ESPEN Congress Leipzig 2013 - A life inside: probiotics in practice Functional bowel disorders: less drugs, more bugs? P. Ducrotte (FR)
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ESPEN Congress Leipzig 2013
A life inside: probiotics in practice
Functional bowel disorders: less drugs, more bugs?
P. Ducrotte (FR)
UMR 1073
Functional bowel disorders :
Functional bowel
less drugs, disorders
more bugs :
less drugs, more bugs
Philippe DUCROTTE
Philippe DUCROTTE
Rouen University Hospital
Rouen University Hospital
(France)
(France)
ESPENESPEN
Leipzig 30/08/2013
Leipzig 31/08/2013p
Disclosures • Almirall • Bayer Santé • Cephalon • Given Imaging • Mayoly-Spindler • Rosell-Lallemand
Functional bowel disorders
Functional
Functional Constipation
Bloating
Irritable Bowel
Syndrome
(IBS)
Functional
Functional
Diarrhoea
Abdominal
Pain
Drossman DA et al Gastroenterology 2006;130:1377-90
Irritable bowel syndrome
Recurrent abdominal pain
(or discomfort)
• > 3 days per month during the last 3
months
• improved by defaecation
Alteration in bowel habits
• Diarrhoea and/or constipation
• Change in stool frequency and/or
stool form during pain exacerbation
Duration of symptoms > 6 months
Drossman DA et al Gastroenterology 2006;130:1377-90
Irritable Bowel Syndrome Common disabling disorder (prevalence : 8-10%) Major impact on patient’s quality of life Unmet needs with standard therapeutic options (antispasmodics, bulking agents, antidepressants...).
Questions • What is the rationale to discuss the use of probiotics for the relief of symptoms in IBS ? • What are the demonstrated effects of probiotics ? • What is the evidence for the efficacy of probiotics in IBS ?
Pathophysiology of IBS : a multifactorial disease
Dysfunction of the
brain gut-axis
Pathophysiology of IBS : a multifactorial disease
Central Mechanisms
Peripheral Mechanisms
Dysmotility
Altered permeability
Abnormal metabolism of bile acids
Hypersensivity
Low grade with sensitization of
inflammation sensory endings
Pathophysiology of IBS : a multifactorial disease
Peripheral Mechanisms
Dysmotility
Altered permeability
MICROBIOTA
Abnormal metabolism of bile acids
Hypersensivity
Low grade with sensitization of
inflammation sensory endingsIBS can be a post-infectious IBS
15 - 20 %
PI-IBS
Non PI-IBS
OR : 5.86 (IC 95 % : 3.6-9.4)
• Mainly IBS-D
• Higher risk when infection documented
Thabane M et al. Aliment Pharmacol Ther 2007; 26 : 535-44Risk factors of post-infectious IBS
after acute gastroenteritis
Spiller R et al Gastroenterology 2009;136:1979-88Hypersensitivity can be transferred
through fecal microbiota
« germ-free» rats
Microbiota Normosensitive
from normosensitive rats
healthy controls
« germ-free» rats
Crouzet L et al Neurogastroenterol Motil 2013;25:272-82Hypersensitivity can be transferred
through fecal microbiota
« germ-free» rats
Microbiota Normosensitive
from normosensitive rats
healthy controls
« germ-free» rats
Microbiota
from hypersensitive Hypersensitive
IBS patients rats
Colonic compliance, permeability, mast cells : NS
Crouzet L et al Neurogastroenterol Motil 2013;25:272-82Qualitative differences in faecal microbiota
between IBS patients and controls
Jeffery IB et al Gut 2012;61:997-1006
Simren M et al Gut 2012;62:159-176Qualitative differences in faecal microbiota
between IBS patients and controls
Less diversity
Less lactobacilli Jeffery IB et al Gut 2012;61:997-1006
Less bifidobacteriae Simren M et al Gut 2012;62:159-176Cross-talk Microbiota-Enteric nervous system
SCFAs 1
2,3
1.Soret R et al Gastroenterology 2010
2.Jimenez M Neurogastroenterol 2010
3.Krueger D et al Neurogastroenterol 2010Main end-products of in vitro starch fermentation by faecal
microbiota in C-IBS patients and healthy controls
HC C-IBS p
Sulfides (µg/mL) 498 + 160 1150 + 120 < 0.0001
Hydrogen (µmol/mL) 0.3 + 0.3 1.4 + 0.6 0.008
Methane (µmol/mL) 5.5 0.8 + 0.8 NS
(n=2) (n=3)
Total SCFA (mM) 71.4 + 12.1 60.7 + 12.8 NS
Acetate (mM) 46.1 + 6.5 41.4 + 9.8 NS
Propionate (mM) 13.1 + 4.4 9.7 + 2.1 NS
Butyrate (mM) 12.3 + 1.7 9.6 + 1.9 0.03
Lactate (mM) 1.1 + 0.5 1.2 + 0.7 NS
Chassard C et al Aliment Pharmacol Ther 2012;1-11Actual working hypothesis
Dysbiosis
Activation of Dysregulation of
Activation of
immune enteric nervous
nociceptive
response system
sensory pathways
Increased
intestinal Visceral Hypersenstivity
permeabilityQuestions • What is the rationale to discuss the use of probiotics for the relief of symptoms in IBS ? • What are the demonstrated effects of probiotics ? • What is the evidence for the efficacy of probiotics in IBS ?
Probiotics : mechanisms of action
1.
Pathogens Probiotics
Antimicrobial
factorsProbiotics : mechanisms of action 2.
Probiotics : mechanisms of action
3
3.
.
From Gareau MG et al Nat Rev Gastroenterol Hepatol 2010;9:503-14Questions • What is the rationale to discuss the use of probiotics for the relief of symptoms in IBS ? • What are the demonstrated effects of probiotics ? • What is the evidence for the efficacy of probiotics in IBS ?
Placebo controlled clinical trials of single or mixed probiotic preparations in IBS
More than
3000 patientsProbiotics in IBS :
Limitations of the published trials
1. Unpowered trials
Studies (n)
1 – 40 50 – 99 100 – 199 200 – 299 300 - 399
Randomized patients (n)
2. Suboptimal Design :
Inadequate blind, short duration, inappropriate end-points, lack of ITT analysis
3. For most strains : no reproducible evidence of efficacyProbiotics in IBS : Results of meta-analyses
Trials In favor of Global result
probiotics
Selected Analyzed
Mc Farland 38 20 YES Persistence of symptoms :
2008 OR : 0.77 (IC 95% = 0.62-0.99)
UK NICE 13 13 YES Improvement
2008 OR : 1.57 (IC 95% = 1.31-1,87)
Hoveyda 22 14 YES Improvement :
2009 OR : 1.6 (IC 95% = 1.2-2.2)
Brennan 16 16 YES Only one effective strain :
2009 B.infantis 35624
Moayyedi 26 18 YES Persistence of symptoms :
2010 OR : 0.71 (IC 95%= 0.57-0.88)
NNT = 4
Ortiz-Lucas 24 10 YES Reduction of abdominal pain
2013 and distensionEvidence for a strain dependant effect
Example
O’Mahony L et al Gastroenterology 2005;128:541-51Efficacy in any IBS sub-type ? • Probiotics have been mainly tested in IBS-D • No actual evidence of a greater efficacy in a particular IBS sub-type
Probiotics and bloating in IBS
Before
After
Control
DN -173010
Plethysmographic belt
Agrawal A et al Aliment Pharmacol Ther 2009;29:104-14Pathophysiology of IBS
Central mechanisms
Abnormal pain
processing related Maladaptive
to mood disorders coping
SomatizationLimbic area
Exposure to a stressor
alters intestinal microbiota 1
Vagus nerve
Dysbiosis can promote anxiety and
alter cognitive functions 2
Production of mediators (GABA, serotonin…)
1. Bailey MT et al Brain Behav Immun 2011;25:397-407
2. Cryan JF et al Neurogastroenterol Motil 2011,23:187-92Lactobacilli and HPA axis
Lactobacillus acidophilus / Lactobacillus helveticus
CRH
*
#
ng/ml
Gareau M et al Gut 2007;56:1522-8Probiotics can modify stress-related symptoms
Mixture of probiotics (L.acidophilus R-52 + B.Longum R-175) for 3 weeks
Anorexia Bloating Abdominal Pain Diarrhoea
Nausea Epigastric pain Constipation
Reduction of intensity
p=0.009
p=0.004
Diop L et al Nutrition Res 2008;28:1-5Methane and slow transit
Stool frequency Constipation severity
Pimentel M et al Dig Dis Sci 2003;48:86-92
Kunkel D et al Dig Dis Sci 2011;56:1612-8
Furnari M et al J Gastrointestin Liver Dis 2012;2:157-63Meta-analysis of the effects of
probiotics on colonic transit time
• 11 trials
• 464 patients and healthy
volunteers
• Jadad scale for RCTs : 3 (2-5)
• B.Lactis HN019
• B.Lactis DN-173010
• More effective
– In constipated patients
– in older patients
Miller JE et al World J Gastroenterol 2013;19:4718-25Some probiotics can relieve constipation
Exemple : Lactobacillus DN-173010
Guyonnet D et al Aliment Pharmacol Ther 2007;26:465-76Safety issues
Trials analyzed Serious AE reported
Mc Farland 20 NONE
2008
UK NICE 13 NONE
2008
Hoveyda 14 NONE
2009
Brennan 16 NONE
2009
Moayyedi 18 NONE
2010
Ortiz-Lucas 20 NONE
2013Conclusions
IBS
• Probiotics, as a therapeutic category,
seem a possible promising therapeutic
option.
• Studies of specific strains indicate that
although some probiotics may improve
individual symptoms, few have a global
benefitCurrently available strategies for
modifying gut microbiota
Less effective More effective
More invasive
And/or less safe
Gut-directed
antibiotics
Probiotics
Prebiotics
Exclusion diets
FODMAP diet
Stopping PPIs
Less invasive
And/or saferRole of probiotics in the graduated treatment
approach for IBS patients
Multidisciplinary approach
Reference to a pain center
Severe
+
Pharmacotherapy Moderate
Psychological treatments
PROBIOTICS ?
+
Education Mild
Reassurance
Dietary modificationsSeveral questions to answer Which strain(s) ? One strain or a mixture ? Who are the patients candidates ? Which dose ? Which duration of treatment ?
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