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

1. Gut-liver axis
Prof. A. Gasbarrini
Università Cattolica Sacro Cuore - Roma

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. 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. 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. Liver-gut axis
Blood flow Intestinal barrier
Diet
Immune System GUT Microbiota
Physiological condition

6. Liver-gut axis
HCV/HBV CELIAC DISEASE
Diet
ETOH/DRUG IBD
Pathological condition

7. Gut Microbiota
and GI and Liver diseases
What’s new?

8. Gut Barrier
and Microbiota

9. Bile
Bad Good Water acids
bacteria bacteria
Colon
Loosely
Lumen Food adherent
antigens Ileum mucus layer
Stomach
Duodenum
and Firmly adherent
ptors Jejunum mucus layer
Adhesions molecules
Non-Immune Endothelium Immune
cells And fibroblasts
Nerve and miocytes
cells

10. GUT barrier
Gut Microbiota
(bacteria, yeasts, bacteriophages)
Mucosal
Barrier
Acquired
Epithelial and
barrier Innate
immunity
Endocrine
system
Vascular and Neuroenteric system
lymphatic systems Digestive enzymes

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. Gut Virome
Phage-bacteria relationships
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
Berg Miller et al, Environ Microbiol 2011

13. Human Gut Virome
Inter-individual variation and dynamic response to diet
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
Minot et al, Genome Res 2011

14. Human Gut Bacteriome
the Second Genome of human body
Most people share:
1. A core microbiota that comprises 50-100
bacterial species
2. A core microbiome harboring more than
6000 functional gene groups
Zhu, Protein Cells 2010

15. The
Minimal Core
Gut Genome
And
Metagenome
Qin J et
al, Nature 2010

16. COMPOSITION OF THE GUT MICROBIOTA:
MOLECULAR APPROACH
Eckburg et al, Science 2005

18. BF
Bacteroidetes
>Firmicutes
EU
Firmicutes
>Bacteroidetes
De Filippo et al, PNAS 2010

19. The Universe of Gut Microbiota…
…is related to Diet composition
Ley RE et al, Science 2008

20. HUMAN MICROBIOME PROJECTS:
3 main enterotypes
Enterotypes are identifiable by the variation in the levels
of one of three genera:
ENTEROTYPE 1: Bacteroides
ENTEROTYPE 2: Prevotella
ENTEROTYPE 3: Ruminococcus
Arumugam – Nature 2011

21. Bacterial diversity is affected by ageing
Ottmann N et al. Front Cell Infect Microb 2012

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. 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!

24. Nell S, Nature 2010

25. 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

26. Infant Gut Microbiota composition is crucial for
IMMUNOLOGICAL EDUCATION
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

27. 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!

28. Hashida H et al. Nat Chem Biol 2012

30. 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!

31. Metabolic function of GUT microbiota
•Gut microbiota is an excellent anaerobic
energetic bioreactor
•Consumes, stores and redestributes energy
•Allows us to extract calories from
otherwise indigestible carbohydrates
METABOLOMA

32. 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

33. 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

34. SCFA produced by microbiota affects lipid storage
1. SCFA bind to
the G-protein
coupled
receptors Gpr41
and Gpr42
2. Gpr41/42
activation
blocks epithelial
expression of
fasting-induced
adipocyte factor
(Fiaf), a
circulating LPL
inhibitor
Tilg H, Gatroenterology 2009

35. The “Second Meal” effect
Diamant M et al., Ob Rev 2010

36. PYRAMID OF LIFE: human body
Metabolomics
1400
Chemicals
Proteomics
2500 Enzymes
Genomics
25.000 Genes
Kau et al, Nature 2011 Qin et al, Nature 2011

37. 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

38. 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
Ibrahim M et al, Bioch Bioph Res Comm 2012

39. Diet, microbiota, and the epithelial cell:
the ‘‘NUTRIENT SENSOR pathway’’
Tilg H, J Hepatology 2010

40. 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 Mollicutes
Alteration 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

41. The CORE GUT MICROBIOME of OBESE
Obesity is associated control obese
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

42. Hyperinsulinemic clamp ALLOGENIC (9) Hyperinsulinemic clamp
S.I. biopsies Random S.I. biopsies
6 wks
Fecal 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

43. 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!

44. GUT microbiota and drug/toxin metabolism
Mutualistic bacteria influence:
1. Drug bioavailability
Different effects of commonly used therapeutics in
different geographic and cultural populations
PharmacogeneticsPharmacometabonomics
Tyroxine
L-Dopa
Tilg et al, J Clin Inv 2011 Cennamo et al, New Eng J Med 2010

45. Gut Barrier and Microbiota
in GI and Liver diseases

46. 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

47. When these mechanisms fail…
Quali-quantitative alterations of gastric, small
bowel and/or colonic microbiota
Bacterial Overgrowth/Reduction (DYSBIOSIS)
Live bacteria or bacterial fragments translocate
in portal and sistemic circulation
...GI, Liver and Systemic-associated diseases

48. Gut Barrier dysfunction
Intestinal permeability (Leaky gut)

49.  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)

50. Gastro-intestinal and Liver diseases
associated to GUT Microbiota
1. Autoimmune Enteropathy and Celiac disease
2. Inflammatory Bowel Diseases
3. GI Cancer
4. Irritable Bowel Syndrome
5. Intestinal Bacterial Overgrowth
6. Food Intolerance
7. Obesity and Metabolic Syndrome
8. Liver Diseases progression and complications
9. …

51. Gastro-intestinal and Liver diseases
associated to GUT Microbiota
1. Autoimmune Enteropathy and Celiac disease
2. Inflammatory Bowel Diseases
3. GI Cancer
4. Irritable Bowel Syndrome
5. Intestinal Bacterial Overgrowth
6. Food Intolerance
7. Obesity and Metabolic Syndrome
8. Liver Diseases progression and complications
9. …

52. Pathological gut-liver axis
Autoimmune enteropathy
(celiac disease and IBD)
Immune system • Hepatic injury

53. GALT FUNCTIONS
• Apoptotic intestinal
• Pathogen antigens cells antigens
• Food antigens
• Microbiota antigens
Antigen presentation
Immunity response Self-antigen tolerance
Immunosurveillance Immunotolerance
 
infections allergies

54. GALT FUNCTIONS
• Apoptotic intestinal
• Pathogen antigens cells antigens
• Food antigens
• Microbiota antigens
Antigen presentation
Immunity response Self-antigen tolerance
Immunosurveillance Celiac
Immunotolerance
 
disease
infections allergies

55. Pathological gut-liver axis
Celiac disease
Immune system • Hepatic injury

56. Hepatobiliary disorders in Celiac disease
1. Cryptogenetic liver disorders (celiac hepatitis)
Non specific reactive generally mild histological
hepatitis
Usually reverts to normal after gluten-free diet
2. 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

57. 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

58. Hepatobiliary disorders in Celiac disease
Rubio Tapia et al, Hepatology 2007

59. Pathogenesis of Hepatobiliary
disorders in Celiac disease
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)
Volta U, Clin Rev Allerg Immunol 2008

60. Pathological gut-liver axis
Inflammatory Bowel Diseases
Immune system • Hepatic injury

61. Hepatobiliary disorders in IBD
Baumgart D, World J Gastroenterol 2008

62. What is new on hepatobiliary disorders in IBD?
Better understanding of immune
liver-gut cross-talk
Immune system • Hepatic injury

63. Genetic
predisposition
Dietary, pathoge Immune system
ns, drugs…
IBD disregulation
Life style (smoking,
diet, stress),
gut microbiota

64. 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

65. 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

66. 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

67. Gastro-intestinal and Liver diseases
associated to GUT Microbiota
1. Autoimmune Enteropathy and Celiac disease
2. Inflammatory Bowel Diseases
3. GI Cancer
4. Irritable Bowel Syndrome
5. Intestinal Bacterial Overgrowth
6. Food Intolerance
7. Obesity and Metabolic Syndrome
8. Liver Diseases progression and complications
9. …

68. Liver-gut axis derangement
Alcohol NAFLD
Drug Autoimmune
HBV/HCV CBP/CSP
Ascites/PBS Fibrosis/Portal
hypertension
HRS
Infections
HCC
Bleeding
Hepatic Encephalopathy

69. Fibrosis/Portal
Alcool hypertension NAFLD/
NASH
HBV/ Auto
HCV immunity
Encephalopathy/HRS HCC
Ascites/PBS/Infections

70. Fibrosis/Portal
Alcool hypertension NAFLD/
NASH
HBV/ Auto
HCV immunity
Encephalopathy/HRS HCC
Ascites/PBS/Infections

71. Pathological liver-gut axis
Portal hypertension
Intestinal bacterial Increased intestinal
overgrowth permeability
Bacterial or bacterial antigens traslocation
LPS translocation in the portal
bloodstream 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

72. Intestinal bacterial
LPS activates Toll-
Like receptor 4 on
hepatic stellate cells
TGF-b signaling
and liver fibrosis
Seki E et al Hepatology 2009

73. TLR4-mutant mice
Collagen Deposition
Results: Reduction of Expression of alpha-SMA
hepatic fibrogenesis
and macrophage
infiltration in TLR4-
mutant mice
Macrophage infiltration
Seki E et al. Hepatology 2009

74. Pathological liver-gut axis
Portal hypertension
Intestinal bacterial Increased intestinal
dysbiosis/overgrowth permeability
Bacterial or bacterial antigens traslocation
PBS Endotoxemia Sepsis
Cachexia Hyperdynamic
circulatory state

75. Chen et al.
Hepatol 2011
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
149 predominant taxonomic
units in cirrhotics

76. Fibrosis/Portal
Alcool hypertension NAFLD/
NASH
HBV/ Auto
HCV immunity
Encephalopathy HCC
Ascites/PBS

77. 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 2011
Abu-Shanab et al., Nat Rev Gast Hep 2011 Delzenne et al., Nat Rev Endocrinol 2011

78. GUT microbiota and NAFLD/NASH
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
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

79. GUT HYPERPERMEABILITY LEADS TO
METABOLIC ENDOTOXEMIA
Cani et al, Pharm Ther 2010
Miele and Gasbarrini, Hepatology 2009
Scarpellini and Gasbarrini, Am J Gastro 2010

80. 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

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

82. 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

83. Gut microbiota and Bariatric Surgery
Li J V et al. Gut 2011

84. Gut microbiota and Bariatric Surgery
Li J V et al. Gut 2011

85. Fibrosis/Portal
Alcohol hypertension NAFLD/
NASH
HBV/ Auto
HCV immunity
Encephalopathy HCC
Ascites/PBS

86. Alcohol and gut
Szabo G et al. Dig Dis 2010

87. 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

88. Alcohol and gut-liver axis: Ist HIT
DIRECT DAMAGE
DAMAGE BY ETHANOL METABOLITES
↓ Anti-inflammatory
activity of adiponectin
Schaffert CS World J Gastroenterol 2009 Tilg H et al. J Hepatology2011

89. 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
modifications
Schaffert CS World J Gastroenterol 2009 Tilg H et al. J Hepatology2011

90. Fibrosis/Portal
Alcohol hypertension NAFLD/
NASH
HBV/ Auto
HCV immunity
Encephalopathy HCC
Ascites/PBS

91. Jalan R J Hepatol 2010

92. 1. Might microbiota be modulated
in liver disease?
2. Could microbiota modulation be
safe and effective in liver disease?

93. GUT MICROBIOTA MODULATION
Diet and Nutritional Support
Caloric amount, minerals, vitamins
Diet composition (low fat and red meat, high fibers..)
Removal of predisposing conditions
Treat 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
Antibiotics
Biotherapy

94. ANTIBIOTICS FOR DYSBIOSIS
in chronic liver diseases
TOPIC: rifaximin…
SYSTEMIC:
nitroimidazolics, fluoroquinolones…
BIOTHERAPY FOR DYSBIOSIS
in chronic liver diseases
BCAAs, lactulose, probiotics, prebiotics, mic
robiota infusion…
Clinical indication:
hepatic

95. Kawaguchi T et al.
WJG 2012

96. 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.

97. 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 WEEKS
Number of patient: 42

98. n of speeding tickets
n of illegal turns
= n of collisions
Reduction
of driving errors

99. 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

100. Rifaximin… A matter of budget?
Rifaximin costs more than lactulose:
$1120 vs $150 per month in the USA

102. 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

103. 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.

104. Meta-analysis of 14 RCT (650 pts) +3
cohort studies (161 pts):
Rifaximin vs. other antibiotics
• more effective
Rifaximin vs. non-absorbable disaccharides
• more effective
• better tolerated
• less frequent and shorter
hospitalization
Lawrence KR Klee JA. Pharmacotherapy 2008

105. Rifaximin in HE:
Open issues
• Prophylactic, first or second-
line treatment?
• Emergence of resistance?
• Drug interactions?

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

107. 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

108. ..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

109. 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

110. 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 the
restoration of normal parameters of portal treatment period
bacterial 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 the
toxic metabolites and reduction in plasma wash-out period only
endotoxins in treated endotoxin in the group treated
patients with probiotics
Cesaro C et al., Dig Liv Dis 2011

111. …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

112. Summary
Liver-gut axis derangements

113. Cerf-Bensussan N al, Nat Rev Immunol. 2010

114. Patologia intestinale epatica
•Enteriti autoimmuni
Celiachia
IBD
•Alterazione quali/quantitativa del GUT
microbiota
Obesita’ e sindrome metabolica
NAFLD/NASH

115. Patologia epatica intestinale
•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

116. Patologia epatica intestinale
•Alterazione quali/quantitativa del
GUT microbiota
Encefalopatia porto-sistemica
•Traslocazione di batteri (mutualisti e
patogeni) e loro frammenti
1. Ascite e ascite refrattaria
2. Peritonite Batterica Spontanea
3. Infezioni sistemiche
4. Cofattore nella progressione della fibrosi
5. Cofattore nello sviluppo di HCC

117. Ist HIT: patologia primitiva del fegato
(virus, ETOH, steatosi…)
IInd HIT: disbiosi, iperpermeabilita’
intestinale, traslocazione di batteri e
frammenti batterici
Progressione dell’epatopatia e sviluppo
di complicanze

119. A dinner plate
from OUR point of view…
Dutton RK Turnbugh PJ, Curr Opin Clin Nutr Metab Care 2012

120. ...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
PRODUCTS
Dutton RK Turnbugh PJ, Curr Opin Clin Nutr Metab Care 2012