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Una la Salute, Una la Malattia
Una la Medicina
© Prof. S. Bardaro - www.amnco.it
© Prof. S. Bardaro - www.amnco.it
© Prof. S. Bardaro [email protected] www.amnco.it
© Prof. S. Bardaro - www.amnco.it
AMBIENTE
STRESS
(Distress – Eustress)
DNA
ALIMENTAZIONE
(Cattiva – Buona)
Sequenza Geni
MATERIALE
Informazione
GENETICO
↕ Espressione e Attività Geni
© Prof. S. Bardaro [email protected] www.amnco.it
© Prof. S. Bardaro - www.amnco.it
Stress
STRESS → GLUCOCORTICOIDS
produced by HPA axis
(Hypothalamic-Pituitary-Adrenal)
© Prof. S. Bardaro [email protected] www.amnco.it
Stress
b) CounterShock
(Parasympathetic )
Alarm
Phase
a) Shock
(Sympathetic )
Resistance
Phase
Inflammation
Breakdown
Phase
Compensazione
Ripresa Sintomi
Malattia Funzionale
Infiammaz. Cronica
Sistemica
Infiammaz. Cronica Grave
Disturbi Eccez. Imprevisti
Morte
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Un aumento cronico del Cortisolo in
circolo è dovuto primariamente a
stress negativi (distress) prolungati
Ciò crea un dirottamento del
responso immune
da Th1 a Th2
Fleshner M, Watkins LR, Lockwood LL et al. Specific changes in lymphocyte subpopulations: a
potential mechanism for stress-induced immunomodulation.
J Neuroimmunol 1992; 41(2): 131-42
Pruett SB. Quantitative aspects of stress-induced immunomodulation.
Int Immunofarmacol 2001; 1(3): 507-20
© Prof. S. Bardaro [email protected] www.amnco.it
Main Different Kinds of Host Immune Response
CD4+ - T helper
Th0 - naive
Th1
Th2
Th3
T-reg
Cytotoxic
Antibody
Tolerant
INF-γ
IL-12
IL-4
IL-13
IL-10
TGF-beta
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Immune Protection and Tolerance
Strong Th1 Immunity
Th1
Defence against Microbial/Viral
Infections and Malignancies
IL-12, IFN-γ, Macrophages, CTL
Dominance of Th2 Immunity
Th2
Pregnancy; Tolerance to Non-Self-MHC
Fetus and Sperm; Il-4, Il-13
© Prof. S. Bardaro - www.amnco.it
Inflammation
Cancer
NOW:
Th1
Acute-Useful Inflammation
Th2
Chronic /Subacute Useless and Harmful
Inflammation
© Prof. S. Bardaro [email protected] www.amnco.it
Stress
Chronic/Subacute Useless and Harmful
Inflammation
© Prof. S. Bardaro [email protected] www.amnco.it
↓↓FOXP3
↑↑CRH
↓↓T Reg
↑↑Th2
↑↑Il-4
© Prof. S. Bardaro [email protected] www.amnco.it
CORTISOL and INSULIN
«..Cortisol counteracts insulin, contributes
to hyperglycemia-causing hepatic
gluconeogenesis and inhibits the peripheral
utilization of glucose (insulin resistance) by
decreasing the translocation of glucose
transporters (especially GLUT4) to the cell
membrane..»
©
Prof. S. Bardaro - www.amnco.it
Obesity
CORTISOL-Resistance
+
+
+
↑ CORTISOL
CORTISOL Inactivity
+
-
INSULIN Inactivity
↑ INSULIN
+
+
INSULIN-Resistance
© Prof. S. Bardaro [email protected] www.amnco.it
Waistline Measurement Helps
to Assess Your Stress Level too
Waistline Measurement Helps
to Assess Your Metabolic
Syndrome Level
© Prof. S. Bardaro - www.amnco.it
Obesity
CORTISOL-Resistance
+
Cancer
+
INSULIN-Resistance
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Cancer
Cancer microenvironment can
display features of T helper type 2
(Th2) inflammation..
© Prof. S. Bardaro [email protected] www.amnco.it
Cancer
The Cancer microenvironment includes a complex network
of immune T-cell subpopulations:
© Prof. S. Bardaro [email protected] www.amnco.it
Cancer
Th2 is a sort of immune privileged state of the tumor microenvironment
© Prof. S. Bardaro [email protected] www.amnco.it
Cancer
↑Cortisol and Cancer
Stress, Aging >>↑Cortisol ,↓DHEA>>Th1→Th2
>>>Cancer
Cancer benefits of stress and gives strenght to stress..
..but doesn’t feel harmful effects of stress
Cancer >>↑Cortisol >>↑Glycolysis
(Paradox)
- Not operant polimorphic cortisol receptors © Prof. S. Bardaro [email protected] www.amnco.it
The HPA-axis is hyperactive in depression.
(1) In neurons of the supraoptic nucleus (SON) >>
increased plasma levels of vasopressin >> enhanced
suicide risk
(2) Increased activity of oxytocin neurons in the
paraventricular nucleus (PVN) >> eating disorders in
depression
(3) Lower vasopressin production and smaller circadian
amplitude in depression in the suprachiasmatic nucleus
(SCN)(the biological clock of the brain) >> sleeping
problems
(4) The hypothalamo-pituitary thyroid (HPT)-axis is
inhibited in depression
© Prof. S. Bardaro - www.amnco.it
Depression
Curr Opin Psychiatry. 2011 Nov;24(6):519-25.
Inflammatory mechanisms in major depressive disorder.
Recent studies support the concept that
inflammatory mechanisms play a crucial
role in the pathomechanisms of
depression
INFLAMMATION
DEPRESSION
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Depression
CYTOKINES – DEPRESSION - CANCER
Th2 e
Monocytic
Th1
Il-4, Il-13, Il-6,
TNF-α
Il-2, Il-12, INF-γ
PRO
ANTI
Depression &
Cancer
Depression &
Cancer
© Prof. S. Bardaro [email protected] www.amnco.it
Depression
Stress
Chr. Stress
&
Depression
Noradr
enaline
CRH
↓
NK
Cortisol
Th2
MMP-2
MMP-9
VEGF
CANCER
© Prof. S. Bardaro [email protected] www.amnco.it
Inflammation (Th2)
IL-1β
Cancer
Depression
Il-1β is a
critical link
between
inflammation
and
oncogenesis
Stress
IL-1β is an essential
mediator of the
effects of stress
IL-1β is a critical
mediator of
anhedonic and
depressive-like
behavior.
IL-1β decreases
neurogenesis in
the adult
hippocampus
© Prof. S. Bardaro [email protected] www.amnco.it
Resistin (Nature, 2000)-Mitchell Lazar
Obesity: ↑ Resistin → ↑ Ins.-Res .→ Diab. 2
DIABESITY
(Diabetes↔Obesity)
Adipocytes
Macrophages
INFLAMBESITY
(Diabetes↔Obesity↔Inflammation)
ATMs: Adipose Tissue Macrophages = 50%
ATMs: Inflammatory cells →↑↑Resistin
Every Inflammated Tissue →↑↑Resistin
© Prof. S. Bardaro [email protected] www.amnco.it
ATMs: Adipose Tissue Macrophages = 50%
M1:
Pro-Infiammatorio
↑ Insulino-Res.
Diabete 2
M2:
Pro-Tumorale
↑Estrogeni locali
CANCRO
© Prof. S. Bardaro
- www.amnco.it
↑Cortisol
↑Prolactin
↓Melatonin
Insulin-Resistance
Th2
Metabolic Growth
↑AntiApoptotic proInflammatory
cytokines
Vagotonic Prevalence
Neoplastic Growth
Sympathicotonic
Norepinephrin Burst
↓Dopamine
© Prof. S. Bardaro - www.amnco.it
OBESITY
INFLAMMATION
CHR. STRESS
DEPRESSION
© Prof. S. Bardaro [email protected] www.amnco.it
Diseases
(CVTumors)
Insulin
Resistance
Obesity
Chronic
Stress
Depression
Inflammati
on
© Prof. S. Bardaro - www.amnco.it
© Prof. S. Bardaro [email protected] www.amnco.it
FAO e OMS
probiotici
“organismi vivi che, somministrati
in quantità adeguata, apportano un
beneficio alla salute dell'ospite”
© Prof. S. Bardaro - www.amnco.it
Contrasto Batteri Patogeni
PROBIOTICI
Meccanismi d’Azione
Bloccano gli effetti dei batteri patogeni con sostanze
battericide e competono con i patogeni e le loro tossine per
l’adesione all’epitelio intestinale
© Prof. S. Bardaro - www.amnco.it
Regolazione Sistema Immune
Regolano il responso immune esaltando l’immunità innata e
modulando il responso infiammatorio indotto dai patogeni
mediante azione sui segnali regolati dai Tool-like Receptors
Protezione Epitelio Intestinale
Regolano l’omeostasi dell’epitelio intestinale promuovendo
la sopravvivenza delle cellule epiteliali, migliorando la
funzione di barriera e stimolando le risposte protettive.
MICROBIOTA
(insieme di microorganismi che popolano il nostro intestino)
“a Forgotten Organ of the Human Body”
© Prof. S. Bardaro - www.amnco.it
SuperOrganismo
Uomo
Corredo
Genetico
Uomo
Cellule
Umane
Genoma
Umano
Cellule
Microbiche
Genoma
Microbiota
(Microbioma)
© Prof. S. Bardaro - www.amnco.it
Intestine is the primary interaction site between the
host and microbiota
© Prof. S. Bardaro - www.amnco.it
L’Intestino ha la funzione di barriera selettiva
meccanica e immunitaria
Mechanisms for preserving mucosal barrier function
© Prof. S. Bardaro - www.amnco.it
Stress and the Gut
«MICROBIOME-GUT-BRAIN Axis»
An altered brain-gut axis has been accepted as
a main pathogenetic mechanism of IBS
Mast cells (MC) are important effectors of brain-gut axis
that translate the stress signals into the release of a wide
range of neurotransmitters and proinflammatory
cytokines, which may profoundly affect the
gastrointestinal physiology
Probiotics may profoundly affect the brain-gut interactions
© Prof. S. Bardaro - www.amnco.it
Stress
induces
hyperpermeability
Lo Stress
induce
iperpermeabilità
of
intestinal
della
barrierabarrier
intestinale
Stress induces changes in
translocation
and central
LoLPS
Stress
crea cambiamenti
cytokine expression
nella traslocazione
dei LPS e nella
espressione centrale di citochine
Increased intestinal permeability is
Iperpermeabilità
un
associated intestinale
with uploadcausa
of
passaggio di LPS che
induce
sintomi
lipopolysaccharides
(LPS)
translocation
that induces depressivi
depressive symptoms
Rottura barriera
Intestinal
barrier intestinale
impairmentè
causa
della patofisiologia
is incriminated
in the dei
disordini intestinali
associati
pathophysiology
of intestinal
con le comorbidità
gut disorders
associated with
psichiatriche
psychiatric
comorbidity
. S. Bardaro - www.amnco.it
Stress
Depression
Rottura barriera
Intestinale
Gut
Microbiota
Probiotics
Endotoxemia
Brain
Neuro
Chemistry
LPS
upload
© Prof. S. Bardaro - www.amnco.it
Neuro
inflammation
I patogeni intestinali comunicano con il SNC e influenzano
i comportamenti emozionali >> Ansia, Depressione
Stress Psicologico altera il Microbiota mediante la
diminuzione di Bifidobacteria e Lactobacilli
Bifidobacteria riducono i livelli di LPS intestinali
e l’attivazione di NF-κB, indotta dai LPS stessi, che
aumenta citochine proinfiammatorie e Cox 2
La diminuzione di Lactobacilli nella flora fecale causata
da Stress è associata ad aumento di infezioni
opportunistiche
© Prof. S. Bardaro - www.amnco.it
Duplice controllo dello Stress
© Prof. S. Bardaro - www.amnco.it
Risposta Ipotalamo Ipofisaria
Alterazione Omeostasi Intestinale
(elevata necrosi cellulare e/o elevata
quantità di clostridi, coli ed
enterococchi)
ACTH e Aromatasi
↑↑ Β-Glicuronidasi
(↓↓ Ac. Glicuronico)
Cortisolo e Estradiolo
riassorbimento di Cortisolo e Estradiolo
(senza elevazione ACTH e Aromatasi
No Risposta Ipotalamo Ipofisaria)
Terreno per
Patologie Th2
(anche Cancro)
aggravate dal Malassorbimento Intestinale
PROBIOTICS , Stress
and Stress-related diseases
Roum Arch Microbiol Immunol. 2011 Apr-Jun;70(2):54-9.
Probiotics--an alternative treatment for various diseases.
Vasile N, Ghindea R, Vassu T.
J Physiol Pharmacol. 2011 Dec;62(6):591-9.
Stress and the gut: pathophysiology, clinical consequences,
diagnostic approach and treatment options.
Konturek PC, Brzozowski T, Konturek SJ.
Psychoneuroendocrinology. 2012 Apr 25.
Prevention of gut leakiness by a probiotic treatment leads to
attenuated HPA response to a chronic psychological stress in rats.
Ait-Belgnaoui A, Durand H, Cartier C, Chaumaz G, Eutamene H, Ferrier L, Houdeau E, Fioramonti J,
Bueno L, Theodorou V.
Psychoneuroendocrinology. 2012 Apr 4
Regulation of the stress response by the gut microbiota:
Implications for psychoneuroendocrinology.
Dinan TG, Cryan JF.
© Prof. S. Bardaro - www.amnco.it
Orv Hetil. 2011 Sep 11;152(37):1477-85.
Role of gastrointestinal inflammations in the
development and treatment of depression
Fehér J, Kovács I, Balacco Gabrieli C
Psychoneuroendocrinology. 2012 Apr 4.
Regulation of depression by the gut microbiota:
Implications for psychoneuroendocrinology
Dinan TG, Cryan JF.
Probiotici efficaci contro Depressione e Stress
(Lattobacillus salivarius, Lactobacillus acidophilus, Bifidobacter lactis)
© Prof. S. Bardaro - www.amnco.it
HPA-axis abnormalities and
CFS – Fibromyalgia - Depression
Z Rheumatol. 1998;57 Suppl 2:67-71.
The hypothalamic-pituitary-adrenal stress axis in fibromyalgia and
chronic fatigue syndrome.
Crofford LJ
Stress. 2007 Mar;10(1):13-25.
The hypothalamo-pituitary-adrenal axis in chronic fatigue syndrome
and fibromyalgia syndrome.
Tanriverdi F, Karaca Z, Unluhizarci K, Kelestimur F
Curr Psychiatry Rep. 2010 Jun;12(3):208-14.
Psychiatric aspects of chronic fatigue syndrome and fibromyalgia.
Van Houdenhove B, Kempke S, Luyten P.
Neurogastroenterol Motil. 2012 Apr;24(4):366
Role of Lactobacillus acidophilus loaded floating beads in chronic
fatigue syndrome: behavioral and biochemical evidences.
Singh PK, Chopra K, Kuhad A, Kaur IP.
© Prof. S. Bardaro - www.amnco.it
Nutr Metab (Lond). 2010; 7: 79.
Gut inflammation in chronic fatigue syndrome
Shaheen E Lakhan 1 and Annette Kirchgessner1
Corticosteroid-Binding Globulin
or
Transcortin
Serpin peptidase inhibitor,
(alpha-1 antiproteinase, antitrypsin)
Controllo
Del
CORTISOLO
Corticosteroid-binding globulin in complex with cortisol
© Prof. S. Bardaro - www.amnco.it
CBG
or
Transcortin
Controllo
Del
CORTISOLO
Anti-Trypsin (Anti distruzione proteine)
Produced by the Liver and Upregulated by Estrogens
(aumenta in gravidanza – diminuisce con epatopatie)
Weak and Strong Stress >> Transcortin Upregulation
Chronic Mild Stress >> Transcortin Downregulation
Lack >> Pain/Fatigue Syndromes (BMS too)
© Prof. S. Bardaro - www.amnco.it
15 JUN 2012 © 2012 Teagasc—The Agriculture and Food Development Authority Journal of Applied
Microbiology © 2012 The Society for Applied Microbiology
γ-Aminobutyric acid
production by culturable
bacteria from the human
intestine
Strains of Lactobacillus and Bifidobacterium were
grown in medium containing monosodium
glutamate (MSG). Growth of the bacteria and
conversion of MSG to GABA..
Batteri Intestinali che producono GABA: Contro STRESS, DEPRESSIONE,
ANSIA, DOLORE, INFIAMMAZIONE, EPILESSIA
© Prof. S. Bardaro - www.amnco.it
↑ CORTISOLO-Resistenza
↑ INSULINO-Resistenza
↓GH
↓
↓Igf1
↓
↑Inflammaging
© Prof. S. Bardaro - www.amnco.it
Proprietà Apoptotiche di IGF-1bp3
Igf-1bp3 ha un potente effetto anticancro
perchè attiva i death receptors sul cancerocita e
poi i recettori al retinolo ed al retinoide x che
apoptosizzano i cancerociti.
Sono gli unici a farlo senza l'intervento dei
mitocondri.
Questo è anche l'effetto anticancro dei flavonoidi
(ACE-inibitori che chelano lo zinco dell'enzima
convertitore), non per l'effetto antiossidante.
© Prof. S. Bardaro - www.amnco.it
Curr Opin Clin Nutr Metab Care. 2003 Sep;6(5):569-76.
Nutritional and metabolic issues in
inflammatory bowel disease.
Cabré E, Gassull MA.
Insulin-like growth factor 1 and Insulin-like growth
factor binding protein 3 are decreased in
inflammatory bowel disease, and disease therapy by
probiotics hardly reverses this situation.
© Prof. S. Bardaro - www.amnco.it
PROBIOTICS and Cancer
BiocelL. 2005 Apr;29(1):15-24.
Reduction of beta-glucuronidase and nitroreductase
activity by yoghurt in a murine colon cancer model.
de Moreno de LeBlanc A, Perdigón G.
Br J Nutr. 2007 Oct;98 Suppl 1:S105-10.
The application of probiotics in cancer.
de Moreno de LeBlanc A, Matar C, Perdigón G.
Int J Food Sci Nutr. 2010 Aug;61(5):473-96.
Cancer-preventing attributes of probiotics: an
update.
Kumar M, Kumar A, Nagpal R, Mohania D, Behare P, Verma V, Kumar P, Poddar D, Aggarwal PK, Henry CJ,
Proc Nutr Soc. 2010 Aug;69(3):421-8. Epub 2010 Jun 16.
The application of probiotic fermented milks in
cancer and intestinal inflammation.
de Moreno de Leblanc A, Perdigón G.
© Prof. S. Bardaro - www.amnco.it
PROBIOTICS and Obesity
Curr Gastroenterol Rep. 2009 Aug;11(4):307-13.
The microbiome and obesity: is obesity linked to our gut
flora?
Tsai F Coyle WJ
J Clin Gastroenterol. 2010 Sep;44 Suppl 1:S16-8.
Obesity, metabolic syndrome, and microbiota: multiple
interactions.
Tilg H
Endocr Rev. 2010 Dec;31(6):817-44. Epub 2010 Jun 30.
Gut microbiota, lipopolysaccharides, and innate immunity in
the pathogenesis of obesity and cardiovascular risk.
Manco M, Putignani L, Bottazzo GF.
Metabolism. 2010 Sep;59(9):1351-7. Epub 2010 Jan 27.
Chronic fatigue syndrome is associated with
metabolic syndrome: results from a case-control
study in Georgia.
. S. Bardaro - www.amnco.it
Maloney EM, Boneva RS, Lin JM, Reeves WC.
© Prof
© Prof. S. Bardaro - www.amnco.it
PROBIOTICI
Th2→Th1
Immunobiology. 2008;213(8):677-92. Epub 2008 Apr 2.
Effects of probiotic bacteria and their genomic DNA on TH1/TH2-cytokine
production by peripheral blood mononuclear cells (PBMCs) of healthy and
allergic subjects.
Ghadimi D, Fölster-Holst R, de Vrese M, Winkler P, Heller KJ, Schrezenmeir J
Biosci Biotechnol Biochem. 2008 Nov;72(11):2847-57. Epub 2008 Nov 7.
Potential of selected strains of lactic acid bacteria to induce a
Th1 immune profile.
Ongol MP, Iguchi T, Tanaka M, Sone T, Ikeda H, Asano K, Nishimura T.
Int Immunopharmacol. 2010 Jun;10(6):694-706. Epub 2010 Apr 7.
Lactic acid bacteria enhance autophagic ability of mononuclear phagocytes
by increasing Th1 autophagy-promoting cytokine (IFN-gamma) and nitric
oxide (NO) levels and reducing Th2 autophagy-restraining cytokines (IL-4
and IL-13) in response to Mycobacterium tuberculosis antigen.
Ghadimi D, de Vrese M, Heller KJ, Schrezenmeir J.
© Prof. S. Bardaro - www.amnco.it
Th17→Th1
Int J Mol Med. 2011 Nov;28(5):817-22. doi: 10.3892/ijmm.2011.755. Epub 2011 Jul 20.
Suppression of Th17 response by Streptococcus
thermophilus ST28 through induction of IFN-γ.
Ogita T, Tanii Y, Morita H, Suzuki T, Tanabe S.
ST28 stimolando espressione e produzione di INF-γ
sopprime l’espressione di IL-17 che determina la
produzione di cellule Th17 (generate da TGF-β+Il-6).
In tal modo si ristabilisce l’equilibrio Th1/Th17.
(Effetto Antinfiammatorio
Anti Autoimmune)
© Prof. S. Bardaro - www.amnco.it
© Prof. S. Bardaro [email protected] www.amnco.it