Role of Microbiome in Gut Inflammatory Responses and Host Genetic Interactions

Transcription

1 Role of Microbiome in Gut Inflammatory Responses and Host Genetic Interactions Dermot McGovern MD, PhD, FRCP F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute Cedars-Sinai Medical Center, Los Angeles

2

3 The IBD Genome signals from 163 genomewide significant loci UC 1p36 IL23R FCGR2A IL10 GPR35 MST1 IL12B MHC CARD9 SERINC3 21q22 CD IL23R ATG16L1 PTGER4 5q31 IL12B CARD9 10q21 NOD New Loci Jostins et al, Nature 2012, Liu et al, Nat. Genetics, 2015

4 70% of IBD Loci Overlap with Other Disease Loci AS 13 fold enrichment Psoriasis 14 fold enrichment T1D 10 fold enrichment 6/7 leprosy loci also IBD loci NOD2 IL23R TNFSF15 RIPK2 LRRK2 C13ORF31 6/8 MSMD genes within IBD loci IL12B STAT1 IRF8 TYK2 STAT3 IFNGR2 Jostins. et al. Nature

5 Ashkenazi Jewish Subjects are Genetically Enriched for CD Genes Rivas et al, submitted 5

6 Characterization of Genetic Loci That Affect Susceptibility to Inflammatory Bowel Disease in African Americans Huang et al, Gastroenterology 2015

7

8 IBD Exposome Rogler, Gerhard; Vavricka, Stephan. Inflammatory Bowel Diseases. 21(2): , February 2015.

9 Luminal Bacteria Stimulate Immune-Mediated Colitis No Bacteria Mice IL-2 -/- IL-10 -/- TCR -/- CD 3 E 26 TG SAMP1/yit DSS CD 45 RB hi SCID Rats B 27 / 2M TG Indomethacin IL-1 TNF Bacteria TH 1 No Colitis No Immune Activation Nonhuman Primate Cotton top tamarin TNF IFN Colitis

10 Altered Microbiome Associated with IBD A human gut microbial gene catalogue Established by metagenomic sequencing Qin. et al. Nature Morgan X, Genome Biol

11 Sartor RB. Gastroenterology. 2010

12 Cause or Effect? DSS DSS disrupts epithelial barrier Colitis!! DSS-induced colitis causes a shift in the intestinal microflora towards pro-inflammatory Gram-negative bacteria During acute colitis E. coli increased in wt and TLR-deficient mice (P<0.05) DSS, dextran sodium sulfate Heimesaat MM, et al. PLoS ONE. 2007;2:e662.

13 The Treatment-Naïve Microbiome in New-Onset Crohn s Disease Pediatric Inception Cohort 450 CD 220 controls Gevers. et al. Cell Host and Microbe

14 The Treatment-Naïve Microbiome in New-Onset Crohn s Disease Gevers et al, Cell Host and Microbe 2014

15 Fucosyltransferase 2 (FUT2) Non-secretor Status is Associated with Crohn s Disease Reprograming of gut microbiome energy metabolism by the FUT2 Crohn s disease risk polymorphism Jones. et al. HMG. 2010; Tonge. et al. ISME

16 Disease-Specific Alterations in the Enteric Virome in Inflammatory Bowel Disease Highlights The enteric virome is abnormal in multiple inflammatory bowel disease patient cohorts The enteric virome richness increases in Crohn s disease and ulcerative colitis Decreases in bacterial diversity and richness in IBD do not explain virome changes Virome changes in Crohn's disease and ulcerative colitis are disease specific Norman et al. Cell

17 Interactions Between Commensal Fungi and the C-Type Lectin Receptor Dectin-1 Influence Colitis DSS-colitis is more severe with: CLEC7A-/- v wild type C tropicalis v S fibuligera No treatment v fluconazole Ilyan. et al. Science

18 'Microbiome' as a Diagnostic in IBD

19 Altered Microbiome Associated with Disease Sub-Types Gevers et al, 2014; Frank et al, PNAS 2007 More likely to be in IBD-subset Younger age at surgery Non-smoker Penetrating disease

20 Faecalibacterium Prausnitzii Is an Anti-Inflammatory Commensal Bacterium Identified by Gut Microbiota Analysis of Crohn Disease Patients F. Prausnitzii associated with decreased risk of recurrence after surgery in CD Sokol. et al. PNAS Effect of F. Prausnitzii on Cytokines

21 IBD-Specific Serologic Immune Markers Antibody Antigen CD (%) UC (%) Non-IBD (%) ASCA Anti S cerevisiae antibody 55%-65% 5% 5% DNase Sensitive panca Histone H 1, bacterial antigen? 10%-25% 50%-65% <5% OmpC E coli 38%-50% 2% <5% cbir Flagellin 50% 6% 8% Anti-I2 P fluorescens 54% 2% <5% Dubinsky MC. Inflamm Bowel Dis. 2008; Oct 14 Suppl 2:S185-6.

22 Antimicrobial Markers to Predict Disease Behavior Frequency of Disease Behavior (%) 100 *P trend < Uncomplicated Penetrating Stricturing* Surgery N=199 Dubinsky M et al. Clin Gastroenterol Hepatol. 2008;6: N=262 N=194 Number of Immune Responses 3 N=57

23 Longitudinal Status of Serologies Predicts CD Phenotype Before Diagnosis (PREDICTS Study) Methods I00 patients with incident CD (ICD-9 codes) Serum samples from DOD Serum Repository (2, 4, 6, years before and at diagnosis) Disease type at diagnosis (ICD-9, CPT codes) Complicated (stricturing, intestinal penetrating, or history of resection) vs uncomplicated Results Titers of 4 CD-associated markers (ASCA-IgA, ASCA-IgG, anti-a4-fla2, anti-flax) prior to diagnoses were higher in complicated vs uncomplicated CD Choung R, et al. Presented at DDW May 16, Abstract 78. Serum markers are detectable well before the diagnosis of CD and can predict development of complications

24 Incidence of IBD Is Highest in Developed Countries. IBD Is Emerging as a Global Disease. Incidence & Prevalence of Crohn s Disease Before Molodecky N, et al. Gastroenterology Jan; 142(1):

25 'It Must Be Something to Do with My Diet Doctor' Dixon. et al. Inflamm Bowel Dis

26 Polysaccharide Additives and IBD Dixon. et al. Inflamm Bowel Dis

27 Chassaing. et al. Nature

28 Food Emulsifiers Promote Colitis and Metabolic Syndrome Chassaing. et al. Nature

29 Exome Chip Consortium Search for Rare Variants with Large Effect Sizes European Ancestry non-jewish case control study Total of 23,789 subjects Li et al, Gastroenterology in press

30 SLC39A8 and CD SLC39A8 - Zinc transporter Mediates zinc influx into cytosol expression in T cells, stimulated MΦ and macrophages Zn concentrations enhance intracellular bacterial clearance via autophagy Deficiency associated with risk of CD SLC39A8 Ala391Thr Not associated with UC: is associated with lipids, hypertension, obesity, & schizophrenia Li et al, Gastroenterology in press

31 Microbiomal Composition of Lavage Samples Li et al, Gastroenterology in press

32 ? Mediates Its Effect via the Microbiome Genera Depleted in Thr Carriers & CD & Overweight controls: Anaerostipes Coprococcus Roseburia Lachnospira SMB53 Li et al, Gastroenterology in press Genera Depleted in Thr Carriers & CD F. Prausnitzii Rumnicoccus Gravus

33 Bacteroides fragilis Bacteroides fragilis is a gram-negative, obligate anaerobic bacteria B. fragilis is a prominent symbiont of in the human GI tract B. fragilis produces molecules that beneficially modulate the immune system of animals Polysaccharides (PSA) is a novel cell surface molecule that promotes potent anti-inflammatory responses Polysaccharide A (PSA)

34 Polysaccharide a (PSA) from Bacteroides Fragilis Protects Mice in Preclinical Models of Colitis Colitis Mazmanian et al., Cell (2005); Mazmanian et al., Nature (2008); Round et al., PNAS (2010); Lee et al., Science (2010); Round et al., Science (2011); Shen et al., Cell Host & Microbe (2012); Lee et al., Nature (2013); Dasgupta et al., Cell Host & Microbe, 2014 ATG16L1 is required for protection from experimental colitis by B. fragilis OMVs

35 A Potentially Novel Etiology for Crohn's Disease? Bacterial clearance Autophagy Prevents ER stress Chuh et al, Science 2016

36 A Potentially Novel Etiology for Crohn's Disease? TLR2 NOD2 B. fragilis PSA-containing OMVs Non-canonical autophagy Bacterial clearance Reduced inflammation Prevents ER stress Increased T Reg responses and protection from colitis Chuh et al, Science 2016

37 A Potentially Novel Etiology for Crohn's Disease? ATG* NOD2* Non-canonical autophagy X Bacterial clearance Reduced inflammation X Increased T Reg responses and protection from colitis B. fragilis Prevents ER stress PSA-containing OMVs Inflammation Hypothesis: at least in a subset of CD patients, a defect in ATG16L1 or NOD2 results in reduced bacterial sensing of beneficial signals from the gut microbiome Chuh et al, Science 2016

38 Prediction of At Risk Individuals IBD GEM Project Will enable true estimation of penetrance Intestinal barrier Bacterial flora Immune function Environmental exposures Genetic susceptibility 0.3% per year 75 new cases??

39 HMP2

40 Conclusions and Summary Age of -omic Data and precision medicine Alterations in microbiome likely contribute to IBD and are associated with disease severity Novel insights into disease pathogenesis and? opportunities for therapeutic intervention DTC testing available and coming to a clinic near you soon!

41 Acknowledgements Cedars-Sinai Dalin Li, Talin Haritunians, Stephan Targan, Janine Bilsborough, David Underhill, David Shih, Suzanne Devkota, Rob Barrett, Kathrin Michelsen, Rivkah Gonsky, Clive Svendsen Cal Tech Sarkis Mazmanian NIDDK, NIH HMP2 CCFA European Union Helmsley Charitable Trust Helmsley VEOIBD Scott Snapper, Alexio Muise Wash U Skip Virgin, Thad Stappenbeck, Scott Handley MLI Consortium Jon Braun, James Borneman, Justin Sonnenberg, Albert Fornance NIDDK IBD Genetics Consortium and International IBDGC Broad/Harvard Curtis Huttenheimer, Mark Daly, Ramnik Xavier