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12/13/2012
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Subra Kugathasan, MDProfessor of Pediatrics & Human genetics
Marcus Professor of Pediatric Gastroenterology
Emory University & Children’s Healthcare of Atlanta
Evolution of IBD: Research Lessons Learned
I have the following financial relationships to disclose:JanssenUCB
IBD: The Pediatric Burden & the impact of Pediatric IBD research
• 1.2 million people with IBD in the US, estimated 80‐100,000 children with IBD
• About 20‐25% of all IBD is diagnosed during the pediatric age
• Identification of BIOTYPE = Genotype + Phenotype+ Immunotype + Bacteriotype + ??? clearest in pediatric IBD leading to Risk stratification and personalized therapy in IBD.
• The cause of IBD !• Differential diagnosis between CD and UC (colonic disease)
• Limited endoscopic approaches & lack of good small bowel imaging
• Surgery: the only answer to failure of medical therapy (sulfasalazine and steroid)
• Complete lack of studies in the pediatric age group while knowing pediatric disease is different from adult disease?
• Inability to induce long lasting remission (& mucosal healing)
Major Issues in IBD Diagnosis and TherapyPlagued us over the last few decades!
• IBD epidemiology & natural history
• Pediatric disease activity index: PCDAI & PUCAI
• TNF in stool leading to discovery of anti‐TNF as groundbreaking therapy in IBD
• Gene discoveries and therapeutic targets
• Microbiome, diet and intestinal inflammation
• Risk Prognostication in IBD
• Evolution of collaborative research in pediatrics compared to single center/investigator effort
Evolution of IBD:What have we learned in the last 50 years?
• Fine mapping of existing loci• Missing heritability• Genotype‐phenotype correlation• Metagenetics• Disease biology• Biomarker of disease severity• Pharmacogenomics• Genomic‐based therapeutic targets
Immunochip163 confirmed IBD lociloci overlap with mycobacterial infection.Pathways are shared with host response
Tysk et al. Gut 1988;29:990‐996Hugot JP et al. Nature 1996;379:821–3Ogura Y et al. Nature 2001;411:603–6Barrett JC et al. Nat. Genet; 40:955‐962Franke A et al. Nat. Genet; 42:1118‐25Anderson CA et al. Nat. Genet; 43:246‐52
Many loci are shared, few are specificLoci segregates specific disease mechanism
CDIBD
UC
Innate ImmunityNOD2; LRRK2
Function not clearly definedNKX2‐3; CREM; C11Orf30; ORMDL3; RTEL1; PTGER4; KIF21B; CDKAL1; ZNF365
• Genetics of IBD is shared with many other complex disorders. The genetic research has become less organ-specific, but focuses of molecular level and common pathways.
• Identification of clusters of ‘Bio-types’ can be used to target specific biological pathways.
• Firm genomic diagnosis can be used for definitive therapies to reverse the IBD
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Microbiome, diet and intestinal inflammation
Evidence for gut microbial dysbiosis in IBD
R Balfour Sartor and Sarkis K Mazmanian. Am J Gastroenterol 2012
Our environment determines the compositionof the gut microbiota
Frank et al PNAS 2007 Manichanh C et al Gut. 2006:205‐11
Diet shapes the gut microbiota
Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14691‐6
Rural Africa (Burkina Faso)
Urban Europe (Florence, Italy)
High carbohydrate, fiber and non‐animal protein Children breast‐fed up to the age of 2
Typical western diet high in animal protein.Children breast‐fed for up to age of 1.
Dietary patterns are associatedwith specific gut microbial patterns
Wu G et al. Sciencexpress / September 1, 2011 / 10.1126/science.1208344
CarbohydratesProtein & animal fat
Nickerson & McDonald (unpublished data)
Western diet (malto +)Normal diet (malto -)
FL82 AIEC biofilm formation
Maltodextrin: a common additive that improvestexture and palatability found in many foods, sweeteners (Splenda), drugs, cosmetics, etc.
Intestinal epithelial cells (HT29) infected with salmonella in the absence (normal diet) and presence (Western diet)of matodextrin: malto suppresses autophagy ➞ less killing ➞ more residual colonies ➞excess of bacteria
Modulation of bacterial function
by food additives
Different bacterial species induce different phenotypes of colitis in IL-10-deficient mice
In patients with ileal CD Fusobacteria were dramatically increasedcompared to control subjects
Preliminary microbial analysis show bothdecreased and increased taxa in risk cohort Fecal microbiota transplant for IBD
17 case series: 41 patients with IBD (27 UC)
• reduction of symptoms: 76%
• cessation of IBD medications: 76%
• disease remission: 63%
• resolution of concurrent C. difficile: 100%
Anderson et al, Aliment Pharmacol Ther. 2012
Perhaps, we can do selective FMT based on individual's flora and genetics
Can the host’s mucosal gene expression at the time of diagnosis predict complications?
– Non IBD (control)Red – Inflammatory (B1)Blue – Stricturing and penetrating (B2/B3)
Clusters
Ted Denson & RISK study team
Evolution of IBD Risk Stratification
Research Lessons learned
• Small proportion (20%) of CD accounts for 80% of complicated disease (and healthcare needs)
• These high risk patients are identifiable at the time of diagnosis with relatively low cost
• Individualized care based on RISK• Best approach for risk/benefit ratio• Reduce overall cost in long term
Remember the Key note speech delivered by Dr Clark
IBD: The Pediatric Burden & the impact of Pediatric IBD research
• 1.2 million people with IBD in the US, estimated 80‐100,000 children with IBD
• About 20‐25% of all IBD is diagnosed during the pediatric age
• Identification of BIOTYPE = Genotype + Phenotype+ Immunotype + Bacteriotype + ??? Future of IBD management.
ImmuneResponse
I
ImmuneResponse
ll
ImmuneResponse
lll
Immune responses
Outcomebiotypes
IBD l
IBD ll
IBDlll
Hypothesis: IBD biotypes drive the IBD phenotype and outcome
Bacterial
Bacteriall
Bacterialll
Gene l
Genell
Genelll
Genetic variability
Microbial variability
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Exposome
Metabolome
Transcriptome
Epigenome
Proteome
MicrobiomeEpimmunome
Inflammasome
Genome
Resolvome
Apoptosome Phenome
Responsome
Antibodome
IBD patientand associated“omes” network
IBD patientand associated“omes” network
“How Everything is Connected to Everything”A-L Barabási. Plume Books 2003
The interactomeThe interactome
Stead WW. Beyond expert-based practice. IOM Institute of Medicine. Evidence-based medicine and the changing nature of health care:The National Academies Press 2008
Clinical featuresDeep ulcerations etc.
Microbiome
Genetic variationand gene expression
Serology / immunotypes
RISK Stratification in the puzzle
of pediatric IBD
Close integration of 4 in‐depth
critical components
The Future
ACKNOWLEDGEMENT
Topics and contents I have chosen for the talk were suggested by the following IBD’ologists and scientists:
Francisco SylvesterJoel RoshJeff HyamsJim MarkowitzMarla DubinskyTed DensonAlex MuiseTim BoyleClaudio Fiocchi
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Timing as a critical factor in IBD:early life stress, “sensitive period”,
and IBD evolution
Life with IBDEarly disease Late disease
Less plasticity, “insensitive” period
Life before IBD
Trigger
Clinicalsymptoms,diagnosis
Exposome, GXG, GXE,epigenetics, etc.
Life after IBD
Therapy
Unknownultimateoutcome
Remissionrecurrencesmedications
hospitalizationsoperations
cancer, etc.
Response / no responseto therapy
?
Sensitive period
Early life events: fetal development, exposome contact, immune priming, GXG and GXE interactions, epigenetics, etc.