1. Antigen presenting cells (APC)
Induction of pathogenic vs. regulatory T cells depends on APC /T cell interactions
Antigen presenting cells (APC)
process and present bacterial antigens, are activated by bacterial adjuvants
IL-10
IFNa/b
IL-12,18, 23
CD-80
CD-86
CD-80
CD-86
MHC
CTLA-4
MHC Ag
CD40 Ag
CD-28
TCR
TCR
IL-10
TGFb
CD40L
TGFb
IFNg
IL-17
TR1, TH3
Treg
CD25
TH1, 17
Effector (microbial clearance, inflammation) Regulatory (homeostasis)

2. Mediator Balance Anti-inflammatory Pro-inflammatory IL-10 TGFb
IL-1Ra, IL-11
IFNa/b
PGE2, PGJ2
TNF
IL-1b, IL-6
IL-12 / 18 / 23
IL-4, IFNg, IL-13, IL-17, IL-21
Tolerance
(Homeostasis)
Loss of tolerance
(Inflammation)

3. Aggressive early onset Crohn’s disease in IL-10 receptor deficient families
Glocker, NEJM 2010
Immune cells from these patients
were hyper-responsive to bacterial
products and did not respond to IL-10
suppression
One patient with refractory
disease had complete remission
with a bone marrow transplant
from a sibling who lacked
this gene
(corrected genetic defect in
immune cells)

4. Selective Correction of Mediator Imbalance
Anti-inflammatory
Pro-inflammatory
IL-10
TGFb
IL-1Ra, IL-11
IFNa/b
PGE2, PGJ2
TNF
IL-1b, IL-6
IL-12 / 18 / 23
IL-4, IFNg, IL-13, IL-17, IL-21
Tolerance
(Homeostasis)
Loss of tolerance
(Inflammation)

5. Therapeutic Manipulation of Intestinal Bacteria (individual profile): Selectively Alter Beneficial vs. Detrimental Species
Protective
Probiotic
Injurious
Pro-inflammatory
Lactobacillus sp.
Bifidobacterium sp.
E. coli Nissle
Saccharomyces boulardii
Bacteroides thetaiotaomicron
Faecalibacterium prausnitzii
Clostridium subsets
Bacteroides vulgatus, B. theta
Enterococcus faecalis
E. coli - enteroadherent / invasive
Klebsiella pneumoniae
Bifidobacterium animalis
Fusobacterium varium
Intestinal Helicobacter species

6. Improving current techniques to restore a healthy microbiome
Select approach and targets based on analysis of an individual’s microbiota pattern (customized approach)
Concentrate on protective resident species that have good chance to colonize and function in the intestine
Refine bacteriotherapy and determine its effectiveness in IBD – will require long term longitudinal studies in carefully characterized patients
Determine if dietary approaches can alter composition and function of enteric microbiota in therapeutic / preventive manner
Test the promise of genetically engineered bacteria

7. Harnessing translational research to improve clinical outcomes
Identifying clinically relevant pathways to develop new drugs or repurpose existing agents
Predicting natural history of disease in an individual
Predicting which patient will respond to a given therapy
Correcting abnormal pathways- cures and preventions

8. Where do we need to go with IBD treatment?
Current vs. optimal
(individualized treatment)

9. Current Paradigm for the Sequential Treatment of Crohn’s Disease and UC (“Bottom up”)
Surgery
Bowel rest (SB)
Severe/refractory
Cyclosporine, Natalizumab
TNF antagonist
Moderate
AZA/6-MP/MTX
Systemic corticosteroids
TNF antagonists ( early intervention?)
Mild
Topical or rapidly metabolized corticosteroids
Antibiotics (Crohn’s colitis)
ASA (colitis)
ASA, aminosalicylates; AZA, azathioprine; 6-MP, 6-mercaptopurine; MTX, methotrexate

10. The concept of Top-Down Therapy
Steroids
AZA / MTX
Combination
Infliximab

11. Why not treat every IBD patient with the most aggressive therapy at diagnosis?
Most patients have a benign course and don’t need aggressive therapy- < 50% of Crohn’s disease pts need systemic steroids, smaller number anti- TNF
Aggressive immunosuppression increases risk of infections and tumors
We don’t know long term toxicities of newer medications
New therapies are expensive!

12. New paradigms of treatment
Match the aggressiveness of treatment with the (potential) aggressiveness of disease
Treat disease correctly the first time!

13. New Paradigm for Treating Subsets of IBD patients: Match the aggressiveness of treatment with the predicted aggressiveness of disease
Predicted disease
activity
Surgery
Bowel rest (SB)
Severe/refractory
Get it right the
first time!
Cyclosporine, Natalizumab
TNF antagonist
Moderate
AZA/6-MP/MTX
Systemic corticosteroids
TNF antagonists ( early intervention?)
Mild
Topical or rapidly metabolized corticosteroids
Antibiotics (Crohn’s colitis)
ASA (colitis)
ASA, aminosalicylates; AZA, azathioprine; 6-MP, 6-mercaptopurine; MTX, methotrexate

14. Contrasting current approaches to treating IBD and cancer
Cancers
Check genotype (prognosis, treatment guide and family screening)
Clinical, imaging assessment of extent (aggressiveness, clinical pattern)
Analyze tissue for receptor expression, enzyme levels, histologic grade of aggressiveness/differentiation, depth of extension (results determine which therapy used, prognosis)
Targeted /individualized approach
expectations of cures
IBD
Assess location and extent of disease
Treat all patients the same (bottom up or top down), with some variation for aggressiveness
Generic approach
(30-40% remission rate,
no cure)

15. Defining IBD: current vs. future
Names vs Mechanistic subsets UC CD
IBD1
IBD2
IBD3
IBD4
Disease behavior, mechanisms
From Dermot McGovern

16. response to bacterial antigen
Individualizing therapy for IBD subtypes: Different mechanisms, different features, different therapies
Genetic mutations
NOD2
ATG16L1
IL-23R
Gene (s) IV
Immunologic
response to bacterial antigen
ASCA, OmpC, I2+ ?
Flagellin
Clinical
IBD I -
aggressi
ve SB dz
IBD III
Mild
SB dz
IBD II UC
like
IBD IV ?
Clinic
Treatment
Rx 1
?defensins
Antibiotic
GM-CSF
Antibx?
Anti-
IL-23(?)
Therapy 4
Clinical Phenotype
CD I-aggressive SB dz
SB dz
? course
CD II
CD IV
fistula
IT is this unique immune response that translates clinically into an individual’s unique clinical phenotype on presentation.
The question however has been posed whether there exists disease specific markers that manifest the disease related immune response and perhaps represent the phenotype.

17. How to predict which patient will:
Have an aggressive course?
Respond to a potential treatment?
Have complications of disease or therapy?
Understand mechanisms of disease in an individual at time of diagnosis
Genetic, microbial, immunologic profiles
and clinical phenotype

18. Pediatric Research Network
Investigating unique needs of children and adolescents with IBD
28 centers have enrolled 1800 newly diagnosed patients with IBD (2/3 Crohn’s disease)
Goals: identify serum biomarkers, immune markers, fecal bacteria, genes and clinical features that predict at the time of diagnosis which child will develop severe, complicated vs. mild Crohn’s disease and which individual will respond to each medication
Clinical Implications: When a patient is diagnosed, initiate treatment with a medication that will almost certainly work well, prevent complications with aggressive therapy in patients with high risk of aggressive disease courses and complications, but use nontoxic drugs for low risk pts: minimize drug toxicity and cost
Building a multi-center research consortium is especially important if we are to help the approximately 140,000 children and adolescents under 18 to overcome Crohn’s and colitis. We already know that treating these youngsters is hampered by a significant lack of scientific data on the use of the various therapies in young people because drug trials are not consistently performed in adolescents, and rarely with children under the age of 14.
Like the Clinical Alliance, a multi-center consortia of leading pediatric researchers is urgently needed to enable researchers to address critical scientific knowledge gaps. CCFA’s Pediatric Research Network is starting with 7 centers in Hartford, Cincinnati, Atlanta, Philadelphia, Los Angeles, Milwaukee and Long Island, who have agreed to share data through a common database. These centers are collecting DNA, stool and serum samples from newly diagnosed patients under the age of 18 and will track these patients over time. For the initial study, the researchers hope to identify biomarkers that will help doctors to predict at the time of diagnosis which child will develop severe Crohn’s disease so that these children can be treated aggressively very early in the course of their disease. Early and aggressive treatment for children at high risk of developing severe disease may minimize symptoms and prevent future complications, as well as spare those who are likely to develop only mild to moderate disease to avoid the more powerful treatments that they really don’t need.

19. 2 patients with Crohn’s disease, 2 different treatments (2020)
Patient A:
Tissue shows low F. prausnitzii, high AI E. coli
Genotype – NOD 2 polymorphism
Treatment: Ciprofloxacin x 1 month, F. prausnitzii probiotic weekly, daily plantain extract (prevent AIEC binding) (backup- early resection and prevent recurrence with F. prausnitzii probiotic )
No clinical symptoms or Rx complications for 15 years
Patient B:
Genotype IL-23R polymorphism
Treatment: prolonged administration anti- IL-23 antibody (backup: bone marrow transplant from sibling without IL-23R gene defect)
No further Crohn’s disease symptoms for 15 yrs

20. What needs to be done to cure a patient with IBD?
Understand mechanisms of disease in an individual
Genetic, microbial, immunologic profiles
and clinical phenotype
2. Fix the problem
Correct underlying defective pathway OR
Permanently block inflammatory response
Nontoxic medication that induces a sustained, complete remission

21. Correct underlying defective pathway
Gene: replace abnormal gene (gene therapy, bone marrow transplant) or correct abnormal function (replace defective protein, block abnormal function)
Microbiome: permanently alter microbiota (fecal transplant, eliminate aggressive bacteria, restore protective bacteria), change diet, effective probiotic
Immunologic pathway: Block aggressive responses in sustained, nontoxic approach, permanently augment (restore) protective responses

22. CCFA Initiatives that can help develop new approaches to correcting causative IBD defects
Genetics- Determine function of major IBD risk genes (now 163 total) and how the abnormal genes and pathways interact. Once abnormal mechanisms are identified, strategies to correct them with new or existing medications can be developed
Microbiome: Identify key causative and protective bacterial species and infectious triggers. Once identified, realistic strategies to eliminate/ block detrimental species, augment concentration or function of protective species, and avoid triggering agents (? Immunization) can be developed

23. What needs to be done to prevent onset of IBD in a high risk individual?
Identify which person is at risk of developing IBD
Genetic, microbial, immunologic profiles
2. Fix the problem
Correct underlying defective pathway OR
Eliminate environmental triggers
Alter microbial profile
Alter immune response

24. In 2014, we have built the foundation to better understand the role of microbiota in intestinal diseases. Can we use this information to:
Treat disease or prevent relapses by manipulating the environment (altering diet, environmental, triggers, bacteria, fecal transplant)?
Deliver optimal individual treatment based on clinical features and genetic, microbial and immunologic profiles?
Cure patients with disease by correcting defects or permanently normalizing responses?
Prevent disease in susceptible individuals by manipulating their environment or correcting the underlying defect?

25. Individualizing therapy for IBD subtypes: Different mechanisms, different features, different therapies
Genetic mutations
NOD2
ATG16L1
IL-23R
Gene (s) IV
Bacterial
profile
Adh/inv
E. coli
Klebs
F. prausnit
Claustrid
Clinical
IBD I -
aggressi
ve SB dz
IBD III
Mild
SB dz
IBD II UC
like
IBD IV ?
Clinic
Treatment
Rx 1 block pili
Antibiotic
GM-CSF
Antibx
Anti-
IL-23
F. prausnitzi
Replace
Claustrid
Clinical Phenotype
CD I-aggressive SB dz
SB dz
Post-op recur course
CD II
CD IV
fistula
IT is this unique immune response that translates clinically into an individual’s unique clinical phenotype on presentation.
The question however has been posed whether there exists disease specific markers that manifest the disease related immune response and perhaps represent the phenotype.

26. Sequential, safer approach to treating IBD: Maintain long term remission by alternative approaches
IL-1b
TNF
IL-12
IFNg
Eliminate antigenic drive
Antibiotics, probiotics
prebiotics, fecal transplant, diet,
block bacterial binding,
enhance bacterial
killing (stimulate defensins, GM-CSF, hydroxychloroquin)
Restore mucosal barrier function SCFAs, probiotics fiber/prebiotics Growth factors, trefoil factor, epithelial stem cells
Promote regulatory cell activity (TR1, TH3 , Treg, B cells, DC) Rapamycin, Omega 3 FAs, retinoic acid, vit D Bacteroides fragilis PSA. Clostridium subsets, F. prausnitzii, worms
Paralyze TH1, TH17, innate immune responses
Steroids, biologics

27. How can PCORI help?
Identify environmental triggers (dietary factors, allergens, infections, stress, etc)
Provide biosamples (Blood, saliva, feces) for translational research
recruit clinically defined subsets for clinical trials