Brain-Gut-Microbiota Interactions and Intestinal...
Transcript of Brain-Gut-Microbiota Interactions and Intestinal...
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Wendy A. Henderson, PhD, CRNP, FAANChief, Digestive Disorders UnitDivision of Intramural Research
Brain-Gut-Microbiota Interactions and Intestinal Health
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Wendy A. Henderson, PhD, MSN, CRNP
Early Life Brain-Gut Microbiota Signaling
Cong, Henderson, et al., Advances in Neonatal Care, 2015
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Wendy A. Henderson, PhD, MSN, CRNP
Nutri-epigenetics
Joseph, Abey, Henderson, ONF, 2016
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Wendy A. Henderson, PhD, MSN, CRNP
Key Facts About Stress Effects on Intestinal Health
Up to 20% of the US population report stress induced gastrointestinal (GI) symptoms
Single most common reason for emergency visits Top 10 reasons for outpatient visits 30 billion in costs annually Evidence that chronic stress affects intestinal
health across the lifespan
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Wendy A. Henderson, PhD, CRNP, FAAN
Biobehavioral Branch: Dr. Wendy Henderson
Targeted Treatments
Stress-InducedGastrointestinal
Symptoms
Phenotypic Characterization
Personalized Profile
Implementation Science
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Wendy A. Henderson, PhD, MSN, CRNP
Innovation-Gastrointestinal Pain Pointer
Developed by Henderson & Zuccolotto, PHS Invention #E-175-2010
Henderson et al., Gastroenterology Nursing, 2017
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Brain-Gut Natural History Study
Hypothesis:
Design:
Male/Female Age 13-45 years No known organic cause
NIH Clinical Trial #NCT00824941
STRESS
Intestinal Permeability
Microbial Translocation
Abdominal Pain
Control IBS
OverweightControl
IBS + Overweight
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+
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Wendy A. Henderson, PhD, CRNP, FAAN
VariableOveralln = 90
Controln = 62
IBSn = 28
IBS-Dn = 13
IBS-Cn = 12
Gender n (%)
Male 45 (50%) 33 (53.2%) 12 (42.9%) 5 (38.5%) 5 (41.7%)
Female 45 (50%) 29 (46.8%) 16 (57.1%) 8 (61.5%) 7 (58.3%)
Race n (%)
White 45 (50%) 30 (48.4%) 15 (53.6%) 8 (61.5%) 6 (50%)
Black 26 (28.9%) 17 (27.4%) 9 (32.1%) 2 (15.4%) 6 (50%)
Asian 13 (14.4%) 10 (16.1%) 3 (5.2%) 2 (15.4%) 0
Other 6 (6.7%) 5 (8.1%) 1 (3.6%) 1 (7.7%) 0
Age (yrs) 27.82 7.85 28.22 8.05 26.93 7.45 26.62 6.99 27.50 8.09
Participant CharacteristicsProtocol 09-NR-0064, PI Henderson
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Wendy A. Henderson, PhD, CRNP, FAAN
Non-invasive Method to Assess Intestinal Permeability
Del Valle Pinero, et al., Henderson, Clinica Chimica Acta, 2013
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Wendy A. Henderson, PhD, CRNP, FAAN
Novel LC-MS Method to Intestinal Permeability
Del Valle Pinero et al., Henderson, Clinica Chimica Acta, 2013
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Wendy A. Henderson, PhD, CRNP, FAAN
Induce Stress Experimentally
Del Valle Pinero, et al., Henderson, Clinica Chimica Acta, 2013
Protocol 09-NR-0064, PI HendersonN=126 enrolled
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Wendy A. Henderson, PhD, MSN, CRNP
Human Response to Sugar Challenge and the Microbiome
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Wendy A. Henderson, PhD, MSN, CRNP
Microbial taxa associated with Visceral Pain
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Brain-Gut Natural History Study
NIH Clinical Trial #NCT00824941
STRESS
Intestinal Permeability
Microbial Translocation
Abdominal Pain
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Model of Microbial Translocation
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Model of Microbial Translocation
IFABP: p = NS
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Model of Microbial Translocation
IFABP: p = NS
LBP: p = 0.014
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Model of Microbial Translocation
IFABP: p = NS
sCD14: p = 0.067
LBP: p = 0.014
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Pathway Analysis of Significant Genes
Abey, et al., Henderson, BBA Clinical, 2016
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Electron Microscopy of Gold-labeled Plasma EVs
CD9 Lysozyme
IGg2aIGg1 MUC1 MUC2
+MT Control +MT Control
Abey, et al., Henderson, BBA Clinical, 2016
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Time = 0 h Time = 8 h
[-Lyz]
[+Lyz]
Top Canonical Pathways from Affymetrix
Pyridoxal 5-phosphate Salvage PathwaySalvage Pathways of Pyrimidine RibonucleotidesAtherosclerosis Signaling
Top Molecular and Cellular Functions from Affymetrix
Cell-To-Cell Signaling and Interaction Cellular Movement Cellular Assembly and Organization
Abey, et al., Henderson, BBA Clinical, 2016
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0.5
1
1.5
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CD9 NT5E PD-L1 IL7R CD68
Fold
RN
A or
Pro
tein
(-Ly
z / +
Lyz)
RNA [-Lyz]
RNA [+Lyz]
Protein [-Lyz]
Protein [+Lyz]
Significant RNA and Protein with Lysozyme
Nanostring analysis of epithelial cells which survived this injury for 8 h [+ vs -Lyz] shows five RNA/Proteins which are part of LYZ-specific molecular cell response to injury or stress:
Abey, et al., Henderson, BBA Clinical, 2016
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Lysozyme: innate immunity and antimicrobial
Lysozyme
Abey, et al., Henderson, BBA Clinical, 2016
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Wendy A. Henderson, PhD, MSN, CRNP
Mucosa Adherent Microbiome
Fourie, et al., Henderson, Gut Microbes, 2016
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Wendy A. Henderson, PhD, MSN, CRNP
Chronic Stress Murine Model
Fourie, et al., Henderson, Gut Microbes, 2017
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Wendy A. Henderson, PhD, MSN, CRNP
Chronic Stress and Murine Microbiota
Circular cladogram (LEfSe analysis) showing taxa that are more abundantly expressed in water avoidance (WA) stressed animals (i.e. animals which exhibit persistent stress induced gastrointestinal symptoms) in green and taxa more abundantly expressed in control (C) animals in red. Enrichment of the phyla Proteobacteria (n) and Actinobacteria (c) are characteristic of WA animals.
Fourie, et al., Henderson, Gut Microbes, 2017
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Wendy A. Henderson, PhD, MSN, CRNPFourie et al., Henderson. Gastroenterology, 2015, 148(4):S-777.
Host-Microbiome Interaction
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Effects on Epithelial Cell Barrier Function
Barrier function measured in response to Dexamethasone and Butyrate exposure:
Butyrate
Cell-cell junctions mediate gut epithelial permeability
TEER measures epithelial permeability
Robinson, Abey, et al., Henderson, under review.
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ZO-1 Occludin Merge
Untreated
+DEX
Occludin: trans-membrane protein which facilitates barrierfunction of the epithelial tight junction.
ZO-1: scaffolding protein physically linking the actincytoskeleton to Occludin and other trans-membrane tightjunction proteins.
+DEX+Butyrate
Disruption of Tight Junctions by Dexamethasone and Butyrate
Robinson, Abey, et al., Henderson, under review.
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Untreated ChronicDexamethasone
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Targeted Treatments
Grenham et al., Frontiers in Physiology, 2011
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Wendy A. Henderson, PhD, MSN, CRNP
Ongoing and Future Studies
Targeting GI Epithelial Integrity to Improve Arterial Inflammation in HIV
Collaboration with Dr. Janet Lo Assistant Professor of MedicineMassachusetts General HospitalHarvard Medical SchoolFunding: NIH 1R01HL123351
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Study Aims
Aim 1: Cross-sectional study to investigate the relationship between:
Aim 2: RCT to investigate the effects of a GLP-2 analogue (teduglutide) on:
GI epithelial integrity Intestinal permeability Markers of microbial translocation, Markers of immune activation Evidence of coronary atherosclerosis/arterial
inflammation
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Hypothesis
We hypothesize that increased microbial translocation resulting from impaired epithelial integrity and impaired mucosal immunitytriggers the innate immune system, causing proatherogenic monocyteand macrophage activation and atherosclerotic disease development in HIV disease.
GI Epithelial Integrity
Microbial Translocation
Immune Activation
Atherosclerosis and Arterial Inflammation
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Study Procedures
Gut epithelial integrity/barrier function Colonoscopy/Endoscopy
Tissue biopsyGI epithelial tight junctionsGI epithelial apoptosisCharacterize tissue T-cells and
macrophages Blood: Microbial translocation Intestinal permeability Microbiome
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VISIT 3:Colonoscopy
EGD
VISIT 4:FDG-PET
VISIT 2:Intestinal
PermeabilityDEXA
HR-pQCT
VISIT 1:(Screen Visit)Cardiac CTA*
VISIT 9:Colonoscopy
EGD
VISIT 10:FDG-PET
VISIT 8:Intestinal
PermeabilityDEXA
HR-pQCT
VISIT 7:Cardiac CTA
BASELINE VISITS INTERVENTION END OF STUDY VISITS
STUDY DESIGN
60 HIV+ Subjects
10 Healthy Controls
10 HIV+ Subjects (Visits 1-2)
10 Healthy Controls (Visits 1-2)
Cross Sectional Study:
20 Healthy Controls 70 HIV+ Subjects
Flow of participants
*Only for participants who do Visits 1-4
VISIT 5 & 6(Safety Visits)
Daily SQ injection of teduglutide or
placebo for 6 months
Aim 1: 7 HIV patients and 9 Healthy Controls
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VISIT 3:Colonoscopy
EGD
VISIT 4:FDG-PET
VISIT 5 & 6(Safety Visits)
Daily SQ injection of teduglutide or
placebo for 6 months
VISIT 2:Intestinal
PermeabilityDEXA
HR-pQCT
VISIT 1:(Screen Visit)Cardiac CTA*
VISIT 9:Colonoscopy
EGD
VISIT 10:FDG-PET
VISIT 8:Intestinal
PermeabilityDEXA
HR-pQCT
VISIT 7:Cardiac CTA
BASELINE VISITS INTERVENTION END OF STUDY VISITS
STUDY DESIGNFlow of participants
60 HIV+ Subjects
10 Healthy Controls
10 HIV+ Subjects (Visits 1-2)
10 Healthy Controls (Visits 1-2) Interventional Study:
60 HIV+ Subjects
Randomization
Aim 2: 6 HIV patients enrolledAim 1: 7 HIV patients and 9 Healthy Controls
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VISIT 3:Colonoscopy
EGD
VISIT 4:FDG-PET
VISIT 2:Intestinal
PermeabilityDEXA
HR-pQCT
VISIT 1:(Screen Visit)Cardiac CTA*
VISIT 9:Colonoscopy
EGD
VISIT 10:FDG-PET
VISIT 8:Intestinal
PermeabilityDEXA
HR-pQCT
VISIT 7:Cardiac CTA
BASELINE VISITS INTERVENTION END OF STUDY VISITS
STUDY DESIGNFlow of participants
60 HIV+ Subjects
10 Healthy Controls
10 HIV+ Subjects (Visits 1-2)
10 Healthy Controls (Visits 1-2) Interventional Study:
60 HIV+ Subjects
VISIT 5 & 6(Safety Visits)
Daily SQ injection of teduglutide or
placebo for 6 months
Aim 2: 6 HIV patients enrolledAim 1: 7 HIV patients and 9 Healthy Controls
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VISIT 3:Colonoscopy
EGD
VISIT 4:FDG-PET
VISIT 2:Intestinal
PermeabilityDEXA
HR-pQCT
VISIT 1:(Screen Visit)Cardiac CTA
VISIT 9:Colonoscopy
EGD
VISIT 10:FDG-PET
VISIT 8:Intestinal
PermeabilityDEXA
HR-pQCT
VISIT 7:Cardiac CTA
BASELINE VISITS INTERVENTION END OF STUDY VISITS
STUDY DESIGNFlow of participants
60 HIV+ Subjects
10 Healthy Controls
10 HIV+ Subjects (Visits 1-2)
10 Healthy Controls (Visits 1-2) Interventional Study:
60 HIV+ Subjects
VISIT 5 & 6(Safety Visits)
Daily SQ injection of teduglutide or
placebo for 6 months
Aim 2: 6 HIV patients enrolledAim 1: 7 HIV patients and 9 Healthy Controls
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Microbial AssaysSchematic depicting lateral flow assay in one arm
Proposed schematic for multiplexed detection of diarrhea-causing pathogens
Nonprovisional Worldwide PCT Patent Application No.: PCT/US16/32788Kim, Henderson, Abey, Fourie, & Ferguson, 2015
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Microbial AssaysSchematic depicting lateral flow assay in one arm
Proposed schematic for multiplexed detection of diarrhea-causing pathogens
Worldwide PCT Patent Application No.: PCT/US16/32788Kim, Henderson, Abey, Fourie, & Ferguson, 2016
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Wendy A. Henderson, PhD, CRNP, FAAN
Biobehavioral Branch: Dr. Wendy Henderson
Clinical Applications
Stress-Induced Gastrointestinal
Symptoms
Gastrointestinal Pain Pointer
Personalized Profile
Implementation Science
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AcknowledgmentsLab Members:Ana Diallo, PhD, MPH, BSN, Postdoctoral IRTAJeffrey Robinson, PhD, Postdoctoral IRTAChristina Boulineaux, MS, Postbac IRTAStephanie Prescott, MSN, CRNP, GPP student
Prior Lab Members:Paule Joseph, PhD, MSN, CRNP, Postdoctoral IRTA, OWD FundedKristen Weaver, PhD, BS, BSN, MSN, CRNP, GPP StudentNatneal Kenea, BS, Special VolunteerOnyi Ozyochi, BS, Special Volunteer, OTIE fundedLeeAnne Sherwin, PhD, MS, CRNP, Special VolunteerFaye Harrell, MSN, CRNP, Special VolunteerNicolaas Fourie, PhD, Special VolunteerSarah Abey, PhD, BSN, Prior- Nurse Specialist, Research
Collaborators:Kong Chen, PhD (NIDDK)Colleen Hadigan, MD (NIAID)David Kleiner, MD, PhD (NCI)Alan Remaley, MD, PhD (NHLBI, DLM)Lorenzo Leggio, MD, PhD (NIAAA & NIDA)Peter Walter, PhD, (NIDDK)
NINRDivision of Intramural ResearchDan Wang, PhDAnn Cashion, PhD, RN, FAANSue Wingate, PhD, CRNPBrian Walitt, MD, MPH
Extramural Collaborators:Margaret Heitkemper, PhD, RN, U of Washington Anthony Zuccolato, PST, Inc.Chang Hee Kim, PhD, GoDxJohn Wiley, U of MichiganGreg Goyne, Nanostring Tech. Rob Shulman, BaylorSecondGenomeNCI- Fredrick
ParticipantsCNS IRBMetabolic UnitCC Nurses & Staff
Office of Workforce DiversityOffice of Intramural Training and EducationCommunity College Summer Enrichment ProgramAmgen
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Wendy A. Henderson, PhD, CRNP, FAANChief, Digestive Disorders UnitDivision of Intramural Research
Brain-Gut-Microbiota Interactions and Intestinal Health
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ChronicDEX and Butyrate
Slide Number 1Early Life Brain-Gut Microbiota SignalingNutri-epigeneticsKey Facts About Stress Effects on Intestinal HealthSlide Number 5Innovation-Gastrointestinal Pain PointerBrain-Gut Natural History StudySlide Number 8Slide Number 9Slide Number 10Slide Number 11Human Response to Sugar Challenge and the MicrobiomeMicrobial taxa associated with Visceral PainBrain-Gut Natural History StudyModel of Microbial TranslocationModel of Microbial TranslocationModel of Microbial TranslocationModel of Microbial TranslocationPathway Analysis of Significant GenesElectron Microscopy of Gold-labeled Plasma EVsSlide Number 21Significant RNA and Protein with LysozymeLysozyme: innate immunity and antimicrobial Mucosa Adherent MicrobiomeChronic Stress Murine ModelChronic Stress and Murine MicrobiotaHost-Microbiome InteractionEffects on Epithelial Cell Barrier FunctionDisruption of Tight Junctions by Dexamethasone and ButyrateSlide Number 30Targeted TreatmentsOngoing and Future StudiesStudy AimsHypothesisStudy ProceduresSTUDY DESIGNSTUDY DESIGNSTUDY DESIGNSTUDY DESIGNMicrobial AssaysMicrobial AssaysSlide Number 42AcknowledgmentsSlide Number 44Slide Number 45