy DonorTo C. Diff PatientsSource: Knight Lab, UCSD

LS Weekly Weight During Period of 16S Microbiome AnalysisAbrupt Change in Weight and in Symptoms at January 1, 2014AntibioticsPrednisoneLialdaUcerisFrequent IBD SymptomsWeight LossFew IBD SymptomsWeight GainSource: Larry Smarr, UCSDBlue Dots weekly average weightRed Dot-Stool Samples Taken

In 2016 We Are Extending My Stool Time Series byCollaborating with the UCSD Knight Lab

Larrys 40 Stool Samples Over 3.5 Years to Robs lab on April 30, 2015

LS Gut Microbiome Time Series by Taxonomy16S Evolution by Family-No Clear Separation at January 2014

Data from Justine Debelius & Jose Navas, Knight Lab, UCSD; Larry Smarr Analysis, January 2016

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LS Gut Microbiome Time Series by Shannon Alpha-DiversityHints at Change Around January 2014Source: Justine Debelius, Knight Lab

Shannon -DiversityPoints represent the average of 10 rarefaction instances at 15,000 sequences/sample.

Error bars are the standard deviation.

Red line is the boxcar moving average over 3 points.PhylogeneticDistanceLS Weight

Time Development Over 3.5 Years of Larry Smarrs Gut Microbiome Ecology:Unifrac Distance of 16S OTUs Transformed into Principle Coordinates

Blue: 1/2012 to 1/2014

Red: 1/2014 to 8/1/2015Movie and Data Analysis by Justine Debelius & Jose Navas, Knight Lab, UCSDUnweighted UniFrac Distance of 16S OTUs was Computed and then Transformed into Principle Coordinates Space Using QIIME. Principle Coordinates were Visualized in Emperor.

Larry Smarr Gut Microbiome Ecology Shifted After Drug Therapy Between Two Time-Stable Equilibriums Correlated to Physical Symptoms

Lialda & Uceris

12/1/13 to 1/1/1412/1/13-1/1/14

Frequent IBD SymptomsWeight Loss

5/1/12 to 12/1/14Blue Balls on Diagram to the Right Few IBD SymptomsWeight Gain

1/1/14 to 1/1/16Red Balls on Diagram to the Right Principal Coordinate Analysis of Microbiome Ecology

PCoA by Justine Debelius and Jose Navas, Knight Lab, UCSDWeight Data from Larry Smarr, Calit2, UCSDAntibioticsPrednisone

1/1/12 to 5/1/125/1/12Weekly Weight (Red Dots Stool Sample)Few IBD SymptomsWeight Gain

1/1/14 to 1/1/16Red Balls on Diagram to the Right

Significantly Different Genus EvolutionDuring LS Time Series

FirmicutesBacteriodetesProteobacteriaActinobacteriaTenericutesAnalysis by Justine Debelius, UCSD

Candidate OTU by PhylaChanges Before and After Jan. 2014Lost before 1/2014Gained after 1/2014Firmicutes3833Bacteriodetes17Proteobacteria12Actinobacteria01Tenerictues21Cyanobacteria11Total4543

Analysis by Justine Debelius, UCSDKruskal-Wallis Test with an FDR q < 0.1.

Tree of all otus with frd_p < 0.1 after Chi-square test.

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To Expand IBD Project the Knight/Smarr Labs Were Awarded ~ 1 CPU-Century Supercomputing TimeSmarr Gut Microbiome Time SeriesFrom 7 Samples Over 1.5 Years To 50 Samples Over 4 Years

IBD Patients: From 5 Crohns Disease and 2 Ulcerative Colitis Patients to ~100 Patients50 Carefully Phenotyped Patients Drawn from Sandborn BioBank43 Metagenomes from the RISK Cohort of Newly Diagnosed IBD patients

New Software Suite from Knight LabRe-annotation of Reference Genomes, Functional / Taxonomic VariationsNovel Compute-Intensive Assembly Algorithms from Pavel Pevzner

8x Compute Resources Over Prior Study

Thanks to Our Great Team!Calit2@UCSD Future Patient TeamJerry SheehanTom DeFanti Joe Keefe John GrahamKevin PatrickMehrdad YazdaniJurgen Schulze Andrew Prudhomme Philip Weber Fred RaabErnesto Ramirez

JCVI TeamKaren Nelson Shibu Yooseph Manolito Torralba

AyasdiDevi RamananPek LumUCSD Metagenomics TeamWeizhong Li Sitao Wu

SDSC TeamMichael Norman Mahidhar Tatineni Robert Sinkovits

UCSD Health Sciences TeamDavid BrennerRob Knight Lab Justine Debelius Jose Navas Gail Ackermann Greg HumphreyWilliam J. Sandborn Lab Elisabeth Evans John Chang Brigid Boland

Dell/R SystemsBrian KucicJohn Thompson