Asse fegato-intestino: quali le evidenze attuali? - Gastrolearning®

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Asse fegato-intestino: quali le evidenze attuali? - Prof. A. Gasbarrini (Università Cattolica Sacro Cuore - Roma)

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Asse fegato-intestino: quali le evidenze attuali? - Gastrolearning®

  1. 1. Gut-liver axis Prof. A. Gasbarrini Università Cattolica Sacro Cuore - Roma
  2. 2. Gut-liver axis •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
  3. 3. Gut-liver axis 70% OF LIVER BLOOD SUPPLY IS THE DIRECT VENOUS OUTFLOW OF THE INTESTINE…LIVER IS CONTINUALLY EXPOSED TO GUT-DERIVED FACTORS INCLUDING BACTERIA AND BACTERIAL COMPONENTS
  4. 4. Liver tolerance to intestinal bacteria To combat this continuous influx, the liver contains a large number of resident immune cells…Kupffer cells Lymphocytes …and other non Endothelial cells parenchimal and Stellate cells cells: Son G. et al. Gastroenterol Res Pract 2010
  5. 5. Liver-gut axis Blood flow Intestinal barrier DietImmune System GUT Microbiota Physiological condition
  6. 6. Liver-gut axisHCV/HBV CELIAC DISEASE DietETOH/DRUG IBD Pathological condition
  7. 7. Gut Microbiotaand GI and Liver diseases What’s new?
  8. 8. Gut Barrierand Microbiota
  9. 9. Bile Bad Good Water acids bacteria bacteria Colon Loosely Lumen Food adherent antigens Ileum mucus layer Stomach Duodenum and Firmly adherentptors Jejunum mucus layer Adhesions molecules Non-Immune Endothelium Immune cells And fibroblasts Nerve and miocytes cells
  10. 10. GUT barrier Gut Microbiota (bacteria, yeasts, bacteriophages) Mucosal Barrier AcquiredEpithelial and barrier Innate immunityEndocrine system Vascular and Neuroenteric system lymphatic systems Digestive enzymes
  11. 11. Gut Micome Candida 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
  12. 12. Gut Virome Phage-bacteria relationshipsRandom pyrosequencing of virus-enriched metagenomes havebeen isolated from bovine rumenIn the bovine rumen have been isolated up to 28.000 differentviral genotypesThe majority (∼78%) of sequences did not match any previouslydescribed virusPro phages outnumbered lytic phages approximately 2:1Metabolic profiling revealed an enrichment of sequences withputative functional roles in DNA and protein metabolism, but alow proportion of sequences assigned to carbohydrate andamino acid metabolism Berg Miller et al, Environ Microbiol 2011
  13. 13. Human Gut ViromeInter-individual variation and dynamic response to dietImmense populations of viruses are present in the human gutand other body sites: the Human “Virome“Viromes from human subjects on a controlled feeding regimenwere assessed: longitudinal fecal samples were analyzed bymetagenomic sequencing of DNA from virus-like particles (VLP)and total microbial communitiesParallel deep-sequencing analysis of bacterial populationsshowed covaration of the virome with the larger microbiomeInter-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 Minot et al, Genome Res 2011
  14. 14. Human Gut Bacteriome the Second Genome of human bodyMost people share:1. A core microbiota that comprises 50-100 bacterial species2. A core microbiome harboring more than 6000 functional gene groups Zhu, Protein Cells 2010
  15. 15. TheMinimal CoreGut Genome AndMetagenomeQin J etal, Nature 2010
  16. 16. COMPOSITION OF THE GUT MICROBIOTA: MOLECULAR APPROACH Eckburg et al, Science 2005
  17. 17. BFBacteroidetes>Firmicutes EU Firmicutes>Bacteroidetes De Filippo et al, PNAS 2010
  18. 18. The Universe of Gut Microbiota……is related to Diet composition Ley RE et al, Science 2008
  19. 19. HUMAN MICROBIOME PROJECTS: 3 main enterotypesEnterotypes are identifiable by the variation in the levelsof one of three genera:ENTEROTYPE 1: BacteroidesENTEROTYPE 2: PrevotellaENTEROTYPE 3: Ruminococcus Arumugam – Nature 2011
  20. 20. Bacterial diversity is affected by ageing Ottmann N et al. Front Cell Infect Microb 2012
  21. 21. EFFECTS OF GUT MICROBIOTA ON HOST HEALTHBarrier effectImmunocompetence/ToleranceSynthesisMetabolic/Trophic functionDrug methabolismBehavior conditioning But…specific effects in each GI tract!
  22. 22. EFFECTS OF GUT MICROBIOTA ON HOST HEALTHBarrier effectImmunocompetence/ToleranceSynthesisMetabolic/Trophic functionDrug methabolismBehavior conditioning But…specific effects in each GI tract!
  23. 23. Nell S, Nature 2010
  24. 24. Microbiota stimulates IMMUNITY throught PRRs Luminal Mi.AMPs Specific PRRs  LPS (Gram -) TLR-4  UPEC/Profilin TLR-11  Flagellin TLR-5  Peptidoglican/lipopeptide TLR-1 e TLR-2  Bacterial lipopeptide TLR-2 e TLR-6  ds RNA TLR-3  Fibronectina (many bacteria) α5β1 integrin  Lipothecoic acid (Gram +) TLR-2  Lipooligosaccharide PAF Endosomial Mi.AMPs Specific PRRs  ss RNA TLR-6 e TLR-7  CpG DNA TLR-9 Modified by Balfour Sartor, Gastroenterology 2008
  25. 25. Infant Gut Microbiota composition is crucial for IMMUNOLOGICAL EDUCATIONHospital deliveries, caesareansections, special-care baby unitadmissions, smaller familysize, widespread use ofantibiotics, good hygiene, nature ofthe 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
  26. 26. EFFECTS OF GUT MICROBIOTA ON HOST HEALTHBarrier effectImmunocompetence/ToleranceSynthesisMetabolic/Trophic functionDrug methabolismBehavior conditioning But…specific effects in each GI tract!
  27. 27. Hashida H et al. Nat Chem Biol 2012
  28. 28. EFFECTS OF GUT MICROBIOTA ON HOST HEALTHBarrier effectImmunocompetence/ToleranceSynthesisMetabolic/Trophic functionDrug methabolismBehavior conditioning But…specific effects in each GI tract!
  29. 29. Metabolic function of GUT microbiota•Gut microbiota is an excellent anaerobicenergetic bioreactor•Consumes, stores and redestributes energy•Allows us to extract calories fromotherwise indigestible carbohydrates METABOLOMA
  30. 30. GUT microbiota has a powerful metabolic action in ruminants: herbivores derive 70% of their energy intake from microbial breakdown of dietary plant polysaccharides Brulc et a al, PLoS ONE 2011 HJ Flint et al. Nature Review Microbiol 2008
  31. 31. Metabolic functions of GUT microbiota in humans1. Harvest calories from complex polysaccharides trought production of short chain fatty acids (SCFA) and monosaccharydes2. Affects lipid storage and metabolism (also through SCFA)3. Affects food metabolism
  32. 32. SCFA produced by microbiota affects lipid storage1. SCFA bind tothe G-proteincoupledreceptors Gpr41and Gpr422. Gpr41/42activationblocks epithelialexpression offasting-inducedadipocyte factor(Fiaf), acirculating LPLinhibitor Tilg H, Gatroenterology 2009
  33. 33. The “Second Meal” effect Diamant M et al., Ob Rev 2010
  34. 34. PYRAMID OF LIFE: human body Metabolomics 1400 Chemicals Proteomics 2500 Enzymes Genomics 25.000 GenesKau et al, Nature 2011 Qin et al, Nature 2011
  35. 35. PYRAMID OF LIFE: human gut microbiota Metabolomics >25.000 Chemicals Proteomics >58.000 Enzymes Genomics >3.000.000 Genes Kau et al, Nature 2011 Qin et al, Nature 2011
  36. 36. The gut microbiota plays an essential rolein the catabolism of dietary fibers intometabolizable monosaccharides anddisaccharides. Dietary fibers have beenidentified as strong, positive dietary factorsin the prevention of obesity. Angelakis E et al, Future Microbiol 2012 Ibrahim M et al, Bioch Bioph Res Comm 2012
  37. 37. Diet, microbiota, and the epithelial cell: the ‘‘NUTRIENT SENSOR pathway’’Tilg H, J Hepatology 2010
  38. 38. Gut microbiota has a role in obesityChanges 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 ofsugars• Enrichment for genes encoding beta-fructosidasesConsequences• Increased capacity to import “Western-diet”-typical carbohydrates• Increased capacity to metabolize imported sugars Tilg H, Gatroenterology 2009
  39. 39. The CORE GUT MICROBIOME of OBESEObesity is associated control obesewith reducedbacterial diversity,phylum-level changesin the microbiotaand alteredrepresentationof bacterial genesandmetabolic pathwaysBACTEROIDETES/ FIRMICUTES: adiposity index Turnbaugh – Nature 2009
  40. 40. Hyperinsulinemic clamp ALLOGENIC (9) Hyperinsulinemic clampS.I. biopsies Random S.I. biopsies 6 wksFecal samples AUTOLOGOUS (9) Fecal samples Gut Microbiota infusion improvement in peripheral insulin sensitivity after allogenic Allogenic Autologous gut microbiota infusion and a trend toward improvement in hepatic insulin sensitivity
  41. 41. EFFECTS OF GUT MICROBIOTA ON HOST HEALTHBarrier effectImmunocompetence/ToleranceSynthesisMetabolic/Trophic functionDrug metabolismBehavior conditioning But…specific effects in each GI tract!
  42. 42. GUT microbiota and drug/toxin metabolism Mutualistic bacteria influence:1. Drug bioavailabilityDifferent effects of commonly used therapeutics indifferent geographic and cultural populations PharmacogeneticsPharmacometabonomics Tyroxine L-DopaTilg et al, J Clin Inv 2011 Cennamo et al, New Eng J Med 2010
  43. 43. Gut Barrier and Microbiota in GI and Liver diseases
  44. 44. HOW THE GUT BARRIER-MICROBIOTA BALANCE IS MANTAINED? Secretion of : Gastric acid Mucus/Biliary salts Mucosal Ig Mucosal pH Mucosal barrier integrity Intestinal motility Local mucosal and systemic immunity Interactions among different bacteria species Balanced diet
  45. 45. When these mechanisms fail… Quali-quantitative alterations of gastric, small bowel and/or colonic microbiotaBacterial Overgrowth/Reduction (DYSBIOSIS)Live bacteria or bacterial fragments translocate in portal and sistemic circulation ...GI, Liver and Systemic-associated diseases
  46. 46. Gut Barrier dysfunctionIntestinal permeability (Leaky gut)
  47. 47.  Damage of liver resident immune cells Gastric acid barrier damage All these events Local mucosal and occur during GI systemic immunity and Liver alterations Diseases Intestinal barrier disruption (leaky gut)
  48. 48. Gastro-intestinal and Liver diseases associated to GUT Microbiota1. Autoimmune Enteropathy and Celiac disease2. Inflammatory Bowel Diseases3. GI Cancer4. Irritable Bowel Syndrome5. Intestinal Bacterial Overgrowth6. Food Intolerance7. Obesity and Metabolic Syndrome8. Liver Diseases progression and complications9. …
  49. 49. Gastro-intestinal and Liver diseases associated to GUT Microbiota1. Autoimmune Enteropathy and Celiac disease2. Inflammatory Bowel Diseases3. GI Cancer4. Irritable Bowel Syndrome5. Intestinal Bacterial Overgrowth6. Food Intolerance7. Obesity and Metabolic Syndrome8. Liver Diseases progression and complications9. …
  50. 50. Pathological gut-liver axis Autoimmune enteropathy (celiac disease and IBD)Immune system • Hepatic injury
  51. 51. GALT FUNCTIONS • Apoptotic intestinal• Pathogen antigens cells antigens • Food antigens • Microbiota antigens Antigen presentationImmunity response Self-antigen tolerance Immunosurveillance Immunotolerance   infections allergies
  52. 52. GALT FUNCTIONS • Apoptotic intestinal• Pathogen antigens cells antigens • Food antigens • Microbiota antigens Antigen presentationImmunity response Self-antigen tolerance Immunosurveillance Celiac Immunotolerance   disease infections allergies
  53. 53. Pathological gut-liver axis Celiac diseaseImmune system • Hepatic injury
  54. 54. Hepatobiliary disorders in Celiac disease1. Cryptogenetic liver disorders (celiac hepatitis) Non specific reactive generally mild histological hepatitis Usually reverts to normal after gluten-free diet2. Associated to “autoimmune liver disorders” Primary biliary cirrhosis (3-7%) Primary sclerosing cholangitis (2-3%) Autoimmune hepatitis (3-6%) Usually does not improve after gluten-free diet Volta U, Clin Rev Allerg Immunol 2008
  55. 55. Hepatobiliary disorders in Celiac disease 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 5.21 Chronic hepatitis HR 5.84 PSC HR 4.46 PBC HR 10.16 Fatty liver HR 6.06 Cirrhosis HR 2.23 Ludvigsson et al, Clin Gatroenterol Hepatol 2007
  56. 56. Hepatobiliary disorders in Celiac disease Rubio Tapia et al, Hepatology 2007
  57. 57. Pathogenesis of Hepatobiliary disorders in Celiac disease1. Genetic predisposition2. Intestinal inflammation (anti-tTG reach transglutaminase 2)3. Malabsorption and long-standing malnutrition4. Small Bowel Bacterial overgrowth with increase in bacterial antigen pool and enzymatic neoantigen production5. Increased intestinal permeability with arrival of toxins and antigens in the hepatobiliary system (transglutaminase 2 are also present in the liver) Volta U, Clin Rev Allerg Immunol 2008
  58. 58. Pathological gut-liver axisInflammatory Bowel DiseasesImmune system • Hepatic injury
  59. 59. Hepatobiliary disorders in IBD Baumgart D, World J Gastroenterol 2008
  60. 60. What is new on hepatobiliary disorders in IBD? Better understanding of immune liver-gut cross-talk Immune system • Hepatic injury
  61. 61. Genetic predispositionDietary, pathoge Immune system ns, drugs… IBD disregulation Life style (smoking, diet, stress), gut microbiota
  62. 62. Recruitment lymphocytes to the liver Normal liver  The adhesion molecules are expressed at low level However, MadCAM-1 and CCL25 are not expressed Adams and al, Nat Rev Immunol 2006
  63. 63. Recruitment lymphocytes to the liver During inflammatory bowel disease  Increase of adhesion molecules expression  Induction of MadCAM-1 and CCL25 expression Adams and al, Nat Rev Immunol 2006
  64. 64. Hepatic damage in intestinal diseases Abnormal flow of intestinal antigens crossing altered mucosal barrier Abnormal activation of gut specific T-cells Recruitment by the liver of activated gut specific T-cells Liver injury Adams and al, Nat Rev Immunol 2007
  65. 65. Gastro-intestinal and Liver diseases associated to GUT Microbiota1. Autoimmune Enteropathy and Celiac disease2. Inflammatory Bowel Diseases3. GI Cancer4. Irritable Bowel Syndrome5. Intestinal Bacterial Overgrowth6. Food Intolerance7. Obesity and Metabolic Syndrome8. Liver Diseases progression and complications9. …
  66. 66. Liver-gut axis derangement Alcohol NAFLD Drug Autoimmune HBV/HCV CBP/CSPAscites/PBS Fibrosis/Portal hypertension HRS Infections HCC Bleeding Hepatic Encephalopathy
  67. 67. Fibrosis/Portal Alcool hypertension NAFLD/ NASHHBV/ AutoHCV immunityEncephalopathy/HRS HCCAscites/PBS/Infections
  68. 68. Fibrosis/Portal Alcool hypertension NAFLD/ NASHHBV/ AutoHCV immunityEncephalopathy/HRS HCCAscites/PBS/Infections
  69. 69. Pathological liver-gut axis Portal hypertension Intestinal bacterial Increased intestinal overgrowth permeability Bacterial or bacterial antigens traslocation LPS translocation in the portalbloodstream could activate hepatic fibrosis Gomez Hurtado I et al, PLoS ONE 2011 Seki et al, J Physiol 2011 Thalheimer et al., Eur J Gastroenterol Hepatol 2010
  70. 70. Intestinal bacterialLPS activates Toll-Like receptor 4 onhepatic stellate cells TGF-b signalingand liver fibrosis Seki E et al Hepatology 2009
  71. 71. TLR4-mutant mice Collagen DepositionResults: Reduction of Expression of alpha-SMA hepatic fibrogenesis and macrophageinfiltration in TLR4- mutant mice Macrophage infiltrationSeki E et al. Hepatology 2009
  72. 72. Pathological liver-gut axis Portal hypertension Intestinal bacterial Increased intestinaldysbiosis/overgrowth permeability Bacterial or bacterial antigens traslocation PBS Endotoxemia Sepsis Cachexia Hyperdynamic circulatory state
  73. 73. Chen et al. Hepatol 2011To analyze fecal microbial community was analyzed by way of 454pyrosequencing of the 16S ribosomal RNA V3 region followed by real-timequantitative polymerase chain reaction 149 predominant taxonomic units in cirrhotics
  74. 74. Fibrosis/PortalAlcool hypertension NAFLD/ NASHHBV/ AutoHCV immunity Encephalopathy HCC Ascites/PBS
  75. 75. GUT microbiota and NAFLD Colonization of germ-free mice with a microbial population from obese mice stimulates triglyceride synthesis and glycogenesis in the liver De Gottardi A, J Hepatology 2011Abu-Shanab et al., Nat Rev Gast Hep 2011 Delzenne et al., Nat Rev Endocrinol 2011
  76. 76. GUT microbiota and NAFLD/NASHThe consumption of trans-fatty acids has increased dramatically inthe last decades and mice fed trans-fatty acids develop larger liverswith NASH-like lesions and insulin resistance HIGH-FAT OR HIGH- CARBOHYDRATE DIET IN HUMANS: •↓ Bifidobacteria •↓ Genes coding for tight junction proteins (↑ intestinal permeability, ↑ circulating LPS concentrations and ↑ Endotoxiemia ) Tilg H, J Hepatology 2010 Frazier TH, J Parent Ent Nutrition 2011
  77. 77. GUT HYPERPERMEABILITY LEADS TO METABOLIC ENDOTOXEMIA Cani et al, Pharm Ther 2010 Miele and Gasbarrini, Hepatology 2009 Scarpellini and Gasbarrini, Am J Gastro 2010
  78. 78. 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) Zhu L et al., Hepatology 2012
  79. 79. Characterization of the gut microbiome in NASH an endogenous alcohol-ptroducing microbiotaAbundance 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 liverinflammation, suggest a role for alcohol producing microbiota inthe pathogenesis of NASH Zhu L et al., Hepatology 2012
  80. 80. Hypothesis for bacteria-induced metabolic disease High Fat Diet Ist HIT Change Microbiota Increased permeability PAMPs absorption IInd HIT Endotoxemia Inflammation Metabolic disorders Canì, Diabetes 2010
  81. 81. Gut microbiota and Bariatric Surgery Li J V et al. Gut 2011
  82. 82. Gut microbiota and Bariatric Surgery Li J V et al. Gut 2011
  83. 83. Fibrosis/PortalAlcohol hypertension NAFLD/ NASHHBV/ AutoHCV immunity Encephalopathy HCC Ascites/PBS
  84. 84. Alcohol and gut Szabo G et al. Dig Dis 2010
  85. 85. Alcohol and Gut Alcohol causes disruption of tight junction protein, ZO-1 Ethanol decreases transepithelial electrical resistance(TEER) in gut epithelial cells Szabo G et al. Dig Dis 2010
  86. 86. Alcohol and gut-liver axis: Ist HIT DIRECT DAMAGE DAMAGE BY ETHANOL METABOLITES ↓ Anti-inflammatory activity of adiponectinSchaffert CS World J Gastroenterol 2009 Tilg H et al. J Hepatology2011
  87. 87. Alcohol and gut-liver axis: IInd HIT DAMAGE BY BACTERIAL PRODUCTS ↓ phagocitic activity of Kupffer cells Ethanol damages gut barrier Ethanol induces SIBO and microbiota modificationsSchaffert CS World J Gastroenterol 2009 Tilg H et al. J Hepatology2011
  88. 88. Fibrosis/PortalAlcohol hypertension NAFLD/ NASH HBV/ Auto HCV immunity Encephalopathy HCC Ascites/PBS
  89. 89. Jalan R J Hepatol 2010
  90. 90. 1. Might microbiota be modulatedin liver disease?2. Could microbiota modulation besafe and effective in liver disease?
  91. 91. GUT MICROBIOTA MODULATIONDiet and Nutritional SupportCaloric amount, minerals, vitaminsDiet composition (low fat and red meat, high fibers..)Removal of predisposing conditionsTreat diabetes, endocrine, other motility disorders..Surgery or prokinetics when indicatedStop PPI/antiacid, immunosoppressants or otherdrugs that affect motility or the immune system..DrugsAntibioticsBiotherapy
  92. 92. ANTIBIOTICS FOR DYSBIOSIS in chronic liver diseasesTOPIC: rifaximin…SYSTEMIC:nitroimidazolics, fluoroquinolones… BIOTHERAPY FOR DYSBIOSIS in chronic liver diseasesBCAAs, lactulose, probiotics, prebiotics, microbiota infusion… Clinical indication: hepatic
  93. 93. Kawaguchi T et al. WJG 2012
  94. 94. 299 pts history of HE, RCT (multicenter, double-blind, placebo-controlled) Recurrence of HE: 22.1% (31 of 140) rifaximin vs. 45.9% (73 of 159) placebo pts Incidence of recurrent HE: reduced by 550 mg twice daily for 6 months 58% (90% + lactulose) 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.
  95. 95. BACKGROUND: MHE patients have an increased risk ofdriving offenses and have poor insight into their driving skills.AIM: study the effect of RIFAXIMIN 550 MG twice a day ondriving performance using a driving simulator; Secondaryoutcomes studied were cognitive performance, quality oflife, and change in the systemic inflammatory milieu andneuroglial function markers.METHODS: RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROL RIFAXIMIN 550 MG TWICE A DAY for 8 WEEKS Number of patient: 42
  96. 96. n of speeding tickets n of illegal turns = n of collisions Reduction of driving errors
  97. 97. 219 Patients (multicentric RCT) with cirrhosisin remission from HE and with documented history of recurrent HE episodesrifaximin 550 mg twice daily (N = 101) or placebo (N = 118) for 6 months
  98. 98. Rifaximin… A matter of budget? Rifaximin costs more than lactulose: $1120 vs $150 per month in the USA
  99. 99. Rifaximin… A matter of budget? Rifaximin costs more than lactulose: $1120 vs $150 per month in the USA…however, the total annual costing of rifaximinhas been reported to be less than lactulose when hospital admissions are taken into account
  100. 100. 299 pts history of HE, RCT (multicenter, double-blind, placebo-controlled) Recurrence of HE: 22.1% (31 of 140) rifaximin vs. 45.9% (73 of 159) placebo pts Incidence of recurrent HE: reduced by 550 mg twice daily for 6 months 58% (90% + lactulose) 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.
  101. 101. Meta-analysis of 14 RCT (650 pts) +3cohort studies (161 pts):Rifaximin vs. other antibiotics • more effectiveRifaximin vs. non-absorbable disaccharides • more effective • better tolerated • less frequent and shorter hospitalization Lawrence KR Klee JA. Pharmacotherapy 2008
  102. 102. Rifaximin in HE: Open issues• Prophylactic, first or second- line treatment?• Emergence of resistance?• Drug interactions?
  103. 103. Resistance to rifaximin is by chromosomal alteration in the DNA-dependent RNA polymeraseIt is NOT plasmid-mediated: NOT TRASMITTABLE Resistant bacteria disappear after a 5 day course, but data after long term teratment are not present at this time Scarpignato C et al. Digestion 2006 http://www.fda.gov
  104. 104. Clinically significant drug interactions are not significant with rifaximinRifaximin undergoes efflux through P-glycoprotein and does nothave interactions with other substrates for the P-glycoproteinEven at concentrations of 200 ng/mL, rifaximin did not inhibitcytochrome P450; in vitro the ability to induce cytochrome P4503A4 was half that of rifampin200 mg 3 times daily did not alter the pharmacokinetics of oralmidazolam; 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
  105. 105. ..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
  106. 106. PRO/PRE-BIOTICS: a role in cirrhosis?•To preserve the natural biological balance of the intestinaltract•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 portalhypertension and both local and systemic hemodynamicalterations•To prevent and/or correct HE Cesaro C et al., Dig Liv Dis 2011
  107. 107. PRO/PRE-BIOTICS: a role in cirrhosis? Most used in studies have been Lactobacilli and Bifidobacteria (move with much more difficulty trough intact epithelium) THE RISK OF TRASLOCATION… Improvement of liver Prevention HE function of infections This result was An improvement in the Results similar to attributed to the hemodynamic lactulose during therestoration of normal parameters of portal treatment periodbacterial flora in the circulation with a and the maintenance gut, resulting in modification of of the therapeutic lower absorption of microbiota and a effect during thetoxic metabolites and reduction in plasma wash-out period onlyendotoxins in treated endotoxin in the group treated patients with probiotics Cesaro C et al., Dig Liv Dis 2011
  108. 108. …a role for probiotics in liver disease? Single strain Safety Multistrain Stability Bacteria Dietary Yeast Integrators Live Drugs Heat inacivated Dosage Spore Duration Vegetative form Way of administration
  109. 109. SummaryLiver-gut axis derangements
  110. 110. Cerf-Bensussan N al, Nat Rev Immunol. 2010
  111. 111. Patologia intestinale epatica•Enteriti autoimmuni Celiachia IBD•Alterazione quali/quantitativa del GUTmicrobiota Obesita’ e sindrome metabolica NAFLD/NASH
  112. 112. Patologia epatica intestinale•Il progredire di una epatopatia siassocia a alterazioni della barrieraintestinale e del GUT microbiota1.Ipertensione portale con stasi venosa tissutalee alterata permeabilita’ intestinale2.Alterazioni quali/quantitativa del GUTmicrobiota3.Traslocazione di batteri (mutualisti epatogeni) e di loro frammenti
  113. 113. Patologia epatica intestinale•Alterazione quali/quantitativa delGUT microbiotaEncefalopatia porto-sistemica•Traslocazione di batteri (mutualisti epatogeni) e loro frammenti1. Ascite e ascite refrattaria2. Peritonite Batterica Spontanea3. Infezioni sistemiche4. Cofattore nella progressione della fibrosi5. Cofattore nello sviluppo di HCC
  114. 114. Ist HIT: patologia primitiva del fegato (virus, ETOH, steatosi…) IInd HIT: disbiosi, iperpermeabilita’ intestinale, traslocazione di batteri e frammenti battericiProgressione dell’epatopatia e sviluppo di complicanze
  115. 115. A dinner plate from OUR point of view…Dutton RK Turnbugh PJ, Curr Opin Clin Nutr Metab Care 2012
  116. 116. ...A dinner plate from a METAGENOMIC point of view Bacteria from Ellagic acid foods Coffee fiber Starch Polysaccharides Probiotics Polyphenols Oligosaccharides SCFAs (acetate, butyrate, Inulin propionate, succinate) Fructans Soy Isoflavones Phosphatidylcholine Glucosinolates Heterocyclic amines Xanthohumol Nitrosamines Porphyrans Amino acids Lignans SCFA PRODUCTSDutton RK Turnbugh PJ, Curr Opin Clin Nutr Metab Care 2012

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