Principal Investigator/Director, GIM Foundation Little Rock, - - PowerPoint PPT Presentation

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Principal Investigator/Director, GIM Foundation Little Rock, - - PowerPoint PPT Presentation

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Esophagogastrointestinal Motility Disorders Wellcome Images Arun Chaudhury, MD Principal Investigator/Director, GIM Foundation Little Rock, Arkansas, USA Need for external acquisition of nutrition The gastrointestinal (GI) tract Anaerobic

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Esophagogastrointestinal Motility Disorders

Arun Chaudhury, MD

Principal Investigator/Director, GIM Foundation Little Rock, Arkansas, USA

Wellcome Images

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Need for external acquisition of nutrition

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The gastrointestinal (GI) tract

  • Anaerobic fermenter
  • Long winding asymmetric tract with STOPCOCKS
  • mostly silent except at the front and backend

(belch/wind)…sometimes borborygmus

  • Don’t forget to ask your patients whether they

have “Passed Gas”..ask directly…sine qua non of patency of intestinal lumen in ICU/surgical ward

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Layered organization

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Enteric Nervous System

  • Sensor
  • Progressive motility
  • Secretomotor
  • Vasomotor
  • Toxin detection
  • Pain
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Hao et al, 2016, Developmental Biology

Nitric oxide (NO) Acetylcholine (ACh)

Principal Neurotransmitters

neurons glia

laminar preparation slice

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Wellcome Images

Myenteric Ganglia (Auerbach’s Plexi)

Sandwiched!

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Dogiel neurons: IPANs (intrinsic primary afferent neurons) & interneurons

The JUNCTION

Chaudhury et al, 2014, Frontiers in Medicine (Gastroenterology)

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Can one drink during sirshasan?

Franz Ingelfinger

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Simultaneous Fluoroscopy & Esophageal Manometry

Dodds WJ, Christensen J, Dent J, Arndorfer RC, Wood JD. Pharmacologic investigation of primary peristalsis in smooth muscle portion of opossum

  • esophagus. Am J Physiol 1979;237(6):E561–E566
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Gradients of Contractions in the Opossum Esophagus

Norman Weisbrodt & James Christensen, Gastroenterology, 1972 Goyal and Chaudhury 2008, Journal of Clinical Gastroenterology

LES

Tonic

Esophageal body

Phasic

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Relaxation as well!

Norman Weisbrodt & James Christensen, Gastroenterology, 1972

LES Esophageal body

Goyal and Chaudhury 2008, Journal of Clinical Gastroenterology First rigorous evidence of

INHIBITORY NEURO-SMOOTH MUSCLE NEUROTRANSMISSION

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Ascending Excitation, Descending Inhibition

Goyal and Chaudhury, 2008

Accommodation of bolus

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Burnstock et al Br J Pharmacol 1970

ATP as a NANC neurotransmitter

Turkey Fish Guinea-pig tenia coli Superfusion assay, Sir John Vane

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impale KCl Amplify mV signals

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Atropine Guanethidine

Inhibitory Junction Potential (IJP)

Apamin Apamin + L-NAME

Fast IJP Slow IJP

Shuba MF; Zagordynuk & Maggi; Goyal & He; Burnstock; Chaudhury; Furness; Jimenez M.

Compound IJP

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Neural prejunctional release Calcium dependent

Characteristics of IJP

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One neurone,

  • ne neurotransmitter

Sir Henry Dale

Wellcome Images

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?Multiplicity of neurotransmitters during enteric neuro-smooth muscle neurotransmission

Burnstock; Chaudhury

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Gut nerve stimulation releases nitric oxide (NO)

Bult et al 1990

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Defects in Nitrergic Function may y explain gut motility y disorders

Prejunctional Junctional Post-Junctional Chaudhury & Mashimo, Ch 13, 3rd Edition, Current Diagnosis and Treatment in Gastroenterology

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TONIC PHASIC Chaudhury & Mashimo, Ch 13, 3rd Edition, Current Diagnosis and Treatment in Gastroenterology Hypotensive Hypertensive

Manometry aids defi finitive ve diagnosis

Reflux

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Chaudhury & Mashimo, Ch 13, 3rd Edition, Current Diagnosis and Treatment in Gastroenterology

Achalasia Diff ffuse Esophageal Spasm

NCCP, Non- cardiac chest pain

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Proventricular dilation disease

Last et al 2012, JSAVA

Goyal and Chaudhury, Gastroenterology, 2010; Chaudhury, Gastroenterology, 2015

Bornaviridae

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Bioelectronics of Nitric Oxide (NO) synthesis

Active nNOS Inactive nNOS Chaudhury et al 2008, 2009 Non-vesicular transmitter follows Sherringtonian laws of neurotransmission

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Molecular adaptors of nNOS

  • LC8/DLC8/PIN
  • PSD95
  • BH4

Chaudhury Gangula

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Molecular handoffs in nitrergic neurotransmission

  • Phelan-McDermid syndrome & cyclical vomiting

LC8 + shank3 LC8 + nNOS Chaudhury 2014 nNOS in cortical cytoskeleton

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LC8/DLC8/PIN

Chaudhury et al 2008, 2011, 2012, 2014

LC8 = BOTH anterograde + retrograde movement

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Chaudhury et al 2011, 2012

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Chaudhury et al 2011, 2012

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Chaudhury et al 2011, 2012

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Chaudhury et al 2011, 2012

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DAF, diaminofluorescein Nipkow spinning disc confocal Chaudhury et al 2011

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Fast IJP reduced in DBA/2J mice

Chaudhury et al 2011

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Slow IJP reduced in DBA/2J mice

Chaudhury et al 2012

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First demonstration of molecular basis of coordination for tandem release of neurotransmitters by molecular motors during a coordinated neurophysiological event

Chaudhury

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Chaudhury et al Plos One 2014 Fundus CCP

Loss of relaxation in penile cavernosa & gastric fundus of DBA/2J mice

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Chaudhury, He, unpublished

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Control Streptozocin (STZ)

Nitrergic neurons look similar in wild-type & diabetic rat jejunum

Chaudhury et al 2014 nNOS nNOS

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nNOS uniformly distributed in wild-type & diabetic rat jejunal nerve terminals

Chaudhury et al 2014

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Myosin Va reduced in diabetic rat jejunal nerve terminals

Control Diabetes Chaudhury et al 2014 Image J, NIH

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Defective axonal transport of myosin Va or intra-varicosity transport of nNOS may underlie the pathophysiology of diabetic gastroparesis

Project in Progression

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Idiopathic Gastroparesis

Alvarez et al, 2015, 143-45, Acute Gastric Dysfunction after Catheter Ablation of Atrial Fibrillation, J Medical Cases

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Food for thought

Are there similarity in mechanisms of diabetic gastroparesis and obesity?

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IJPs recordable in small intestines

Gwynne and Bornstein 2007

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GI motility pathophysiology in Celiac Disease and Down syndrome: Lessons from Snell’s Waltzer

A model of myosin 6 deficiency

Enhanced methylation Chaudhury et al 2017

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May involve multiple mechanisms

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Carrascosa et al, 2014, 2718-21, J Clin Microbiol

Ogilvie’s syndrome

VIROCHIP

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Park and Lee 2015, 436-439, Clinical Endoscopy

Phyto-Bezoar

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The 3rd Party: Interstitial Cell of Cajal (ICC)

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ICC: Intercalated or interspersed?

Sanders et al 2014

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Genomic Knockout of ICC

Klein et al 2013

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SLOW WAVE INTACT fIJP + sIJP

Klein et al 2013

Intact IJP in ICC genomic knockout mice

Chaudhury 2013; Chaudhury 2016

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Mechanisms of retropulsion: Toggling of the prospective circuit

Technische Universitat Munchen

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sheep rabbit

Lessons in motility from fecal pellet shapes & intestinal segmentations

Technische Universitat Munchen

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Human Megacolon

Chagas disease Chaudhury, Srinivas, et al, Frontiers in Pathology, Peer review, 2017 Knee-elbow position Listless colon

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Chaudhury, Srinivas, et al, Frontiers in Pathology, Peer review, 2017

Animal model of Hirschsprung’s disease

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HSV2 intestinal myopathy: A Model for constipation

Chaudhury, Srinivas, et al, Frontiers in Pathology, Peer review, 2017 Khoury-Hanold et al, Cell Host & Microbe, 2016

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What is the basis for multisystem involvement?

  • 2 siblings from Ecuador, 11 and 14 yrs old
  • Seizure disorders, pervasive neurodevelopmental disorder
  • Achalasia
  • Tuberculosis and recurrent fungal infections

Pedroza, Chaudhury 2017

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Microbiome (virus, bacteria, fungus, prion) & ENS

Neuroimmune interactions…an unexplored area In ancient China, the first meal of a child was mother’s fecal pellet Necrotizing enterocolitis, etc….antibiotic overuse in NICU Intestinal gas, bloating, SIBO

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Rational approaches to identification of pathophysiology

  • Skeletal muscle biopsy…nNOS location
  • nNOS in neutrophil…dimer assay
  • Defects in secretory capacity…platelet assay
  • Skin melanosome assay for myosin Va
  • Whole thickness intestinal bx and over the scope

clipping is still not a reality

Chaudhury 2016 Patent worthy

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Enteric musculomotor transmission & The Opioid Epidemic

Lay et al, 2016, G252-G266, American Journal of Physiology Gastrointestinal and Liver

MOR = µ-opioid receptor NOS = neuronal nitric oxide synthase

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Insights from Mother Nature

Alapaca Do humming birds develop gastroparesis? Gastric emptying mechanisms

  • f sloth

Low amplitude IJP in stomach, Szurszewski, abstract Chaudhury, 2017 Chaudhury, 2017

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Phenotype reversal in Ulcerative Colitis

  • Role of nicotinic receptors?

Satish Rao

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SLC17A9 (Vesicular nucleotide transporter, VNUT) knockout mice have apparently normal appearing GI tract and normal fecal pellet output

Delve to figure out the molecular basis of FUNCTIONAL BOWEL DISORDERS

Find BIOMARKERS of FUNCTIONAL BOWEL DISORDERS

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Summary

  • Pathophysiology of esophagogastrointestinal motility disorders often difficult to discern
  • Obtain detailed HISTORY, ask patients to maintain diary, do NOT discount symptoms
  • Detailed communication and empathy with patients, along with expert dietary consult

(regarding FODMAP diet, fibers etc)

  • Subtle molecular defects, mostly involving neurotransmission at multiple levels
  • The defects may involve both upper and lower GI tract (for example, alternating

constipation and diarrhea may co-exist with refractory GERD in an irritable bowel syndrome patient)

  • All defects of GI motility affects the final common pathway of IJP
  • Lot remains to be known
  • Think physiology and pathology (e.g., why do we belch after a coke…?any relation to

TLESR, reflux disease and biliary reflux)

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Lessons for other organ systems from enteric neurotransmission

  • Similarity in mechanisms of insulin release with fast and slow IJP
  • Aortic stiffening, widening of pulse pressure and nNOS-mediated NO

release in tunica intima

  • Flow through low pressure system..pancreatic/cystic duct, portal vein,

pulmonary vein, fallopian tube

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Bioelectronic medicine for ameliorating gastrointestinal motility disorders

  • Lessons from sex medicine
  • Bioelectronic medicine…on

demand de novo synthesis of NO…very very difficult challenge in pharmacology for functional bowel disorders

cordycepin

Yartsa gunbu

Patent worthy Chaudhury 2017

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Look for pharmacology everywhere!

Chikoo & Myosin V; Chaudhury, 2017, patent worthy

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Outstanding research questions

  • Though tonic, LES and pylorus differ…LES relax with a sweep of primary

peristaltic wave….NO synthesis in pylorus is stochastic…what is the luminal stimulus that drive gastric emptying?

  • Segmentation…what determines the ends and the length of the segment
  • What is the luminal sensor
  • How millions of food molecules with different structures distinguished

from few thousands toxins, also of different structures…is there a quantal difference in serotonin release

  • Street food and ENS
  • ENS of hyena
  • Milk Oligosaccharide and neurotransmission
  • DIETARY FIBERS and neurotransmission
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Acknowledgments

  • Sayan Biswas, Kolkata
  • Susmita Biswas, Kolkata
  • Jacqueline Zanoni, Maringa,

Brazil

  • Renata Perreira, Maringa, Brazil
  • Hemant Thatte, Professor of

Surgery, Harvard Medical School

  • Raj K Goyal, Mallinckrodt

Professor of Medicine, Harvard Medical School

  • Luis Alberto Pedroza

Dean Srinivas, for your kind invitation Faculty & Staff, ESIC Medical College ESIC Medical College SanathNagar Funding

  • Self
  • Friends of GIM Foundation
  • NIH

A Shariff, AIIMS, New Delhi Mousumi Chaudhury, GIM Foundation

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Mutter Museum, Philadelphia

Thank you all!

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Importance in Medicine & Medical Research

Independent validation

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Slides will be uploaded to

www.arunchaudhury.org