microbiome and bacterial-overgrowth (sibo and ibs) · microbiome and bacterial-overgrowth (sibo and...
TRANSCRIPT
Microbiome and Bacterial-Overgrowth
(SIBO and IBS)
Bible Class
15th oct. 2014
Universitätsklinik für Viszerale Chirurgie und Medizin
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Content – Overview - Topics
The microbiome:
Nomenclature
Background information
Related clinical problems
Small-intestinal-bacterial overgrowth:
Diagnostics
Treatment
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Microbiome - Nomenclature
Symbiosis =
Commensalism =
Parasitism =
Competition =
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Microbiome - Nomenclature
Symbiosis =
Commensalism =
Parasitism =
Competition =
win-win
win-zero
win-loose
loose-loose
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Microbiome - Nomenclature
Formal rank
Example Numbers
Domain Bacteria
Phylum Proteobacteria > 50
Class Gamma-Proteobacteria 5
Order Enterobacteriales 15
Family Enterobacteriacea 1
Genus Escherichia >50
Species E.coli > 10
Subspecies EIEC - serotypes > 100
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Microbiome - Nomenclature
Formal rank
Example Numbers
Domain Bacteria
Phylum Proteobacteria > 50
Class Gamma-Proteobacteria 5
Order Enterobacteriales 15
Family Enterobacteriacea 1
Genus Escherichia >50
Species E.coli > 10
Subspecies EIEC - serotypes > 100
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Microbiome - Nomenclature
Formal rank
Example Numbers
Domain Bacteria
Phylum Proteobacteria > 50
Class Gamma-Proteobacteria 5
Order Enterobacteriales 15
Family Enterobacteriacea 1
Genus Escherichia >50
Species E.coli > 10
Subspecies EIEC - serotypes > 100
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
What proportion of microbiome – species can be
cultured ?
Less than 20 %
Techniques to study human microbiome ?
16rRNS: who is out /in there ?
Metagenomics: what genes are present in those bacteria ?
Meta-Transcriptomics/Proteomics: what are they doing ?
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Microbiome - Nomenclature
Alpha-Diversity = Bacterial/Species richness
Beta-Diversity = Number of Taxa unique for the ecosystem
Simpson Diversity Index
Sorensen Similarity Index
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Dysbiosis: «Index»
NOT standardized medical term
refers to microbial imbalance
e.g.
Microbiome - Nomenclature
[total abundance in organisms increased in CD]
[total abundance of organisms decreased in CD]
Or
“Good”
“Bad”
Gevers et al. Cell Host Microbe 2014
Bajaj et al. Jhepatol. 2014
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Dysbiosis: «Index»
NOT standardized medical term
refers to microbial imbalance
e.g.
Microbiome - Nomenclature
[total abundance in organisms increased in CD]
[total abundance of organisms decreased in CD]
Or
“Good”
“Bad”
Gevers et al. Cell Host Microbe 2014
Bajaj et al. Jhepatol. 2014
high MD-index >1 in most cases
strong reduction in the species richness
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Gevers et al. Cell Host Microbe 2014
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
In principle, a healthy microbiota is defined
by high diversity and an ability to resist
change under physiological stress.
In contrast, microbiota associated with
disease is defined by lower species diversity,
fewer beneficial microbes and/or the
presence of pathobionts.
Role of Dysbiosis for Disease Processes ?
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
How many times more bacteria than host cells
usually life within the human gut
containing how much genomic information ?
Numbers: 10 times !!
Genomic information: 100 times
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
How many times more bacteria than host cells
usually life within the human gut
containing how much genomic information ?
Numbers: 10 times !!
Genomic information: 100 times
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
„Normal“ Microbiota across intestinal wall
Kim YS et al. Curr Opin Gastro 2010
Lumen
Inner Layer Mucus
Outer Layer Mucus
Gu
t F
lora
Com
part
ments
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Juge N. Trends Microbiol. 2012 ;20(1):30-9
Removable by aspiration
Too firm To be removed
Mucus Layers across intestinal wall
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
At which intervals do bacteria replicate in-vivo ?
(e.g. in mice mono-colonised with E.coli)
Lumen – Colon:
Mucus – Colon:
every 8 -10 hours
every (1-) 2 hours
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
At which intervals do bacteria replicate in-vivo ?
(e.g. in mice mono-colonised with E.coli)
Lumen – Colon:
Mucus – Colon:
every 8 -10 hours
every (1-) 2 hours
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
What are the main phyla in human colon
Firmicutes
Bacteroidetes
Actinobacteria
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Enterotypes of the human gut microbiome
Arumugam et al. Nature 2011
39 individuals (fecal samples), 4 european countries
Assessing phylogenetic composition
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Enterotypes of the human gut microbiome
Arumugam et al. Nature 2011
39 individuals (fecal samples), 4 european countries
Assessing phylogenetic composition
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Organ-System
Evidence for role of microbiome
«Dysbiosis»
Infections Clostridium difficile √ √
Metabolism Obesity
Diabetes type -2
√
√
√
√
Gastrointestinal IBD
IBS
Coeliac disease
√
√
√
√
√
√
Liver Fibrogenesis/corrhosis
complications of cirrhosis
(e.g. SBP, HE, HRS)
NASH, ASH
√
√
√
√
√
√
√
√
Evidence of microbiome involvement in diseases
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Organ-System
Evidence for role
of microbiome
Gefäss-system Atherosklerose
Hematology ITP
Brain/Neurology Multiple Sclerosis
Parkinson
Depression
Autism, Schizophrenia
Carcinogenesis HCC
KRCa
Evidence of microbiome involvement in diseases
√
√ √ √ √ √ √ √
Atopic dermatitis, rhinitis, poylcystic ovar, chronic pain/fatigue syndrome,
HIV, Antiphospholipid-syndrome…………………………
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
What do we need bacteria in the gut for ?
Salvage energy
Providing Vitamins
Colonization resistance
Shaping immune function
Brain function ?
Modulation/metabolization Xenobiotics
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Intrinsic:
- Motility
- GI-secretions (acid…)
- Genes (e.g. NOD2)….
- Antimicrobial peptides
- Immunity (sIgA)
What factors modulate the microbiome
(quantitative and qualitative) ?
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Intrinsic:
- Motility
- GI-secretions (acid…)
- Genes (e.g. NOD2)….
- Antimicrobial peptides
- Immunity (sIgA)
What factors modulate the microbiome
(quantitative and qualitative) ?
Extrinsic:
- Diet, C2, Pre-/Pro-biotics
- Medications (PPIs, Antibiotics
- Procinetiks, Opioids……
- Stress
- Hygiene
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Microbiome
Complexity + Stability
Probalbility of
Dysbiosis and Disease
HE
ALT
HY
DIS
TU
RB
ED
Physiological
Functions: Disease
Entities:
Modulators of Microbiome
Salvage
energy
Supply
vitamins
Modualte
Xenobiotic
compounds
Shaping human
Immune system
Modulating
Brain function
Genetics Hygiene
Stress
Birth
Route
Diet
Nutrition Drugs
Clostridium
Difficile Infection
Inflammatory
Bowel disease
(UC, MC)
Irritable bowel
syndrome
Bacterial
Overgrowth
NASH
Liver Cirrhosis
Metabolic
Syndrome
Obesity
Modulators, Function and Diseases related to Microbiome
Wiest R et al. in Press
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
„Normal“ Microbiota along GI-Tract
Qu
an
tity
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
„Normal“ Microbiota along GI-Tract
Qu
an
tity
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
What is the definition of SIBO ?
>105
colony forming unit/ml
jejunal cultures and/or
with colonic-type bacteria
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Breath-Testing for SIBO
How does it work ?
13C-D-Xylose Breath-test
H2-Breath-tests (Glukose, Laktulose)
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Breath-Testing for SIBO
Caveats to consider ?
Yu et al. Gut 2011
False positive:
Malabsorption in small intestine->
+ rapid transit to colon-> fermentation
Contamination (oral flora)
False negative:
Bacteria: NO metabolizing encymes ?
Gastroparesis
Non-H2-Producer (10%)
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Breath-Testing for SIBO
Caveats to consider ?
Yu et al. Gut 2011
False positive:
Malabsorption in small intestine->
+ rapid transit to colon-> fermentation
Contamination (oral flora)
False negative:
Bacteria: NO metabolizing encymes ?
Gastroparesis
Non-H2-Producer (10%)
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Sensitivity
Specificity
Glucose-H2-test
40% 80%
Lactulose-H2-test
16-31% 86%
Breath-Testing for SIBO: vs. Gold Standard
Ghosal et al. J Neurogastroenterol Motil 2011;17:312-317)
up to 85% of healthy individuals have an abnormal LHBT
Am J Gastroenterol 2008;103:958 –963
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Current Diagnosis of SIBO – Evidence ?
Meta-Analysis of 71 papers on SIBO in humans
Aim: assess validity of culture + other diagnostic tests
“….not even culture studies met the quality standards
described by Reid et al. ………..”
Khoshini R et al. DigDisSci 2008
Goldstandard:
Endoscopic aspiration upper
jejunum/distal duodenum
Rubins catheter (sterile plugged tip)
Aerobic (and anaerobic) culture
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Current Diagnosis of SIBO – Evidence ?
Meta-Analysis of 71 papers on SIBO in humans
Aim: assess validity of culture + other diagnostic tests
“….not even culture studies met the quality standards
described by Reid et al. ………..”
Khoshini R et al. DigDisSci 2008
Goldstandard:
Endoscopic aspiration upper
jejunum/distal duodenum
Rubins catheter (sterile plugged tip)
Aerobic (and anaerobic) culture
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Pathophysiology - Mechanisms of SIBO
Factor preventing
SIBO
Disease/State
Promoting SIBO
Peristalsis
Gastric acid
Bile acids
Proteolytic encymes
Antimicrobial peptides,
Mucus ?, IgA?
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Pathophysiology - Mechanisms of SIBO
Factor preventing
SIBO
Disease/State
Promoting SIBO
Peristalsis
Gastric acid
Bile acids
Proteolytic encymes
Antimicrobial peptides,
Mucus ?, IgA?
Stasis
Hypo/Anacidity
Cholestasis
Pankreatitis
?
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Pathophysiology - Mechanisms of SIBO
Factor preventing
SIBO
Disease/State
Promoting SIBO
Peristalsis
Gastric acid
Bile acids
Proteolytic encymes
Antimicrobial peptides,
Mucus ?, IgA?
Mechanical obstruction
(post-surgery, -radiation etc.)
Motility disorder
(DM, Scleroderma, …..
Megaduodenum
Stasis in blind loops
PPI-use, atrophic gastritis
Bile outflow-obstruction
Any cause (tumor…..)
Immunological factors:
Hypo-, A-
gammaglobulinemia
AIDS
Chronic pancreatitis
Stasis
Hypo/Anacidity
Cholestasis
Pankreatitis
?
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Pathophysiology - Mechanisms of SIBO
Factor preventing
SIBO
Disease/State
Promoting SIBO
Peristalsis
Gastric acid
Bile acids
Proteolytic encymes
Antimicrobial peptides,
Mucus ?, IgA?
Extra-Intestinal Reservoir, unclassified causes:
Liver cirrhosis, NASH, Cystic fibrosis, renal insufficiency, Cholangitis, enterocolic fistula
…………………………………………………………………………………………………….
Mechanical obstruction
(post-surgery, -radiation etc.)
Motility disorder
(DM, Scleroderma, …..
Megaduodenum
Stasis in blind loops
PPI-use, atrophic gastritis
Bile outflow-obstruction
Any cause (tumor…..)
Immunological factors:
Hypo-, A-
gammaglobulinemia
AIDS
Chronic pancreatitis
Stasis
Hypo/Anacidity
Cholestasis
Pankreatitis
?
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Clinical consequences of SIBO ?
Malassimilation-syndrome due to:
Luminal Maldigestion AND Epithelial Malabsorption
Bile acid deconjugation -> Steatorrhoe
Epithelial injury due to «toxic» deconjugated Bile acids
Bacterial metabolization of US-SCFA-> hydroxy-FA-> diarrhoe
degradation of proteins, inhibition aminoacid absorption-> protein-loosing
Bacterial binding Vitamin B12-> reduced resorption-> anemia
Gas production: bloating, meteorism
Others:
peripheral neuropathy, tetany, osteomalacia, night blindness, dermatitis
Liver injury, nephro-toxicity, arthritis (predom. Jejunum-Ileum-Bypass)
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Treatment of SIBO - How do you do it ?
Rifaximin: e.g. 1200mg/day
Ciproxin: e.g. 1000mg/day (+ Metronidazol)
SDD (Polymyxin+Gentamycin): e.g. 4 x 2 capsules
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Shah et al. APT 2013 Meta-Analysis
Treatment of SIBO - Meta-Analysis
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Shah et al. APT 2013 Meta-Analysis
Treatment of SIBO - Meta-Analysis
Universitätsklinik für Viszerale Chirurgie und Medizin / www.chirurgiebern.ch
Human Intestinal Community Project