asse fegato-intestino: quali le evidenze attuali? - gastrolearning®

Gut-liver axis

Prof. A. GasbarriniUniversità Cattolica Sacro Cuore - Roma

• The gut is populated by commensal mutualistic bacteria with metabolic/immunologic functions

• These mutualistic bacteria live together with low concentrations of pathogen bacteria

• In specific situations (either physiological and pathological), mutualistic bacteria and fragments may translocate to the liver

Gut-liver axis

…LIVER IS CONTINUALLY EXPOSED TO GUT-DERIVED FACTORS INCLUDING BACTERIA AND BACTERIAL

COMPONENTS

70% OF LIVER BLOOD SUPPLY IS THE DIRECT

VENOUS OUTFLOW OF THE INTESTINE

Gut-liver axis

To combat this continuous influx, the liver contains a large number of resident immune cells…

…and other non parenchimal cells:

Kupffer cells Lymphocytes

Endothelial cells and Stellate cells

Liver tolerance to intestinal bacteria

Son G. et al. Gastroenterol Res Pract 2010

Immune System

Diet

GUT Microbiota

Blood flow Intestinal barrier

Liver-gut axis

Physiological condition

ETOH/DRUG

Diet

IBD

HCV/HBV CELIAC DISEASE

Liver-gut axis

Pathological condition

Gut Microbiota and GI and Liver diseases

What’s new?

Gut Barrierand Microbiota

Loosely adherent mucus layer

Firmly adherent mucus layer

Bad bacteria

Good bacteria

Bile acids

Lumen

Ionicreceptors

Water

Stomach

Ileum

Colon

Adhesions molecules

Immune cells

Food antigens

EndotheliumAnd fibroblastsNerve and miocytes

Non-Immune cells

Duodenum and

Jejunum

Acquiredand

Innate immunity

MucosalBarrier

Epithelial barrier

GUT barrier

Vascular and lymphatic systems

Neuroenteric systemDigestive enzymes

Endocrinesystem

Gut Microbiota (bacteria, yeasts, bacteriophages)

Gut MicomeCandida from commensal to pathogen

• Yeasts are commensal to the gut at low concentrations

• Candida overgrowth is a consequence of disturbances in the host’s defense systems: antibiotic therapy and change in physiological gut microbiota, pH, partial CO2 pressure, amino acid availability, iron deficiency…

• Yeast genome can be modified by repeated point mutations («microevolution») in order to overcome host protective measures

Thewes S, Mol Microbiol 2007

Gut Virome Phage-bacteria relationships

Berg Miller et al, Environ Microbiol 2011

Random pyrosequencing of virus-enriched metagenomes have been isolated from bovine rumen

In the bovine rumen have been isolated up to 28.000 different viral genotypes

The majority ( 78%) of sequences did not match any ∼previously described virus

Pro phages outnumbered lytic phages approximately 2:1

Metabolic profiling revealed an enrichment of sequences with putative functional roles in DNA and protein metabolism, but a low proportion of sequences assigned to carbohydrate and amino acid metabolism

Human Gut Virome Inter-individual variation and dynamic response to diet

Minot et al, Genome Res 2011

Immense populations of viruses are present in the human gut and other body sites: the Human “Virome“

Viromes from human subjects on a controlled feeding regimen were assessed: longitudinal fecal samples were analyzed by metagenomic sequencing of DNA from virus-like particles (VLP) and total microbial communities

Parallel deep-sequencing analysis of bacterial populations showed covaration of the virome with the larger microbiome

Inter-individual variations were present and dietary intervention was associated with a change in the virome community to a new

state in which individuals on the same diet converged

Most people share:

1. A core microbiota that comprises 50-100

bacterial species

2. A core microbiome harboring more than

6000 functional gene groups

Human Gut Bacteriomethe Second Genome of human body

Zhu, Protein Cells 2010

Qin J et al, Nature 2010

The

Minimal Core

Gut Genome

And

Metagenome

COMPOSITION OF THE GUT MICROBIOTA:MOLECULAR APPROACH

Eckburg et al, Science 2005

DIET AGE

ORIGIN

BFBacteroidetes>Firmicutes

EUFirmicutes

>Bacteroidetes

De Filippo et al, PNAS 2010

…is related to Diet compositionLey RE et al, Science 2008

The Universe of Gut Microbiota…

HUMAN MICROBIOME PROJECTS: 3 main enterotypes

Enterotypes are identifiable by the variation in the levels of one of three genera:

ENTEROTYPE 1: BacteroidesENTEROTYPE 2: Prevotella ENTEROTYPE 3: Ruminococcus

Arumugam – Nature 2011

Ottmann N et al. Front Cell Infect Microb 2012

Bacterial diversity is affected by ageing

But…specific effects in each GI tract!

EFFECTS OF GUT MICROBIOTA ON HOST HEALTH

Barrier effect Immunocompetence/ToleranceSynthesisMetabolic/Trophic functionDrug methabolismBehavior conditioning

Nell S, Nature 2010

Modified by Balfour Sartor, Gastroenterology 2008

Luminal Mi.AMPs LPS (Gram -) UPEC/Profilin Flagellin Peptidoglican/lipopeptide Bacterial lipopeptide ds RNA Fibronectina (many bacteria) Lipothecoic acid (Gram +) Lipooligosaccharide

Specific PRRs TLR-4 TLR-11 TLR-5 TLR-1 e TLR-2 TLR-2 e TLR-6 TLR-3 α5β1 integrin TLR-2 PAF

Endosomial Mi.AMPs ss RNA CpG DNA

Specific PRRsTLR-6 e TLR-7TLR-9

Microbiota stimulates IMMUNITY throught PRRs

Hospital deliveries, caesarean sections, special-care baby unit admissions, smaller family size, widespread use of antibiotics, good hygiene, nature of the maternal diet..

Lack of exposure of babies to Bifidobacterial species and/or elimination of bifidobacterial species from the bowel (antibiotic therapy) could lead to an umbalance maturation of the immune system (lack of Th2 response removal: immune deviation)

“Immunological Freudianism”Tannock, Semin Immunol 2007

Infant Gut Microbiota composition is crucial for IMMUNOLOGICAL EDUCATION

Hashida H et al. Nat Chem Biol 2012

• Gut microbiota is an excellent anaerobic energetic bioreactor

• Consumes, stores and redestributes energy

• Allows us to extract calories from otherwise indigestible carbohydrates

METABOLOMA

Metabolic function of GUT microbiota

GUT microbiota has a powerful metabolic action in ruminants: herbivores derive 70% of their energy intake from microbial breakdown of

dietary plant polysaccharides

HJ Flint et al. Nature Review Microbiol 2008Brulc et a al, PLoS ONE 2011

Metabolic functions of GUT microbiota in humans

1. Harvest calories from complex polysaccharides trought production of short chain fatty acids (SCFA) and monosaccharydes

2. Affects lipid storage and metabolism (also through SCFA)

3. Affects food metabolism

SCFA produced by microbiota affects lipid storage

Tilg H, Gatroenterology 2009

2. Gpr41/42 activation blocks epithelial expression of fasting-induced adipocyte factor (Fiaf), a circulating LPL inhibitor

1. SCFA bind to the G-protein coupled receptors Gpr41 and Gpr42

Diamant M et al., Ob Rev 2010

The “Second Meal” effect

25.000 Genes

2500 Enzymes

1400 Chemicals

Metabolomics

Proteomics

Genomics

PYRAMID OF LIFE: human body

Kau et al, Nature 2011 Qin et al, Nature 2011

>3.000.000 Genes

>58.000 Enzymes

>25.000 Chemicals

Metabolomics

Proteomics

Genomics

PYRAMID OF LIFE: human gut microbiota

Kau et al, Nature 2011 Qin et al, Nature 2011

Ibrahim M et al, Bioch Bioph Res Comm 2012

The gut microbiota plays an essential role in the catabolism of dietary fibers into metabolizable monosaccharides and disaccharides. Dietary fibers have been identified as strong, positive dietary factors in the prevention of obesity.

Angelakis E et al, Future Microbiol 2012

Diet, microbiota, and the epithelial cell: the ‘‘NUTRIENT SENSOR pathway’’

Tilg H, J Hepatology 2010

Gut microbiota has a role in obesity

Changes in gut microbial ecology• Reduction in Bacteroidetes and proportional increase in Firmicutes• Dramatic fall of overall diversity• Bloom of a single class of Firmicutes: the MollicutesAlteration of metabolic potential• Enrichment for phosphotransferase systems: import and fermentation

of sugars• Enrichment for genes encoding beta-fructosidases Consequences• Increased capacity to import “Western-diet”-typical carbohydrates • Increased capacity to metabolize imported sugars

Tilg H, Gatroenterology 2009

The CORE GUT MICROBIOME of OBESE

Obesity is associated with reduced bacterial diversity, phylum-level changes in the microbiota and altered representation of bacterial genes and metabolic pathways

BACTEROIDETES/ FIRMICUTES: adiposity index

Turnbaugh – Nature 2009

obesecontrol

Hyperinsulinemic clampS.I. biopsiesFecal samples

ALLOGENIC (9)

AUTOLOGOUS (9)

Hyperinsulinemic clampS.I. biopsiesFecal samples

Gut Microbiota infusion

Random6 wks

Allogenic Autologous

improvement in

peripheral insulin

sensitivity after allogenic

gut microbiota infusion

and a trend toward

improvement in hepatic

insulin sensitivity



Barrier effect Immunocompetence/ToleranceSynthesisMetabolic/Trophic functionDrug metabolismBehavior conditioning

Mutualistic bacteria influence:

1. Drug bioavailability

GUT microbiota and drug/toxin metabolism

Different effects of commonly used therapeutics in different geographic and cultural populations

PharmacogeneticsPharmacometabonomics

TyroxineL-Dopa

Tilg et al, J Clin Inv 2011 Cennamo et al, New Eng J Med 2010

Gut Barrier and Microbiotain GI and Liver diseases

HOW THE GUT BARRIER-MICROBIOTA BALANCE IS MANTAINED?

Secretion of : Gastric acidMucus/Biliary saltsMucosal Ig

Mucosal pH Mucosal barrier integrity Intestinal motility Local mucosal and systemic immunity Interactions among different bacteria species Balanced diet

When these mechanisms fail…

Quali-quantitative alterations of gastric, small bowel and/or colonic microbiota

Bacterial Overgrowth/Reduction (DYSBIOSIS)

...GI, Liver and Systemic-associated diseases

Live bacteria or bacterial fragments translocate in portal and sistemic circulation

Gut Barrier dysfunction

Intestinal permeability (Leaky gut)

All these events occur during GI

and Liver Diseases

Damage of liver resident immune cells

Gastric acid barrier

damage

Local mucosal and

systemic immunity

alterations

Intestinal barrier

disruption (leaky gut)

Gastro-intestinal and Liver diseases associated to GUT Microbiota

1. Autoimmune Enteropathy and Celiac disease2. Inflammatory Bowel Diseases3. GI Cancer4. Irritable Bowel Syndrome 5. Intestinal Bacterial Overgrowth6. Food Intolerance7. Obesity and Metabolic Syndrome8. Liver Diseases progression and complications9. …

Immune system

Pathological gut-liver axis

• Hepatic injury

Autoimmune enteropathy (celiac disease and IBD)

GALT FUNCTIONS

Antigen presentation

Immunosurveillance Immunotolerance

infections allergies

• Apoptotic intestinal cells antigens

• Food antigens• Microbiota

antigens

• Pathogen antigens

Self-antigen toleranceImmunity response

GALT FUNCTIONS

Antigen presentation

Immunosurveillance Immunotolerance

infections allergies

• Apoptotic intestinal cells antigens

• Food antigens• Microbiota

antigens

• Pathogen antigens

Self-antigen toleranceImmunity response

Celiac disease

Immune system


• Hepatic injury

Celiac disease

Hepatobiliary disorders in Celiac disease

Volta U, Clin Rev Allerg Immunol 2008

1. Cryptogenetic liver disorders (celiac hepatitis) Non specific reactive generally mild histological hepatitis

2. Associated to “autoimmune liver disorders”Primary biliary cirrhosis (3-7%)Primary sclerosing cholangitis (2-3%)Autoimmune hepatitis (3-6%)

Usually reverts to normal after gluten-free diet

Usually does not improve after gluten-free diet


Ludvigsson et al, Clin Gatroenterol Hepatol 2007

Search for association of CD with liver diseases

13800 CD vs 66000 matched controls

CD was associated with an increase risk of:

Acute hepatitis HR 5.21Chronic hepatitis HR 5.84PSC HR 4.46PBC HR 10.16Fatty liver HR 6.06Cirrhosis HR 2.23


Rubio Tapia et al, Hepatology 2007

Pathogenesis of Hepatobiliary disorders in Celiac disease

Volta U, Clin Rev Allerg Immunol 2008

1. Genetic predisposition

2. Intestinal inflammation (anti-tTG reach transglutaminase 2)

3. Malabsorption and long-standing malnutrition

4. Small Bowel Bacterial overgrowth with increase in bacterial antigen pool and enzymatic neoantigen production

5. Increased intestinal permeability with arrival of toxins and antigens in the hepatobiliary system (transglutaminase 2 are also present in the liver)

Immune system


• Hepatic injury

Inflammatory Bowel Diseases

Hepatobiliary disorders in IBD

Baumgart D, World J Gastroenterol 2008

Immune system

What is new on hepatobiliary disorders in IBD?

• Hepatic injury

Better understanding of immune liver-gut cross-talk

Life style (smoking,diet, stress),

gut microbiota

Immune system disregulation

Dietary, pathogens,

drugs…

Genetic predisposition

IBD

Recruitment lymphocytes to the liver

The adhesion molecules are expressed at low level

However, MadCAM-1 and CCL25 are not expressed

Normal liver

Adams and al, Nat Rev Immunol 2006

Increase of adhesion molecules expression

Induction of MadCAM-1 and CCL25 expression

During inflammatory bowel disease


Recruitment lymphocytes to the liver


Recruitment by the liver of activated gut specific T-cells

Abnormal flow of intestinal antigens crossing altered

mucosal barrier

Liver injury

Abnormal activation of gut specific T-cells

Hepatic damage in intestinal diseases

Gastro-intestinal and Liver diseases associated to GUT Microbiota

1. Autoimmune Enteropathy and Celiac disease2. Inflammatory Bowel Diseases3. GI Cancer4. Irritable Bowel Syndrome 5. Intestinal Bacterial Overgrowth6. Food Intolerance7. Obesity and Metabolic Syndrome8. Liver Diseases progression and complications9. …

Alcohol NAFLD

HBV/HCV

Autoimmune

Fibrosis/Portal hypertension

Hepatic Encephalopathy

Ascites/PBS

Liver-gut axis derangement

HRSInfections

HCCBleeding

CBP/CSP

Drug

Alcool NAFLD/NASH


HBV/HCV

HCC

Auto immunity

Encephalopathy/HRS Ascites/PBS/Infections

Bacterial or bacterial antigens traslocation

Intestinal bacterial overgrowth

Increased intestinal permeability

Pathological liver-gut axis

Portal hypertension

LPS translocation in the portal bloodstream could activate hepatic fibrosis

Gomez Hurtado I et al, PLoS ONE 2011 Seki et al, J Physiol 2011Thalheimer et al., Eur J Gastroenterol Hepatol 2010

Seki E et al Hepatology 2009

Intestinal bacterial LPS activates Toll-Like receptor 4 on hepatic stellate cells

TGF-b signaling and liver fibrosis

Results: Reduction of hepatic fibrogenesis

and macrophage infiltration in TLR4-

mutant mice

Collagen Deposition

Expression of alpha-SMA

Macrophage infiltration

TLR4-mutant mice

Seki E et al. Hepatology 2009

Bacterial or bacterial antigens traslocation

Intestinal bacterial dysbiosis/overgrowth

Increased intestinal permeability

Pathological liver-gut axis

Portal hypertension

PBS

Cachexia

SepsisEndotoxemia

Hyperdynamic circulatory state

149 predominant taxonomic units in cirrhotics

To analyze fecal microbial community was analyzed by way of 454 pyrosequencing of the 16S ribosomal RNA V3 region followed by real-time quantitative polymerase chain reaction

Chen et al.

Hepatol 2011

Alcool NAFLD/NASH


HBV/HCV

HCC

Auto immunity

Encephalopathy Ascites/PBS

De Gottardi A, J Hepatology 2011

GUT microbiota and NAFLD

Colonization of germ-free mice with a microbial population from obese mice stimulates triglyceride

synthesis and glycogenesis in the liver

Delzenne et al., Nat Rev Endocrinol 2011Abu-Shanab et al., Nat Rev Gast Hep 2011

Tilg H, J Hepatology 2010

HIGH-FAT OR HIGH-CARBOHYDRATE DIET IN HUMANS:• ↓ Bifidobacteria• ↓ Genes coding for tight junction

proteins (↑ intestinal permeability, ↑ circulating LPS concentrations and ↑ Endotoxiemia )

The consumption of trans-fatty acids has increased dramatically in the last decades and mice fed trans-fatty acids develop larger livers with NASH-like lesions and insulin resistance

GUT microbiota and NAFLD/NASH

Frazier TH, J Parent Ent Nutrition 2011

Cani et al, Pharm Ther 2010Miele and Gasbarrini, Hepatology 2009Scarpellini and Gasbarrini, Am J Gastro 2010

GUT HYPERPERMEABILITY LEADS TO METABOLIC ENDOTOXEMIA

Zhu L et al., Hepatology 2012

The Gut microbiome in NASH

Three groups of children/adolescents (12-14 yrs) were recruited in this study: NASH patients (22)Obese patients (25) Nealthy controls (16)

Abundance of alcohol producing bacteria in NASH microbiome: the elevated blood ethanol concentration in NASH and the well-established role of alcohol metabolism in oxidative stress and liver inflammation, suggest a role for alcohol producing microbiota in the pathogenesis of NASH

Zhu L et al., Hepatology 2012

Characterization of the gut microbiome in NASH an endogenous alcohol-ptroducing microbiota

Canì, Diabetes 2010

Hypothesis for bacteria-induced metabolic disease

High Fat Diet

Change Microbiota

Increased permeability

PAMPs absorption

Endotoxemia

Inflammation

Metabolic disorders

Ist HIT

IInd HIT

Li J V et al. Gut 2011

Gut microbiota and Bariatric Surgery

Alcohol NAFLD/NASH


HBV/HCV

HCC

Auto immunity


Alcohol and gut

Szabo G et al. Dig Dis 2010

Alcohol and Gut

Szabo G et al. Dig Dis 2010

Alcohol causes disruption of tight junction protein,

ZO-1

Ethanol decreases transepithelial

electrical resistance (TEER) in gut epithelial

cells

Alcohol and gut-liver axis: Ist HIT

Schaffert CS World J Gastroenterol 2009 Tilg H et al. J Hepatology2011

DIRECT DAMAGE

↓ Anti-inflammatory activity of adiponectin

DAMAGE BY ETHANOL METABOLITES

Alcohol and gut-liver axis: IInd HIT

Schaffert CS World J Gastroenterol 2009 Tilg H et al. J Hepatology2011

Ethanol damages gut barrier

↓ phagocitic activity of

Kupffer cells

Ethanol inducesSIBO and microbiota

modifications

DAMAGE BY BACTERIAL PRODUCTS

Alcohol NAFLD/NASH


HBV/HCV

HCC

Auto immunity


Jalan R J Hepatol 2010

1. Might microbiota be modulated in liver disease?

2. Could microbiota modulation be safe and effective in liver disease?

Diet and Nutritional SupportCaloric amount, minerals, vitamins

Diet composition (low fat and red meat, high fibers..)

Removal of predisposing conditionsTreat diabetes, endocrine, other motility disorders..Surgery or prokinetics when indicated

Stop PPI/antiacid, immunosoppressants or other drugs that affect motility or the immune system..

Drugs AntibioticsBiotherapy

GUT MICROBIOTA MODULATION

TOPIC: rifaximin…SYSTEMIC: nitroimidazolics, fluoroquinolones…

ANTIBIOTICS FOR DYSBIOSIS in chronic liver diseases

BIOTHERAPY FOR DYSBIOSIS in chronic liver diseases

BCAAs, lactulose, probiotics, prebiotics, microbiota infusion…

Clinical indication:hepatic encephalopathy, SBP, NAFLD…

Kawaguchi T et al. WJG 2012

Recurrence of HE: 22.1% (31 of 140) rifaximin vs. 45.9% (73 of 159) placebo pts

Incidence of recurrent HE: reduced by 58%

Hospitalization due to HE: reduced by 50% (13.6% rifaximin pts vs. 22.6% placebo pts)

No major adverse events were noted in the rifaximin group. The mortality rate was the same in the two groups.

299 pts history of HE, RCT (multicenter, double-blind, placebo-controlled)

550 mg twice daily for 6 months (90% + lactulose)

BACKGROUND: MHE patients have an increased risk of driving offenses and have poor insight into their driving skills.

AIM: study the effect of RIFAXIMIN 550 MG twice a day on driving performance using a driving simulator; Secondary outcomes studied were cognitive performance, quality of life, and change in the systemic inflammatory milieu and neuroglial function markers.

METHODS: RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROL

RIFAXIMIN 550 MG TWICE A DAY for 8 WEEKSNumber of patient: 42

n of speeding tickets n of illegal turns

= n of collisions

Reduction of driving errors

219 Patients (multicentric RCT) with cirrhosis in remission from HE and with documented history of recurrent HE episodes rifaximin 550 mg twice daily (N = 101) or placebo (N = 118) for 6 months

Rifaximin… A matter of budget?

Rifaximin costs more than lactulose:$1120 vs $150 per month in the USA

Rifaximin… A matter of budget?

Rifaximin costs more than lactulose:$1120 vs $150 per month in the USA

…however, the total annual costing of rifaximin has been reported to be less than lactulose when

hospital admissions are taken into account

Recurrence of HE: 22.1% (31 of 140) rifaximin vs. 45.9% (73 of 159) placebo pts

Incidence of recurrent HE: reduced by 58%

Hospitalization due to HE: reduced by 50% (13.6% rifaximin pts vs. 22.6% placebo pts)

No major adverse events were noted in the rifaximin group. The mortality rate was the same in the two groups.

299 pts history of HE, RCT (multicenter, double-blind, placebo-controlled)

550 mg twice daily for 6 months (90% + lactulose)

Meta-analysis of 14 RCT (650 pts) +3 cohort studies (161 pts):

Rifaximin vs. other antibiotics

Rifaximin vs. non-absorbable disaccharides

Lawrence KR Klee JA. Pharmacotherapy 2008

• more effective • better tolerated • less frequent and shorter

hospitalization

• more effective

• Prophylactic, first or second-line treatment?

• Emergence of resistance?

• Drug interactions?

Rifaximin in HE:Open issues

Resistant bacteria disappear after a 5 day course, but data after long term teratment

are not present at this time

Resistance to rifaximin is by chromosomal alteration in the DNA-dependent RNA polymerase

It is NOT plasmid-mediated: NOT TRASMITTABLE

Scarpignato C et al. Digestion 2006http://www.fda.gov

Clinically significant drug interactions are not significant with rifaximin

Rifaximin undergoes efflux through P-glycoprotein and does not have interactions with other substrates for the P-glycoprotein

Even at concentrations of 200 ng/mL, rifaximin did not inhibit cytochrome P450; in vitro the ability to induce cytochrome P450 3A4 was half that of rifampin

200 mg 3 times daily did not alter the pharmacokinetics of oral midazolam; 550 mg three times daily for 7-14 days only slightly (10%) reduces midazolam exposure

No dose adjustment is recommended when rifaximin is coadministered with other drugs

http://www.fda.gov

..however: caution in severe cirrhotics (>>>Child-Pugh C)

because rifaximin plasma concentrations could reach as high as 10 ng/mL

compared to only 1 ng/mL in controls

http://www.fda.gov

PRO/PRE-BIOTICS: a role in cirrhosis?

• To preserve the natural biological balance of the intestinal

tract

• To modulate the growth of other groups of bacteria

• To stabilize the intestinal mucosal barrier

• To stimulate host resistance to infection

• To reduce the “negative” relationship between portal

hypertension and both local and systemic hemodynamic

alterations

• To prevent and/or correct HE

Cesaro C et al., Dig Liv Dis 2011

An improvement in the hemodynamic

parameters of portal circulation with a

modification ofmicrobiota and a

reduction in plasma endotoxin

Improvement of liver

function

Most used in studies have been Lactobacilli and Bifidobacteria (move with much more difficulty trough intact epithelium)

Prevention of infections

This result was attributed to the

restoration of normal bacterial flora in the

gut, resulting inlower absorption of

toxic metabolites and endotoxins in treated

patients

Results similar to lactulose during the

treatment periodand the maintenance

of the therapeutic effect during the

wash-out period only in the group treated

with probiotics

HETHE RISK OF TRASLOCATION…

Cesaro C et al., Dig Liv Dis 2011

PRO/PRE-BIOTICS: a role in cirrhosis?

…a role for probiotics in liver disease?

Single strainMultistrainBacteriaYeastLiveHeat inacivatedSporeVegetative form

SafetyStabilityDietaryIntegratorsDrugsDosageDurationWay of administration

?

Summary Liver-gut axis derangements

Cerf-Bensussan N al, Nat Rev Immunol. 2010

•Enteriti autoimmuniCeliachiaIBD

•Alterazione quali/quantitativa del GUT microbiota

Obesita’ e sindrome metabolicaNAFLD/NASH

Patologia intestinale epatica

• Il progredire di una epatopatia si associa a alterazioni della barriera intestinale e del GUT microbiota

1.Ipertensione portale con stasi venosa tissutale e alterata permeabilita’ intestinale

2.Alterazioni quali/quantitativa del GUT microbiota

3.Traslocazione di batteri (mutualisti e patogeni) e di loro frammenti

Patologia epatica intestinale

•Alterazione quali/quantitativa del GUT microbiotaEncefalopatia porto-sistemica

•Traslocazione di batteri (mutualisti e patogeni) e loro frammenti1. Ascite e ascite refrattaria2. Peritonite Batterica Spontanea3. Infezioni sistemiche 4. Cofattore nella progressione della fibrosi5. Cofattore nello sviluppo di HCC

Patologia epatica intestinale

Ist HIT: patologia primitiva del fegato (virus, ETOH, steatosi…)

Progressione dell’epatopatia e sviluppo di complicanze

IInd HIT: disbiosi, iperpermeabilita’ intestinale, traslocazione di batteri e

frammenti batterici

A dinner platefrom OUR point of view…

Dutton RK Turnbugh PJ, Curr Opin Clin Nutr Metab Care 2012

...A dinner plate from a METAGENOMIC point of view

Dutton RK Turnbugh PJ, Curr Opin Clin Nutr Metab Care 2012

Ellagic acid Coffee fiberPolyphenols

Starch Polysaccharides Oligosaccharides

SCFAs (acetate, butyrate, propionate, succinate)Inulin

Fructans Soy

Isoflavones Glucosinolates Xanthohumol Porphyrans

Lignans SCFA

PhosphatidylcholineHeterocyclic amines

Nitrosamines Amino acids

Bacteria from foodsProbiotics

PRODUCTS

asse fegato-intestino: quali le evidenze attuali? - gastrolearning®

Education

gutliver axisthe gut

gut micomecandida

gutliver axis70

gutliver axisprof

inphysiological gut

gut barrierand microbiota

human gut bacteriome

gut microbiotaand gi