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
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
But…specific effects in each GI tract!
EFFECTS OF GUT MICROBIOTA ON HOST HEALTH
Barrier effect Immunocompetence/ToleranceSynthesisMetabolic/Trophic functionDrug methabolismBehavior conditioning
Hashida H et al. Nat Chem Biol 2012
But…specific effects in each GI tract!
EFFECTS OF GUT MICROBIOTA ON HOST HEALTH
Barrier effect Immunocompetence/ToleranceSynthesisMetabolic/Trophic functionDrug methabolismBehavior conditioning
• 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
But…specific effects in each GI tract!
EFFECTS OF GUT MICROBIOTA ON HOST HEALTH
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. …
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
Pathological gut-liver axis
• 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
Hepatobiliary disorders in Celiac disease
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
Hepatobiliary disorders in Celiac disease
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
Pathological gut-liver axis
• 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
Adams and al, Nat Rev Immunol 2006
Recruitment lymphocytes to the liver
Adams and al, Nat Rev Immunol 2007
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
Fibrosis/Portal hypertension
HBV/HCV
HCC
Auto immunity
Encephalopathy/HRS Ascites/PBS/Infections
Alcool NAFLD/NASH
Fibrosis/Portal hypertension
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
Fibrosis/Portal hypertension
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
Li J V et al. Gut 2011
Gut microbiota and Bariatric Surgery
Alcohol NAFLD/NASH
Fibrosis/Portal hypertension
HBV/HCV
HCC
Auto immunity
Encephalopathy Ascites/PBS
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
Fibrosis/Portal hypertension
HBV/HCV
HCC
Auto immunity
Encephalopathy Ascites/PBS
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