PAPEL DEL EJE CEREBRO-INTESTINAL EN

LA SALUD y LA ENFERMEDAD

Javier Santos, MD, PhdGrupo de Neuro-inmuno-gastroenterología

Unidad de investigación de Enfermedades Digestivas Institut de Recerca Vall d´Hebron

Servicio de Gastroenterología Hospital Vall d´Hebron Universitad Autònoma de Barcelona

• “Come poco, cena más poco; que la salud de todo el cuerpo se fragua en la oficina del estómago.”

Miguel de Cervantes• “Muchas veces, una cena ligera, un sueño tranquilo y

una mañana serena envalentonaron hasta el heroísmo a un hombre que, con un estómago pesado, pocas horas de sueño y una mañana lluviosa, habría sido un cobarde.” Edmund Burke

GALTBRAIN

ENS

25 MARCH 2005 VOL 307 SCIENCE www.sciencemag.org

medweb.bham.ac.uk/.../ Teaching/GIT/ENS1.gif BRAIN-GUT INTERFACE

Epithelium

1.5 T Food/Year

Epithelial cellsEnteroendocrine cells

M cellsGoblet cellsStem cells

MyofibroblastsExtracellular matrix

Area 400 m2

Junctional complex

Permeable < 2Kda

LA BARRERA INTESTINAL

LaminaPropria

Epithelium

80% Plasma cellsLymph = Spleen

MCs, Eos, DC, M…

Area 400 m2

Permeable < 2Kda

1.5 T Food/Year

EL SISTEMA INMUNE INTESTINAL

ENS

LaminaPropria

Epithelium

80% Plasma cellsLymph = Spleen

MCs, Eos, DC, M…

100 M Neurons-Sensory-Motor

-Interneurons

Area 400 m2

Permeable < 2Kda

EL CEREBRO INTESTINAL

ENS

Laminapropria

Epithelium

Gut lumen

80% Plasma cellsLymph = Spleen

MCs, Eos, DC, M…

100 M Neurons-Sensory

-Motor-Interneurons

> 1000 Sp. bacteria1200 Sp. phages

Virus

Area 400 m2

Permeable < 2Kda

LA FLORA INTESTINAL

Holzer P, et al. J Physiol Pharmacol 2001, 52, 4, 505—521

Extrinsic Innervation of the Gut

Vagal & Spinal afferents & efferents

-Energy and fluid homeostasis-Sensation of discomfort and pain

-Taste buds-Release neuropeptides

Peptidergic innervation of GALT

Bueno, L Gut 2000;47:63iv-65iv

• Substance P

• Somatostatin

• Opioids• VIP• Neurokinin

A• CGRP• NPY• CRH

Mast cells: Integral players of cell-neural circuitry

• 1) Direct and functional innervationby peptidergic and vagal afferents.

• 2) Express receptors for endocrine and paracrine messengers contained in those associated nerve endings.

NE α, β2 SP NK1NGF TrkA, p75His H2CRH CRH1,2SS ?NT ?VIP VIPR1PGE2 EP2,3,4

DIRECT EVIDENCE INDIRECT EVIDENCE

Ach muscarinicOpioids ??NPYCGRP

Mast cells: Integral players of cell-neural circuitry

Mast cells: Integral players of cell-neural circuitry

• 3) Activated by molecules relased upon nerve stimulation.

Suzuki et al;J Immunol 1999, Biol Pharm Bull 2005;28: 155

Mast cells: Integral players of cell-neural circuitry

• 4) Synthethise, store, metabolize and release molecules that modulate neuralresponses.

Cytokines SCF, TNF-α, NGF, TGFβ1, GM-CSF, IFNγ, IFNα/β, MCP-1RANTES,, I-309, MIP-1α, bFGF, lymphothactin, IL-1αendothelin, PDGF-AB, VEGF, PD-ECGF, relaxin,IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, 1L-12, IL-13.

Amines: histamine, 5-HTNeutral Proteases: tryptases, chymasesProteoglycans: heparin, chondroitin sulfateAcid hydrolases: β-hexosaminidase, β-glucuronidase,

β-D-galactosidase, Arylsulfatase A.Lipid mediators: eicosanoids, acetylated phospholipids (PAF..)Others: Cathepsin G, Carboxypeptidase, NO & Oxygen radicals,

VIP, acetylcholinesterase

Mast cells: effector & sensory cells

Postganglionic sympatheticnerve terminal

Peptidergic/Vagalafferents

SPCRH

Hist, 5-HT, tryptaseNGF

NE

Other cellsBlood

vessels

MechanicalChemical

Toxins

CytokinesChemokines

Adhesion moleculesNO, Growth factors

AminesOthers

AlergensSuperallergens

THE MAST CELL-EOSINOPHIL AXIS

Bischoff CS, Gebhardt T. Immune Mechanisms in Inflammatory Bowel Disease, 2006

Functional Disorder

IBS

Organic Disease

MODELO BIO-PSICOSOCIAL

HEALTHY D-IBS

IMMUNOHISTOCHEMISTRY: CD117 (c-Kit)

JEJUNAL MAST CELLS IN IBS

*

Healthy D-IBS0

1

2

3

4

Fold

-cha

nge

*

Healthy D-IBS0

1

2

3

4

Fold

-cha

nge

Tryptase mRNA

Carboxypepetidase A3 mRNA

Guilarte et al Gut, 2007

Mast cell counts

Tryptase release

*

*

IBS MAST CELLS

Barbara et al; GE, 2004, 2007

MAST CELLS IBS COLON

Barbara et al; GE, 2004, 2007

SII: ORIGEN DE LAS ALT MOTORAS Y SENSITIVAS

HEALTHY Control-IBS

Biosci Biotechnol Biochem 2010; 74:232

SII: ALT MOTORAS Y SENSITIVAS

GASES, DISTENSIÓN ABDOMINAL Y FLATULENCIA

“La soberbia no es grandeza sino hinchazón; y

lo que está hinchado parece grande pero no está

sano."San Agustín

“I tell you, we are here on Earth to fart around, and don't let anybody tell you

different.”Kurt Vonnegut, Jr.

“A nadie le huelen sus pedos, ni sus hijos le parecen feos".

En condiciones normales expulsamos

de 0.5 a 2 litros diarios de gas en forma,

fundamentalmente,de ventosidades, y en menor cuantía como…

Y, si no lo expulsamos

Do functional patients have more gas in the gut ?

0

400

healthysubjects

functionalpatients

mL

0

600

*patients

healthy subjects

0 120

GAS HANDLING IN PATIENTS WITH BLOATING

Gas retained(infusedminus

evacuated),ml

Gas infusion,min

Diaphragm

8

12

µV

µV

12

90 60gas infusion, min

Anterior wall

Abdominal accommodation in healthy subjects

µV

20

12

Diaphragm

Anterior wall12

7

µV

0 60gas infusion, min

Abdominal accommodation in patients

with bloating

mL

0

200

*

mm

75

150

*

BASAL DISTENSION

0

60

*mm

ABDOMINAL BLOATING IN FUNCTIONAL GUT DISORDERS

Tórax

*P < 0.05 vs basal Media ± Error St

Tórax

*P < 0.05 vs basal Media ± Error St

correct

somatic

response

reduce gut contents

enhance gut handling

improve gut tolerance

ABDOMINAL BLOATING :TREATMENT OPTIONS

-5

0

5

Flatulence Distension BorborigmiBloating Comfort/discomfortPain

basal diet low-residue diet

Reduce gut content: EFFECT OF DIET

10

0

Rectal evacuation

Valld'Hebron

NORMAL

IMPAIRED

coordination

EMG

Correct somatic responses: BIOFEEDBACK

ELEVADA COMORBILIDAD

Gastroenterology 2002;1140. Am J Gastroenterol 2009;104:Suppl 1

• Ansiedad, Depresión, Somatización, Hipocondría, PTSD. • Fibromialgia• Síndrome de fatiga crónica• Trastornos de la articulación témporo-mandibular • Cefalea migrañosa o tensional• Dolor pélvico crónico• Síndrome de dolor miofascial• Cistitis intersticial• Sensibilidad química múltiple• Síndrome de piernas inquietas• Dispepsia no ulcerosa, disquinesia biliar, reflujo • Alergia e intolerancia alimentaria• Dermatitis, psoriasis• Esclerosis múltiple,…

COMORBILIDAD• En estos pacientes:

– Los síntomas de son más severos y difíciles de tratar.

– Disminuye la calidad de vida – Aumenta el uso de recursos sanitarios y

sociales.– Crece el absentismo laboral y disminuye

la productividad.– Se multiplica la repercusión económica.

Whitehead WE, Palsson O, Jones KR. Gastroenterol 2002;1140-1156.

PREVALENCIA global del ESTREÑIMIENTO

AGRADECIMIENTOSMaria Vicario, PhD

Mar Guilarte, MD, PhD student

Carmen Alonso, MD, PhD student

Cristina Martinez, PhD student

Beatriz Lobo, MD, PhD student

Ana González, PhD

Meritxell Guilá, PhD student

Marc Pigrau, MD, PhD student

María Antolín, PhD

Montse Casellas, technician

Milagros Gallart, technician

Josefina Heredia, administrative

Fernando Azpiroz, MD, PhD

NEURONEURO--IMMUNOIMMUNO--GASTROENTEROLOGY: UNRAVELING INTESTINAL INFLAMMATIONGASTROENTEROLOGY: UNRAVELING INTESTINAL INFLAMMATION

up 30 min. after

down 30 min. after

GENOMICS, PROTEOMICSMETABONOMICS

NEURONEURO--IMMUNOIMMUNO--GASTROENTEROLOGY: UNRAVELING INTESTINAL INFLAMMATIONGASTROENTEROLOGY: UNRAVELING INTESTINAL INFLAMMATION

up 30 min. after

down 30 min. after

up 30 min. after

down 30 min. after

up 30 min. after

down 30 min. after

GENOMICS, PROTEOMICSMETABONOMICS