a life inside: probiotics in practice functional bowel ... · a life inside: probiotics in practice...
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ESPEN Congress Leipzig 2013
A life inside: probiotics in practice
Functional bowel disorders: less drugs, more bugs?
P. Ducrotte (FR)
Functional bowel disorders : less drugs, more bugs
Philippe DUCROTTE
Rouen University Hospital
(France)
ESPEN Leipzig 30/08/2013
UMR 1073
Functional bowel disorders : less drugs, more bugs
Philippe DUCROTTE Rouen University Hospital
(France)
ESPEN Leipzig 31/08/2013p
Disclosures
• Almirall
• Bayer Santé
• Cephalon
• Given Imaging
• Mayoly-Spindler
• Rosell-Lallemand
Functional bowel disorders
Functional Bloating
Functional Diarrhoea
Functional Constipation
Irritable Bowel Syndrome
(IBS) FunctionalAbdominal
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
Dysmotility
Hypersensivity with sensitization of
sensory endings
Low grade inflammation
Altered permeability
Peripheral Mechanisms
Central Mechanisms
Abnormal metabolism of bile acids
Pathophysiology of IBS : a multifactorial disease
Dysmotility
Hypersensivity with sensitization of
sensory endings
Low grade inflammation
Altered permeability
Peripheral Mechanisms
MICROBIOTA Abnormal metabolism of bile acids
IBS can be a post-infectious IBS
15 - 20 % PI-IBS
Thabane M et al. Aliment Pharmacol Ther 2007; 26 : 535-44
OR : 5.86 (IC 95 % : 3.6-9.4)
Non PI-IBS
• Mainly IBS-D • Higher risk when infection documented
Risk factors of post-infectious IBS after acute gastroenteritis
Spiller R et al Gastroenterology 2009;136:1979-88
Hypersensitivity can be transferred through fecal microbiota
Microbiota from normosensitive
healthy controls
« germ-free» rats
Normosensitive rats
Crouzet L et al Neurogastroenterol Motil 2013;25:272-82
« germ-free» rats
Hypersensitivity can be transferred through fecal microbiota
Microbiota from normosensitive
healthy controls
Microbiota from hypersensitive
IBS patients
« germ-free» rats
Normosensitive rats
Hypersensitive rats
Colonic compliance, permeability, mast cells : NS
Crouzet L et al Neurogastroenterol Motil 2013;25:272-82
« germ-free» rats
Jeffery IB et al Gut 2012;61:997-1006 Simren M et al Gut 2012;62:159-176
Qualitative differences in faecal microbiota between IBS patients and controls
Jeffery IB et al Gut 2012;61:997-1006 Simren M et al Gut 2012;62:159-176
Qualitative differences in faecal microbiota between IBS patients and controls
Less diversity Less lactobacilli
Less bifidobacteriae
Cross-talk Microbiota-Enteric nervous system
1.Soret R et al Gastroenterology 2010 2.Jimenez M Neurogastroenterol 2010
3.Krueger D et al Neurogastroenterol 2010
SCFAs 1
2,3
Main 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 (n=2)
0.8 + 0.8 (n=3)
NS
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;1-11
Actual working hypothesis
Dysbiosis
Activation of immune response
Activation of nociceptive
sensory pathways
Dysregulation of enteric nervous
system
Increased intestinal
permeability Visceral Hypersenstivity
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 ?
Probiotics : mechanisms of action
3.
3.
From Gareau MG et al Nat Rev Gastroenterol Hepatol 2010;9:503-14
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 ?
Placebo controlled clinical trials of single or mixed probiotic preparations in IBS
More than 3000 patients
Probiotics in IBS : Limitations of the published trials
1. Unpowered trials
Stu
die
s (
n)
1 – 40 50 – 99 100 – 199 200 – 299 300 - 399 Randomized patients (n)
3. For most strains : no reproducible evidence of efficacy
2. Suboptimal Design : Inadequate blind, short duration, inappropriate end-points, lack of ITT analysis
Probiotics in IBS : Results of meta-analyses Trials In favor of
probiotics Global result
Selected Analyzed
Mc Farland 2008
38 20 YES Persistence of symptoms : OR : 0.77 (IC 95% = 0.62-0.99)
UK NICE 2008
13 13 YES Improvement OR : 1.57 (IC 95% = 1.31-1,87)
Hoveyda 2009
22 14 YES Improvement : OR : 1.6 (IC 95% = 1.2-2.2)
Brennan 2009
16 16 YES Only one effective strain : B.infantis 35624
Moayyedi 2010
26 18 YES Persistence of symptoms : OR : 0.71 (IC 95%= 0.57-0.88) NNT = 4
Ortiz-Lucas 2013
24 10 YES Reduction of abdominal pain and distension
Efficacy 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
Plethysmographic belt
Control DN -173010
Agrawal A et al Aliment Pharmacol Ther 2009;29:104-14
Pathophysiology of IBS
Central mechanisms
Abnormal pain processing related to mood disorders
Somatization
Maladaptive coping
Exposure to a stressor alters intestinal microbiota 1
Dysbiosis can promote anxiety and alter cognitive functions 2
Vagus nerve
Limbic area
Production of mediators (GABA, serotonin…)
1. Bailey MT et al Brain Behav Immun 2011;25:397-407 2. Cryan JF et al Neurogastroenterol Motil 2011,23:187-92
Lactobacilli and HPA axis n
g/m
l
CRH
Gareau M et al Gut 2007;56:1522-8
*
#
Lactobacillus acidophilus / Lactobacillus helveticus
Probiotics can modify stress-related symptoms
Anorexia Bloating Abdominal Pain Diarrhoea Nausea Epigastric pain Constipation
p=0.009
p=0.004
Red
uct
ion
of
inte
nsi
ty
Diop L et al Nutrition Res 2008;28:1-5
Mixture of probiotics (L.acidophilus R-52 + B.Longum R-175) for 3 weeks
Methane 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;2:157-63
Meta-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;19:4718-25
Some probiotics can relieve constipation
Exemple : Lactobacillus DN-173010
Guyonnet D et al Aliment Pharmacol Ther 2007;26:465-76
Safety issues
Trials analyzed Serious AE reported
Mc Farland 2008
20 NONE
UK NICE 2008
13 NONE
Hoveyda 2009
14 NONE
Brennan 2009
16 NONE
Moayyedi 2010
18 NONE
Ortiz-Lucas 2013
20 NONE
Conclusions
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 benefit
Currently available strategies for modifying gut microbiota
Less invasive And/or safer
More invasive And/or less safe
Less effective More effective
Stopping PPIs
FODMAP diet Exclusion diets
Gut-directed antibiotics
Probiotics Prebiotics
Role of probiotics in the graduated treatment approach for IBS patients
Multidisciplinary approach Reference to a pain center
Pharmacotherapy Psychological treatments
Education Reassurance Dietary modifications
+
+
Severe
Moderate
Mild
PROBIOTICS ?