A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference...

59
A.I.S.F. Monothematic Conference 2012 The Gut-Liver Axis: a bidirectional relation in health and disease Alcoholic steatohepatitis Gianluca Svegliati Baroni SOS “Epatopatie croniche e trapianto di fegato” Universita Politecnica Marche-Ospedali Riuniti Ancona Bologna, 5 ottobre 2012

Transcript of A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference...

Page 1: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

A.I.S.F. Monothematic Conference 2012The Gut-Liver Axis:

a bidirectional relation in health and disease

Alcoholic steatohepatitis

Gianluca Svegliati Baroni

SOS “Epatopatie croniche e trapianto di fegato”

Universita Politecnica Marche-Ospedali Riuniti

Ancona

Bologna, 5 ottobre 2012

Page 2: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Il sottoscritto dichiara di non aver avuto negli ultimi 12 mesi conflitto d’interesse in relazione a questa presentazione

e

che la presentazione non contiene discussionedi farmaci in studio o ad uso off-label

Page 3: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

LE CAUSE DELLE MALATTIE EPATICHE:

ALCOL

Consumo di bevande alcoliche

distinzione per classi di età

Abuso di alcol, come causa di patologie al fegato

che portano al decesso del paziente…l’ alcol ha un’ azione epatotossica diretta….agiscecome cofattore di danno accelerando la progressionedelle malattie epatiche croniche da altra causa…ilconsumo di alcol è la più importante determinantedella severità della malattia epatica, causando unincremento di mortalità di tre volte superiore nei forticonsumatori rispetto ai bassi consumatori.

Page 4: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Total number of first liver transplants = 1530

* Autoimmune 0.35%; liver rupture 0.15%

Re-OLTx N. = 100 (7.5%)

THE LIVER MATCH STUDYMain indications for liver transplantation

Angelico M. et al. Dig Liv Dis; 2011.

Page 5: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

0

1,3

6,6

9,3

1,6

6,9 7,2 7,1

1,6

4,3

2,63,1

0

5

10

< 30 30 - 49 50 - 69 > 70

HCV/HBV

Alcol

NAFLD

Prevalenza età-specifica di alterazione degli indici di danno epatico nella popolazione generale di Cittanova (Ita lia

Meridionale) per eziologia, 2002-2003

Pendino et al. Hepatology 2005

%

Page 6: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Population Screened 4671

Excessive drinkers (>30g/day) 947 20.3 %

EtOH-Induced Liver Damage 305 6.5 %

Cirrhosis+HCC (10% symptom.) 33 0.7 %

Bellentani et al., Gut, 1997 and Add.Biol, 2002

“True” Clinical Prevalence of Ethanol induced Liver Diseases

Dionysos 1 (1991-92)

Page 7: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Alcohol Intake O.R. for ALD O.R. for Cirrhosis

Teetottalers 0 0<30 g/day 0 031-60 g/day 8 1061-90 g/day 21 2591-120 g/day 15 53>120 g/day 36 62

Which is the threshold risk of alcohol consumption for ALD in the general Italian healthy population?

Bellentani et al., Gut, 1997

Page 8: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

More than 30 gEtOH/day for more that 10 years

Genetic? Environmental?

From Glass To Bed

(~20%)

(~50%) 10-15 yrs

More than 40-80 gEtOH/day for more that 25 years

(~40-60%)

Chronic Alcoholic Hepatitis

Alcoholic Cirrhosis (3%)

Steatosis (90%)

AASLD Guidelines, Hepatology 2010

Page 9: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

M. Rojkind, N.Y., USA C. S. Lieber, N.Y., USAA.M. Jezequel, Ancona, Italy

G. Svegliati Baroni 1994G. Svegliati Baroni 1997, 1999G. Svegliati Baroni 2001, 2005

Page 10: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

PATOGENESI DELLA STEATOSI EPATICA:THE “MULTI-HIT“ THEORY

FIRST HIT SECOND HIT

?

Alterazioni potenziale redox

•Aumentato up-take e sintesi degli ac. grassi•Ridotta escrezione degli ac.grassi•Ridotta beta-ossidazione

Produzione di ROSDeplezione antiossidanti

•Lipoperossidazione •Induzione di citochine•Infiammazione•Apoptosi

THIRD HIT

•Cirrosi

?

Page 11: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Similarities and Differences in the Pathogenesis of Alc oholicand Nonalcoholic Steatohepatitis (Diehl et al., Sem Liv Dis 2009)

Page 12: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

The natural history of ASH appears to be much more ‘‘aggressi ve’’ thanthat of NASH suggesting that ethanol and/or acetaldehyde ma y haveunique roles in steatohepatitis progression.

Acetaldehyde interacts with various molecules to form adducts that haveimmunogenic properties, and it has also been shown to direct ly activatecollagen gene expression in hepatic stellate cells (Svegliati-Baroni G et al.,1993, 1993, 1994, 1997, 2001, 2005, in press).

Ethanol itself disorders lipid membranes and its (nonoxida tive)metabolism also generates fatty acid ethyl esters that may be cytotoxic(Benedetti A et al., 1993, 1995).

Therefore, chronic exposure to ethanol and/or its metaboli tes may furtherchallenge livers that are concomitantly experiencing stre sses related tolipotoxicity, oxidative and ER stress, and exposure to cyto kines andPAMP recognition receptors, exacerbating hepatocyte inju ry and relatedinflammation and fibrogenesis.

Similarities and Differences in the Pathogenesis of Alc oholicand Nonalcoholic Steatohepatitis (Diehl et al., Sem Liv Dis 2009)

Page 13: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Prevalenza della malnutrizione in pazienti alcolisti

Mendenhall 1984

Page 14: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Mettere diapo colline marchigiane + salame + vino

Page 15: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

16%

46%

76%

95%

0%

20%

40%

60%

80%

100%

Steatosis at US

C (n=67)

HD (n=69)

O (n=66)

O+HD (n=55)

Overall Prevalence

58.3%

Fatty Liver in the Dionysos study

(Too much food is worst than too much alcohol !)

Bellentani et al., Ann.Int.Med., 2000

Page 16: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

EXPERIMENTALS MODELS OF ALCOHOLIC LIVER INJURY

Lieber-DeCarli liquid diet Intragastric infusion model

Page 17: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Synergistic steatohepatitis by moderate obesity and alc oholin mice despite increased adiponectin and p-AMPK

Xu et al., J Hepatol 2011

Page 18: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

TLR4 signalling

TR

IF

Proinflammatory cytokinesTNF-αααα , IL-6, IL-12, CXCL1

IKKεεεε

IRF3

IFN-ββββ transcriptionRANTES, CXCL10

JNK

TRAF6

Nucleus

MD2CD14

TLR4

LPS(HMGB1, Hyaluronan)

TIR

AP

TR

AM

IKK

αα αα

IKK

ββ ββIκκκκBαααα

p50 p65

TBK1

NF κκκκB

TAK1

IRA

K4

IRA

K1

MyD

88

AP-1IRF3

MyD88-dependent pathwayMyD88-independent pathway

Seki, De Minicis, Nat Med. 2007

LPS

Page 19: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Antibiotics Prevent Liver Injury in Rats Following Long -term Exposure toEthanol

Adachi et al., Gastroenterology 1995

Page 20: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Enteric Dysbiosis Associated with a Mouse Model ofAlcoholic Liver Disease

Yan et al., Hepatology 2011

Page 21: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Enteric Dysbiosis Associated with a Mouse Model ofAlcoholic Liver Disease

Yan et al., Hepatology 2011

Page 22: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Enteric Dysbiosis Associated with a Mouse Model ofAlcoholic Liver Disease

Yan et al., Hepatology 2011

Page 23: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Endotoxemia and Gut Barrier Dysfunction in Alcoholic Liver

Disease

Rao R. Hepatology 2009

Page 24: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Plasma endotoxin concentration in plasma in patients w ithalcoholic and non-alcoholic liver disease

0

5

10

15

20

25

Controls Fatty liver Alcoholichepatitis

Alcoholiccirrhosis

Non-alcoholiccirrhosis

Fukui et al., J Hepatol 1991

** p < 0.05 vs nonalcoholic cirrhosis

Page 25: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Increased intestinal permeability to macromolecules and endotoxemia in patients

with chronic alcohol abuse in different stages of alcohol-induced liver disease

0

5

10

15

20

25

30

Controls Steatosis Alcoholic

hepatitis

Cirrhosis

Endotoxin (pg/ml)

0

1

2

3

Controls Steatosis Alcoholic

hepatitis

Cirrhosis

% Urine PEG 400 recovery

Perlasek et al., J Hepatol 2000; Urbaschek et al., Alcoholism Clin Exp Res 2001

p < 0.05 vs controls

Page 26: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Endotoxin levels in patients with alcoholic liver cirrhos is and severe portal hypertension without an acute complicatio n

Trebicka et al., Eur JGastroenterol Hepatol 2011

Page 27: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

TLR4 signalling

TR

IF

Proinflammatory cytokinesTNF-αααα , IL-6, IL-12, CXCL1

IKKεεεε

IRF3

IFN-ββββ transcriptionRANTES, CXCL10

JNK

TRAF6

Nucleus

MD2CD14

TLR4

LPS(HMGB1, Hyaluronan)

TIR

AP

TR

AM

IKK

αα αα

IKK

ββ ββIκκκκBαααα

p50 p65

TBK1

NF κκκκB

TAK1

IRA

K4

IRA

K1

MyD

88

AP-1IRF3

MyD88-dependent pathwayMyD88-independent pathway

Seki, De Minicis, Nat Med. 2007

Page 28: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

HFD

ET-OH

Wild-type

Toll-Like Receptor 4 Is Involved in the Mechanism of Early Alcohol-Induced Liver Injuryin Mice

TLR4-/-

Uesugi, Hepatology 2001

Page 29: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Toll-Like Receptor 4 Is Involved in the Mechanism of Early Alcohol-Induced Liver Injury in Mice

Uesugi, Hepatology 2001

Page 30: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Toll-like receptor 4 mediates alcohol-induced steatohepa titis through bonemarrow-derived and endogenous liver cells in mice

Inokuchi, Alcoholism Clin Exp Res 2011

Page 31: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

TLR2: microbial lipopeptides;

TLR4: lipopolysaccharides (LPSs) from Gram-

TLR1/6: triacyl- and diacyllipopeptides;

TLR3: viral double-stranded RNA;

TLR5: bacterial flagellin.

TLR7 and TLR8: viral single-stranded RNA

Differential Liver Sensitization to Toll-like Receptor Pat hways in Mice With AlcoholicFatty Liver

Gustot et al., Hepatology 2006

Page 32: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

1) The administration of broad-spectrumantibiotics reduced the severity of alcohol-induced fatty liver but did not modify alcohol-induced TLR gene expression;

2) ROS from NADPH oxidase increased the severity of alcohol-induced fatty liver and the expression of liver TLRs;

3) Severe steatosis is the visible part of a “first hit” on the liver, combined with anupregulation of TLRs;

4) The administration of microbial products toEtOH-exposed animals may induce the “second hit” on the liver with inflammatoryinfiltrate and satellitosis formation.

Differential Liver Sensitization to Toll-like Receptor Pat hways in Mice With AlcoholicFatty Liver

Gustot et al., Hepatology 2006

Page 33: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

TLR4 signalling

TR

IF

Proinflammatory cytokinesTNF-αααα , IL-6, IL-12, CXCL1

IKKεεεε

IRF3

IFN-ββββ transcriptionRANTES, CXCL10

JNK

TRAF6

Nucleus

MD2CD14

TLR4

LPS(HMGB1, Hyaluronan)

TIR

AP

TR

AM

IKK

αα αα

IKK

ββ ββIκκκκBαααα

p50 p65

TBK1

NF κκκκB

TAK1

IRA

K4

IRA

K1

MyD

88

AP-1IRF3

MyD88-dependent pathwayMyD88-independent pathway

Seki, De Minicis, Nat Med. 2007

Page 34: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice.

0

1

2

3

4

5

6

7

wild-type p75-/- p55-/-

Deg

ree

ofliv

erin

jury

Yin et al., Gastroenterology1999

Page 35: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

TNF-α

Kishoreet al., AJP 2002; Shi et al., AJP 2002 McMullen et al., Gastroenterology 2005

Page 36: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

The Critical Role of Toll-Like Receptor (TLR) 4 in Alcoho lic Liver DiseaseIs Independent of the Common TLR Adapter MyD88

TR

IF

Proinflammatory cytokinesTNF-αααα , IL-6, IL-12, CXCL1

IKKεεεε

IRF3

IFN-ββββ transcriptionRANTES, CXCL10

JNK

TRAF6

Nucleus

MD2CD14

TLR4

LPS(HMGB1, Hyaluronan)

TIR

AP

TR

AM

IKK

αα αα

IKK

ββ ββIκκκκBαααα

p50 p65

TBK1

NF κκκκB

TAK1

IRA

K4

IRA

K1

MyD

88

AP-1IRF3

MyD88-dependent pathwayMyD88-independent pathway

Hritz et al., Hepatology 2008

Page 37: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Ethanol Augments RANTES/CCL5 Expression in Rat Liver Sin usoidal EndothelialCells and Human Endothelial Cells via Activation of NF-B, HIF-1, and AP-1

Yeligar et al., J Immunol 2008

Page 38: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Tilg & Moschen, Hepatology 2010

The Multiple Parallel Hits Hypothesis

Acetaldehyde

Page 39: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Samuel & Shulman, Cell 2012

Page 40: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Synergistic steatohepatitis by moderate obesity and alc oholin mice despite increased adiponectin and p-AMPK

Xu et al., J Hepatol 2011

ER stress markers

Cell deathsignalingmolecules

Page 41: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Epigenetic Regulation of Hepatic Endoplasmic Reticulum St ress Pathways in the Ethanol-Fed Cystathionine Beta Synthase–Deficient Mous e

Esfandiari et al., AJP 2005; Hepatology 2010

Page 42: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog

Machida et al., PNAS 2009

Page 43: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog

Machida et al., PNAS 2009

Page 44: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

A Randomized, Double-Blinded, Placebo-Controlled Mul ti-CenterTrial of Etanercept in the Treatment of Alcoholic Hepat itis

0

10

20

30

40

50

60

Etanercept Placebo

6-months mortality (%)

0

5

10

15

20

25

30

35

40

Etanercept Placebo

Infectious events (%)

Boetticher et al., Gastroenterology2008

Page 45: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Conclusions

• Alcohol consumption leads to increased intestinalpermeability and endotoxemia, which are involved inthe pathogenesis of ALD ;

• Intestinal microflora not only is the source ofcirculating endotoxins but also plays a role in thegeneration and accumulation of acetaldehyde in thecolonic lumen and has a subsequent influence onepithelial barrier dysfunction;

• Gut-liver axis stimuli represents a major second-hitin the pathogenesis of ASH ;

• It is therefore important to delineate the mechanismsinvolved in endotoxin-mediated liver cell injury todesign preventive and therapeutic strategies for thetreatment of ALD .

Page 46: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Ettore Svegliati BaroniCurriculum vitae

Nato: Ancona, 02/05/2012

Comitato Coordinatore AISF2052-2055 ?

Page 47: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Severity of liver injury in experimental alcoholic liver di sease.Correlation with plasma endotoxin, prostaglandin E2,leukotriene B4, and thromboxane B2.

Nanji et al, Am J Pathol 1993

Page 48: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Plasma levels of soluble tumor necrosis factor receptors p 55 and p75 in patients with alcoholic liver disease of increasin g severity

0

1000

2000

3000

4000

5000

6000

7000

Controls Steatosis Fibrosis Cirrhosis Cirrhosis with

AAH

Cirrhosis with

AAH +++

TNFsRp75 (pg/ml)

*

*

Naveau et al., J Hepatol 1998

* *

Page 49: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Synergistic steatohepatitis by moderate obesity and alc oholin mice despite increased adiponectin and p-AMPK

Xu et al., J Hepatol 2011

M1macrophages

M2macrophages

Page 50: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Overall Prevalence DionysosCohort

Liver Disease Prevalence 1992 (%)

Prevalence 2002 (%)

Persistent alteration of liver enzymes (LE)

27.6 27.2

Persistent alteration of LE with fatty liver (FL)

45 42

NAFLD (alcohol intake < 30 g/die)

25 32

AFLD (alcohol intake > 30 g/die)

20 10

Cirrhosis 1.1 1.0

Page 51: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

L’acetaldeide stimola l’espressione del gene per il collagene (COL1A2).

1 3 12 24

1

23

Fol

d in

crea

se

α2(α2(α2(α2(I) ) ) ) collagen mRNA48

4+ Ac

+ Ac+ cyhx

(Time, Hrs)

B

A

ACCONT

TRANSCRIPTION RATEFOLD INCREASE

1 3 5

C

5

G. Svegliati Baroni 1994G. Svegliati Baroni 1997G. Svegliati Baroni 2001, 2005

Page 52: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

1

αα αα2(

I) C

OLL

AG

EN

mR

NA

FO

LD IN

CR

EA

SE

2

3

CONT + AC

+ CTase

4 AC - + - +

+ CTase

αααα2(I)

S14

A B

G. Svegliati Baroni 1994G. Svegliati Baroni 1997G. Svegliati Baroni 2001, 2005

Page 53: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

G. Svegliati Baroni 1994G. Svegliati Baroni 1997G. Svegliati Baroni 2001, 2005

EFFETTO DI SPECIFICI INIBITORI SULLA SINTESI DI COLLAGENE E FIBRONECTINA

Page 54: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

A.M. Jezequel, Ancona, Italy

Page 55: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis
Page 56: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Plasma levels of soluble tumor necrosis factor receptors p 55 and p75 in patients with alcoholic liver disease of increasin g severity

0

500

1000

1500

2000

2500

3000

3500

4000

4500

Controls Steatosis Fibrosis Cirrhosis Cirrhosis with

AAH

Cirrhosis with

AAH +++

TNFsRp55 (pg/ml)

*

*

Naveau et al., J Hepatol 1998

**

Page 57: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

alcohol-induced liver injury is significantly

ameliorated in mice mutated in the TLR4 gene (Hritz et al., 2008; Uesugi et al., 2001).

Downstream of TLR4, adaptor proteins MyD88 and TRIF are activated for transmitting

their

signals. The TRIF-dependent pathway is more important than the MyD88-dependent

pathway in alcohol-induced liver injury after the Lieber-DeCarli diet feeding (Hritz et al.,

2008; Zhao et al., 2008). The TRIF-dependent pathway induces IRF3 activation and TNF-α

production after chronic ethanol treatment (Zhao et al., 2008).

Questo Zhao 2008 può essere importante per talk Milano-Missale

As reported previously, both TLR4 and

Kupffer cells are critical for the development of experimental alcohol-induced

steatohepatitis (Hritz et al., 2008; Uesugi et al., 2001) (Adachi et al., 1994; Koop et al.,

1997)

Page 58: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

ETANOLO ACETALDEIDE ACETATO

NADPH NADP+

ADHBassa Km

NAD+ NADH

ALDHBassa Km

CYP2E1Alta Km

O2-

NAD+ NADH

Aldeide ossidasiXantina ossidasi

Alta Km

O2-

METABOLISMO DELL’ ETANOLO

Page 59: A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a ... · A.I.S.F. MonothematicConference 2012 The Gut-LiverAxis: a bidirectionalrelation in health and disease Alcoholic steatohepatitis

Pathogenesis of alcohol-induced liver disease: classica lconcepts and recent advances (Seth et al., JGH 2011)