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Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American Cystic Fibrosis Conference Orlando 2012

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Page 1: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Advances in Gastrointestinal Aspects of CF

Drucy Borowitz, MDProfessor of Clinical Pediatrics

State University of New York at Buffalo

“GI”North American Cystic Fibrosis Conference

Orlando 2012

Page 2: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Gain Insights into Gastrointestinal Aspects of CF

• Recognize similarities between the respiratory and GI tracts in CF

• Understand CF GI pathophysiology

• Compare findings in CF animal models and CF infants

• Learn about new technologies to explore CFTR dysfunction

Page 3: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Disclaimer Statement• My employers, the State University of New York at Buffalo and University

Pediatric Associates have received payment for my research and consulting activities; I have not received any personal payments

Page 4: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American
Page 5: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American
Page 6: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Gestational Information: The Respiratory and GI Tracts have the same

Embryologic Origins

Page 7: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Clearance of Obstruction and Infection

LUNGS• ASL hydration and

mucociliary clearance

• Cough

• Antimicrobials from submucosal glands

GI TRACT• Microvillus and luminal

hydration

• Peristalsis

• Antimicrobials from submucosal glands

Page 8: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Normal GI Tract Physiology

Page 9: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

CF-Related Liver Disease• “CFLD” is a spectrum :

– Neonatal cholestasis, microgallbladder, cholelithiasis, biliary tract ductal stones, common bile duct stenosis, sclerosing cholangitis, hepatic steatosis, nodular regenerative hyperplasia

– focal biliary cirrhosis and portal hypertension are the most serious complications

• ~ 5 to 10% of CF patients will develop cirrhosis / PHT in the first 10 years of life – no correlation between ↑ transaminases and cirrhosis / PHT

• PUSH is a CFF-NIDDK collaboration to explore early biomarkers of cirrhosis

Page 10: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Liver

Liver and Pancreatic Ducts Secrete Bicarbonate (HCO3

- ) via CFTR to Neutralize Gastric Acid

(HCO3)

Page 11: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Crypt-villus location of duodenal HCO3

- secretion under cAMP-stimulated conditions:

GI epithelium (especially Brunner’s Glands) also secretes HCO3

- via CFTR

Walker et al, Gastroenterol 2009

Abstract 126

Symposium 15

Page 12: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Why is HCO3 Secretion Important?

• It neutralizes gastric acid– Needed for pH optima of pancreatic enzymes and micelles

• It allows mucins to unfold / hydrate• It promotes bacterial killing• HCO3 secretion ≡ Fluid secretion

Abstracts # 13 & 131

Abstracts # 99 & 501

Page 13: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Bicarbonate Drives Fluid Secretion

Novak et al, J Biol Chem 2011

The normal human pancreas secretes

1-2 L / day

Page 14: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Pancreatic Enzyme and Bicarbonate Secretion have Different Stimuli

Secretin stimulatesduct to secrete

bicarbonate

Cholecystokinin (CCK) stimulatesacini to release enzymes

Page 15: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

How can you measure GI HCO3?

• Measures pH, pressure and temperature

• Single use• Radiofrequency

detector worn outside body

“pH pill”

Page 16: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Gelfond et al, Dig Dis Sci. 2012

Gastric Acid Neutralization is delayed in Subjects with CF

N=20

N=20

Page 17: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Could Activation of CFTR with Ivacaftor ↑ GI Bicarbonate?

• Pancreatic tissue becomes atretic but the duct is still present– MRI– Pathologic studies– PI patients have ↓ but not absent

HCO3 secretion Kopelman et al Gastro 1988

• Submucosal glands are obstructed, but are still present

Page 18: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Small bowel pH changes (1min means)

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110 115 120

03

4

5

6

7

8

Pre VX-770Post VX-770

p< 0.05

8 24

Minutes from gastric emtpying

pH

Gastric Acid Neutralization is normalized in Subjects with CF taking Ivacaftor

N=7

Page 19: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

The Earliest Clinical Consequences of CF are Gastrointestinal

• What is the ontogeny of these conditions?• How can we study them?

• Animal models• Human infants

Meconium ileus (MI)Pancreatic Insufficiency

Page 20: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Google Infants: Human and Otherwise

What have we learned from CF ferrets and pigs?

What have we learned from CF mouse models?

What have we learned from infants with CF ?

Page 21: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Lessons from CF Mice

Bowel obstructions occur despite normal pancreatic

function

Slide courtesy of P. Durie

Restoration of CFTR in intestinal epithelium eliminates

obstructionHodges et al, Am J Physiol GLP 2011

Restoration of 10-15% CFTR will avoid intestinal obstruction

Page 22: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Lessons from CF Ferrets & Pigs• CF Ferrets

• 50% die from MI with perforation in ileum or colon• Have mild pancreatic histopathology at birth

• CF Pigs• 100% penetrance for MI & PI• Pancreatic disease begins in utero & progresses over time

– proinflammatory, complement cascade, proapoptotic, and profibrotic pathways are activated Abu-El-Aija et al, Am J Pathol 2012

MI is not caused by pancreatic dysfunction,but is strongly associated with it

Abstract # 180

Page 23: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Pancreatic Dysfunction in Infants with CF

• Pancreatic insufficiency can be the first clinical manifestation of CF– Occurs in a majority of infants – Occurs prenatally– Treatment with pancreatic

enzyme replacement therapy (PERT) is life-sustaining

Schwachman, Pediatr 1960

Management of complications of steatorrhea can be done by “conservative measures, including strapping of the buttocks, defecating in a reclining position, and measures designed to reduce the frequency and bulk of stool”… (such as ) ...witholding butter, ice cream, peanut butter, potato chips, french fried potatoes, and mayonnaise….”

Page 24: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Advances in Pancreatic Enzyme Replacement Therapy (PERT)

• New Drug Application process improved safety• no longer overfilled• improved stability• free of enveloped viruses

• 5 delayed release PERTs approved by US - FDA• Creon (Abbott)• Zenpep (Aptalis)• Pancreaze (Janssen / J&J)• Pertzye (Digestive Care)• Ultresa (Aptalis)

Abstract # 447

Page 25: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Smyth et al, Lancet 1994

Schwarzenberg et al J Pediatr 1995

Normal vs. Fibrosing Colonopathy

Page 26: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Addressing Issues with PERT DosingPhase IV surveillance study for fibrosing colonopathy is underway

Years

Baby Observational Nutrition Study (BONUS) sub-study to help answer questions about

dosing in infants

Page 27: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Growth Investigations

• BONUS will also help us understand factors that influence growth in the first year of life

• FIRST (Feeding Infants Right -- from the Start)• Explores breastfeeding, respiratory infections and growth

• Docosahexaenoic acid study• Explored the effects of DHA on pancreatic function as

measured by monthly fecal elastase (FE)» FE is unaffected by oral PERT» FE > 200 μg/g and consistent with PS

Page 28: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Schematic Pattern of Evolution of Pancreatic Function in Infants in the

1st Year of Life

O’Sullivan et al, J Pediatr (in press)

Page 29: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Why Do Fecal Elastase Levels Change Early in Life?

• High levels low because pancreatic dysfunction evolves over the 1st year

• An opportunity to modify disease evolution

• Low levels high• Initial levels may be 2 o PI

– “false positive”• Other factors

• Re-measure FE at 1 year of age

Page 30: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Garner Intelligence

Page 31: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Poohed

Page 32: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Microbiomics: Interactive Symbiosis

• Human intestine is colonized by an estimated 100 trillion bacteria– Promote optimal digestion– Maintain epithelial homeostasis– Modulate fat metabolism– Promote angiogenesis and enteric

nerve function– Support resistance to infection

• Dysbiosis in patients or animal models is associated with– inflammatory bowel disease– obesity – cancer– diabetes– allergy

Bronchi

Page 33: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Microbiomic Techniques

• Culture independent using 16S ribosomal RNA • Data are analyzed in terms of:

• Relative abundance • Diversity / Richness• Presence or absence of taxa• Evenness (distribution)• Total bacterial load QPCR

Reference genomes from the human microbiome

Symposium # 10

Page 34: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Bacterial Communities in Mammalian Intestine

Adapted from Hill et al, Mucosal Immunol 2009

Page 35: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Abstract # 326

Page 36: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American
Page 37: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Correlation between Fecal and Respiratory Microbiomes in CF

• 7 infants with CF diagnosed by NBS, followed for 9-21 months

• 14 of 16 genera increasing in the gut were also increasing in the respiratory tract

• For 7 of these 16 genera, gut colonization presages appearance in the respiratory tract

Madan et al, mBio 2012

Page 38: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

a= microbes with increased abundance in the intestines early in life b= later in life

Heat Map and Simpson’s Diversity Index of Respiratory and Fecal Microbiomes

Abstract # 279

Page 39: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

GI and Respiratory Tract Commonalities

• Selective epithelial barrier + mucus-gel layer • Protects against bacteria, pathogens and foreign antigens

• Mucosa-associated lymphoid tissue (MALT)• Regulates antigen sampling, lymphocyte trafficking and

mucosal host defense

• “ It is most likely that it is the similar inflammatory and immune components of these organs that are the cause of the overlap in pathological changes in respiratory and intestinal mucosal diseases”.

Keely et al, Mucosal Immunol. 2012

Page 40: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Go Inside• Immune responses to intestinal

bacteria inflammation:• Bacterial signals• Toll-like receptors• NOD-like receptors• G protein-coupled receptors

• Measureable clinically with lab tests

Hill & Artis, Ann Rev Immunol 2010

and videoendoscopy

Abstract # 522

Page 41: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Capsule Video Endoscopy shows Inflammation in CF Intestine

Healthy jejunum Patient with CF

Videos courtesy of M. Wilschanski, Jerusalem Abstract # 510

Page 42: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Grab Intestine

• New preclinical model systems and clinical trial biomarkers

• Rectal short circuit current measurements (ICM)

• Organoids

Page 43: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Rectal tissue as a biomarker and preclinical model system for CFTR

Initially based on European experience, now TDN-sponsored SOP

Can do direct or suction biopsy Advantages:

Accessible High expression Multiple ex vivo assessments

Can apply reagents not suitable in vivo Can apply agents to apical or basal side ICM , biochemistry, metabolomics, etc.

Abstract # 210

Page 44: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

2K+

3Na+

~

Na/K/2Cl

K+

K+Cl-

cAMP Ca++

Na+Amil

Bum

Cl-

NKCC1

NBC1

Na+HCO3-

KvLQT

IK

CaCCCFTR ENaC

IK BKSKCa++

cAMP

KvLQT

cAMP

Ca++

K+

Adapted from H. DeJonge

Colonocyte Ion Transport

• Differences from respiratory epithelial ion transport:– Presence of K+

secretory pathway– Colon is an

absorptive cell (i.e. has more Cl- secretion )

Page 45: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

0

-100

-50

Time (min)

20 40 60 80

50

100

150

200

250

300

Amil CChIndo

AmilFsk/IBMX Bum

Indo

1B. CF

0

50

150

250

300

350

400

Amil

CCh

Bum

Indo

20 40 60 80

1A. Non-CF

Time (min)

100

200

Bum

Fsk/IBMXIsc

(uA/

cm2)

Standard Rectal ICM Recordings

CFTR response CFTR response

↓ response to F/IBMX, mixed response to CCh b/o K+ transport in absence of CFTR

Abstracts # 175 & 256

Page 46: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Hirtz, S. et al. Gastroenterol, 2004

More CFTR function

Controls Carriers CF-PS CF-PI

CF

TR

cur

rent

-180

-150

-120

-90

-30

-60

30

Intestinal current measurements:genotype/phenotype relationships

Solid line, median; dashed line, 25th and 75th percentiles

Page 47: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Organoids / Enteroids / Colonoids*

• Are 1o cultures that can express crypt and/or luminal domains

• Lgr5+ cells at base of crypts generate all cell types in crypt-villus axis

• Can study– Crypt secretory physiology in an

integrated cell culture environment– Luminal absorptive physiology

• Have been created from • Mouse and human intestine• Mouse and human embryonic stem cells

* See Stelzner et al Am J Physiol GI Liver 2012 for NIH nomenclature

Page 48: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Crypt Culture in 3D Gels – “Enteroids”

Sato et al, Nature 2009

Page 49: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Enteroids isolate intestinal epithelium from microbial population and systemic factors

• Changes caused by microbial environment:• Goblet cell hyperplasia

• Changes intrinsic to epithelium with CFTR dysfunction:

• Hyperproliferation: – May be caused by alkaline pH

– May give clues to ↑ incidence of GI cancers in CF

• Goblet cell degranulation defect: – Mucus that is released stays attached to goblet cells

Liu J et al, Am J Physiol Cell 2012With additional work from L. Clarke lab, Missouri

Page 50: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Goblet Cell Degranulation after Carbachol

Wild Type CF Knock-out Mouse

Normal Degranulation Granules go into the lumen without undergoing dissolution

lumen lumen

Videos courtesy of L. Clarke lab -Missouri

Abstract # 122

Page 51: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

“The submucosal gland contains the elixir of airway health “ – Dr. Jeff Wine

Abstracts # 86, 87, 89

Page 52: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Healthy human organoids F508del / F508del organoids

F508del / F508del organoids treatedwith VX-809 + VX-770

Videos courtesy of J. Beekman lab, Utrecht NL

Forskolin induces rapid swelling of organoids |--30μm --|

|--40μm --|

Page 53: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Forskolin-induced swelling in intestinal human organoids can be quanitated

N=8

N=2

N=11

J. Beekman lab, Utrecht NL

Abstract # 191

Page 54: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

Generalize Insights

• There are similarities between the respiratory and GI tracts

• CFTR dysfunction causes pathology in both via obstruction-infection-inflammation

• Animal models and techniques used to explore one system lend insight to the other

• Treatments that focus on CFTR modulation are likely to improve GI as well as respiratory tract function

Page 55: Advances in Gastrointestinal Aspects of CF Drucy Borowitz, MD Professor of Clinical Pediatrics State University of New York at Buffalo “GI” North American

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