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

Dysfunction of the brain gut-axis

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

Pathogens Probiotics

1.

Antimicrobial factors

Probiotics : mechanisms of action

2.

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

Evidence for a strain dependant effect

Example

O’Mahony L et al Gastroenterology 2005;128:541-51

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 ?

Several questions to answer

Which strain(s) ? One strain or a mixture ? Who are the patients candidates ? Which dose ? Which duration of treatment ?