Probiotics and Antibiotics for IBS: Do Bacteria Matter? July 2, 2006 Yehuda Ringel, MD. Division of Gastroenterology and Hepatology University of North

Probiotics and Antibiotics for IBS: Do Bacteria Matter?

July 2, 2006

Yehuda Ringel, MD.

Division of Gastroenterology and HepatologyUniversity of North Carolina, Chapel Hill, NC.

Tel Aviv Medical Center, Tel Aviv Israel

It is not clear whether the bacteria needs to be present in the intestinal lumen or attached to the intestinal mucosa in order to cause an effect

Intestinal Microflora

• The intestine of an adult human contains approximately 1014 bacteria

• There are more than 500 [?] different species and sub-species

• Intestinal bacteria are embedded in the mucus

Bacteria and IBSBacteria and IBS

IBS and Intestinal Microflora• Very few studies

• Results are not consistent

• Classic culture techniques

Lower numbers of coliform, lactobacilli, and bifidobacteria

(Balsari, Microbiologica 1982)

Higher numbers of E coli, and bacteroides

(Swidsinski,Gastroenterol 1999)

• DNA based studies

Lower amounts of lactobacillus species in fecal flora of patients with D-IBS

? Quantitative and qualitative changes in intestinal microflora in IBS ?


Bacteria and FBDBacteria and FBD

Is there a role for intestinal microflora in Is there a role for intestinal microflora in functional bowel disorders?functional bowel disorders?

End Organ Sensation• Sensory receptors (5HT,CCK)

• “Silent” nociceptors• Bacteria/Inflammation

CNS Modulation• Cortex (S1, Limbic system)• Brainstem

Transmission Pathways• Autonomic Nervous System

• Neuroendocrine System (HPA Axis)

• Spinal pathways

DysregulationAltered GI Altered GI FunctionFunction

Brain-Gut Axis ResearchPsychosocial Factors • Stress/Anxiety/Depression • Abuse

Implications for clinical management Implications for clinical management

Presentation Outline

Epidemiological DataEpidemiological Data- - Post Infectious IBS (PI-IBS)Post Infectious IBS (PI-IBS)- Small Bowel Bacterial Overgrowth (SIBO)- Small Bowel Bacterial Overgrowth (SIBO)- Gas and Bloating- Gas and Bloating


- Animal studies - Animal studies - Human Studies- Human Studies

Perspective and Conclusions Perspective and Conclusions

Physiological Data/ Physiological effectsPhysiological Data/ Physiological effects

- Treatment for PI-IBS - Treatment for PI-IBS

- Treatment for SIBO - Treatment for SIBO

- Data from probiotics trials - Data from probiotics trials

- Data from probiotics trials- Data from probiotics trials


Epidemiological DataEpidemiological Data

(Evidence for bacterial effects on functional gastrointestinal symptoms)

Post Post Infectious IBS (PI-IBS)

Small Bowel Bacterial Overgrowth (SIBO)

Gas and Bloating

Bacteria and IBS- Epidemiological DataBacteria and IBS- Epidemiological Data

Post Infectious IBS (PI-IBS)Post Infectious IBS (PI-IBS)

The term postdysenteric colonic irritability was first used to describe persistent bowel symptoms following an episode of dysentery

A small series reported 12/38 (31%) of inpatients with Salmonella food poisoning had persistent symptoms of diarrhea and urgency at 1 year

Chaudhary NA: “The irritable colon” 1962

A prospective study demonstrated that 26% of patients admitted with acute GE had IBS symptoms at 6 months

McKendrick et al, J Infect 1994

Gwee et al, Lancet 1996Gwee et al, Gut 1999



Author Follow-Up PI-IBS %

Marshal, et al, 2005 2-3yr 380/1137 33.5

McKendrick, et al, 1994 12m 12/38 31

Gwee, et al, 1999 3m 22/100 22

Okhuysen, et al, 2004 6m 6/60 10

Mearin, et al, 2005 12m 24/271 10

Thornley, et al, 2000 6m 9/93 9

Neal, et al, 1997

2003

6m6yr

23/35714/192

77.3

These studies lacked a control group to define the normal incidence of IBS in the absence of infection in general population

Two population studies: Rodríguez et al BMJ 1999Parry et al, Am J Gastroenterol 2003


Post Infectious IBS (PI-IBS)Post Infectious IBS (PI-IBS)A prospective, community-based, case-control study aiming to determine the frequency of FGIDs 6 months after bacterial gastroenteritis.

ALL cases had proven bacterial gastroenteritis, and controls were community-based

FGIDs were diagnosed using self-completed Rome II modular questionnaires at baseline 3 months 6 months

The primary endpoint was the presence of one of three specific FGIDsIBS functional dyspepsiafunctional diarrhea

500 cases and 705 community controls were identified128 cases and 219 controls were consented and eligible108 cases and 206 controls returned the questionnaire/available data for analysis

Parry et al, Am J Gastroenterol 2003



Parry et al, Am J Gastroenterol 2003

At 3 months after bacterial GE Cases (n=108) Controls (n= 206 ) OR (95% CI)

FGIDs 30 (29%) 6 (2.9%)

At 6 months after bacterial GEFGIDs 27 (25%) 6 (2.9%) 11.1 (4-28)

IBS 18 (16.7%) 4 (1.9%) 10.1 (3-31)

Functional diarrhea 6 (5.6%) 0 (0%)

Functional dyspepsia 0 (0%) 0 (0%)

Functional GI Symptoms occur more frequently in people after bacterial GE compared to controls

=> PI-FBD is a real clinical entity



IBS subtypes in 103 patients with new onset of PI-IBS

Dunlop et al, Am J Gastro 2003

• Mainly Diarrhea predominant

• Psychological factors are less common

• Intestinal inflammation is common

• Better prognosis (?)

Distinctive features

Development of persistent GI symptoms following acute onset of GE in individual with previously normal bowel habit

The provoking illness should have at least 2 of the following:- Fever- Diarrhea or vomiting- Positive stool culture

Diagnosis of PI-IBS

Spiller et al, Gastroenterology 2003



Evidence for bacterial effects on functional gastrointestinal symptoms



Gas and Bloating


Small Bowel Bacterial OvergrowthSmall Bowel Bacterial Overgrowth

• A cohort of IBS patients referred for lactulose hydrogen breath (LHB) test demonstrated high prevalence 78% of SIBO

• The successfully treated patients had significant improvement in diarrhea and abdominal pain compared to pts who failed treatment

• 48% of the eradicated group were no longer suffering from IBS

Pimentel et al. Am J Gastroenterol 2000

• More recent studies demonstrated a prevalence of 10 to 75% in patients with functional GI symptoms


Small Bowel Bacterial OvergrowthSmall Bowel Bacterial Overgrowth

Author Breath test # Subjects Prevalence (%)

McCallum, 2005 Glucose 143 38.5

Lupascu, 2005 Glucose 65 30.7

Nucera, 2005 Lactulose 98 65

Walters, 2005 Lactulose 39 10

Noddin, 2005 Lactulose 20 10

Nucera, 2004 Lactulose 200 75

Pimentel, 2003 Lactulose 111 57- 84

Pimentel, 2000 Lactulose 202 76

Prevalence

The large variation in the prevalence indicates the problematic state of this research Better data is needed



Evidence for bacterial effects on functional gastrointestinal symptoms



Gas and Bloating

Gas

Vol

ume

Scor

e

Bloating and Gas in IBSBloating and Gas in IBSBacteria and IBSBacteria and IBS

• Complaints of bloating and gas are common in patients with IBS (80-90%)Chami et al. Am J Gastroenterol 1991

Lin, Lancet 2005

• Abdominal girth is greater in IBS patients both at baseline and after eating

Whorwell et al. Gastroenterol 2003

• Fermentation and gas production (hydrogen and methane) after standardizes meal is significantly greater in IBS King et al. Lancet 1998

• Patients with IBS have higher intestinal gas volume Koide A, et al. Am J Gastroenterol. 2000

The production of gas in the intestine is a result of substrate (sugars) fermentation by intestinal bacteria

Retained Gas and IBS symptoms

Serra et al. Gut 2001

Gas

Vol

ume

Scor

eEvacuation of intestinal gas

in IBS (n=20) and controls (n=20)


Patients with IBS have higher intestinal gas retention, increased perception and abdominal girth

Perception of bloating/gas

Girth Change

Bloating and Gas in IBSBloating and Gas in IBS

http://gut.bmjjournals.com.libproxy.lib.unc.edu/content/vol48/issue1/images/large/991324.f1.jpeg




Physiological DataPhysiological Data

Evidence for bacterial effects on gut sensory and motor functions

Intestinal bacteria and gut function

Barbara et al., Am J Gastroenterol 2005

Enteric microflora play an important role in maintaining normal intestinal function Changes in intestinal microflora can lead to significant alterations in GI function


Main changes in intestinal functions in germ-free animals

Notice the delayed gastric emptying and intestinal transit, and the effects on MMC of germ-free rats


Bercik et al., Gastroenterology 2004

Alteration in intestinal motility and hyperalgesia following intestinal inflammation with Tricinella spiralis in mice

Certain pathogens have specific effects on gut functions that have direct relevance to the pathophysiology of IBS




Putative mechanisms for effects

(1) Release of bacterial substance or products of bacterial fermentation

(2) Activation of enteric immune system (release of inflammatory mediators)

(3) Activation of intestinal neuroendocrine system (release of neuropeptids)

Two examples…



Putative mechanisms for effects (animal model studies)

Bacterial LPS significantly reduced K+-induced contractions in various intestinal segments:

- in duodenum 68%

- in jejunum 58%

- in ileum 52%

The effect of IV injected Lipopolysaccharide (LPS) on intestinal motility

E. Rebollar, Acta Physiol Scand 2003



Putative mechanisms for effects (human studies)

SCFA significantly increases colonic motility and decreases gastric emptying

The effect of intestinal infusion of SCFA on intestinal motility

Cherbut et al, 2003Coffin et al, 1997

SCFA

SCFA

Lipids

salinesaline

Lipids

Data from probiotics trials Data from probiotics trials

Data from antibioticsData from antibiotics trialstrials


Implications for Clinical ManagementImplications for Clinical Management

Data from probiotics trials

Data from antibiotics trials



“microbial balance” - probiotic microflora compete with pathogens for available substrate or binding sites on the intestinal mucosa

Evolution of the use of probiotics in GI disordersEvolution of the use of probiotics in GI disorders

Probiotics were used mainly in context of infection and diarrheal diseases

Immune modulating effects – both intestinally and systemically Use of probiotics in context of chronic inflammation inflammatory bowel diseases (IBD), atopic dermatitis, asthma etc.

Modulating intestinal functions – motility, sensation, secretion Use of probiotics in context of functional GI disorders irritable bowel syndrome (IBS), bloating, functional diarrhea


Probiotics have been shown to have beneficial effects in 4 types of diarrhea:Probiotics have been shown to have beneficial effects in 4 types of diarrhea:

Acute infectious diarrhea (rotavirus diarrhea)

Antibiotic- associated diarrhea

Clostridium difficile

Traveler’s diarrhea +

Probiotics in GIProbiotics in GI

Clinical use of probiotics in GI disordersClinical use of probiotics in GI disorders

Probiotics may have beneficial effects in IBD:Probiotics may have beneficial effects in IBD:

Pouchitis

Ulcerative colitis (UC)

Crohn’s Disease

Some anecdotal clinical trials in other GI conditions:Some anecdotal clinical trials in other GI conditions:Colorectal Cancer, Liver Diseases, Lactose intolerance, Post radiation diarrhea … but currently no support for clinical benefit

Probiotics - Clinical trials in IBS

• Several controlled trials

• Results have been mixed

• Methodological limitations

Probiotics - Clinical trials in IBSProbiotics - Clinical trials in IBS

Clinical trials in IBS – a negative study

Weekly proportions of responders by intention-to-treat (ITT)

Weekly proportions of responders between the two groups were not significant

Individual abdominal bloating scores using a visual analogue scale (mm)

Significant improvement in the VSL#3 group (P = 0.046), but not in the placebo group (P = 0.54).

Kim HJ, Aliment Pharmacol Ther. 2003



Kim HJ, Aliment Pharmacol Ther. 2003


There were no significant differences in GI transit measurements, between the two treatment groups, pre- or post-therapy

Post-treatment gastrointestinal transit measurements

Gastrointestinal transit

VSL#3 group (n = 12)

Placebo group (n = 13)

P value

GE 2 h (% emptied) 54 ± 5 61 ± 6 0.41

GE 4 h (% emptied) 97 ± 2 97 ± 2 0.86

Colonic filling 6h (%) 72 ± 6 67 ± 5 0.62

Post-treatment GC24 3.4 ± 0.4 3.2 ± 0.3 0.70

Post-treatment GC48 4.5 ± 0.3 4.4 ± 0.2 0.99

GC24/48, geometric centre at 24 and 48 h; GE, gastric emptying


Kim HJ, Neurogastroenterol Motil 2005


Weekly scores of flatulence and bloating

VSL#3 vs. placebo twice daily for 8 weeks

Decrease in flatulence

No effect of bloating



VSL# 3 was associated with slower colonic transit compared to placebo (P = 0.05)

Scintigraphic images of colonic transit with VSL# 3 and placebo at baseline and after treatment

Kim HJ, Neurogastroenterol Motil 2005

GC24, geometric centre at 24h

Clinical trials in IBS - a positive study

Composite of IBS symptoms (Likert scale and VAS scores)

Significant reduction in composite scores throughout the treatment period and into the washout phase for B. infantis but not with L. salivarius or placebo (*P < .05)

Abdominal pain scores

Significant improvement in pain/discomfort score during most weeks of the treatment and into the washout phase with B. infantis (*P < .05)


(Likert scale)

O’Mahony et al., Gastroenterology 2005



Mononuclear IL-10/IL-12 in IBS and controls pre- and post-treatment

Evidence for abnormal immune function in IBS patients compared to controls




Mononuclear IL-10/IL-12 in IBS and controls pre- and post-treatment

Evidence for abnormal immune function in IBS patients compared to controls

Normalization of IL10:IL12 ratiowith B. infantis

=> Probiotic strains can normalize immunologic alterations in IBS and this is associated with clinical response


Data from probiotics trials

Data from antibiotics trials



Antibiotics may be beneficial in several conditions related

to IBS:

Prevention of intestinal infection (e.g., traveler’s diarrhea)

Treatment of acute infectious diarrhea

Treatment of SIBO

Treatment of Bloating

Antibiotics - Clinical trials in IBS



Overall improvement in IBS symptoms 38+6% vs. 23+4% (p<0.05)

Clinical responders 37% vs 16% (p<0.05)

In patients with diarrhea: Clinical response 49% vs 23% (p <0.05)

Results

• Randomized, double-blind, placebo-controlled study

• 87 outpatients who met ROME I criteria IBS

• Rifaximin 400 mg TID (n=43) or placebo (n=44) for 10 days

• Primary outcome: global improvement in IBS symptoms

Pimentel et al. Am J Gastroenterol 2005 (abstract)

Antibiotics - Clinical trials in IBS

Antibiotics - Clinical trials in IBSAntibiotics - Clinical trials in IBS

Bloating was also improved

No differences in the constipation group

Antibiotic Treatment for Bloating and Gas

Symptomatic Relief:

• After 20 days 41.3% vs 22.9% (p =0.03)

• After 40 days 28.6% vs 11.5% (p <0.02)

Results

The best outcome was in the group in which neomycin was successful in normalizing the LBT

Symptom improvement correlated with reduction in H2-breath excretion

• Randomized, double-blind, placebo-controlled study

• 124 outpatients with functional GI symptoms

• 70 patients met ROME II criteria for IBS

• Rifaximin 400 mg BID (n=63) or placebo (n=61) for 10 days

• Primary endpoint: subjective global relief of symptom

Sharara AI, et al. AJG 2006; 101:326-333.

Antibiotics - Clinical trials in IBSAntibiotics - Clinical trials in IBS

However…

Conclusions 1. Anecdotal observations suggest alterations in int. microflora in patients with IBS

• The enthusiasm for the use of probiotics or antibiotics in IBS has outpaced the scientific evidence

• The few studies in this area have been small with methodological limitations


2. Epidemiological studies support a role for intestinal infection/inflammation in the pathogenesis of IBS

3. Physiologic studies demonstrated that intestinal infection can lead to abnormalities in intestinal function

4. Several conditions that are thought to be associated with IBS (SIBO, gas) are directly related to intestinal bacteria

5. There is a rational in targeting intestinal bacteria for the treatment of IBS

We need

• More epidemiological data on the prevalence and role of SIBOG in IBS

• Large, well-designed, controlled, clinical trials to investigate the effects of manipulation of intestinal microflora with probiotics, prebiotics, and antibiotics

• Better understanding of the pathophysiology of PI-IBS, bloating and gas

• Better understanding of the complex interactions between the host and intestinal microflora

• Better understanding of the normal intestinal microflora and the alterations of intestinal microflora in specific GI conditions including IBS


Ongoing Research – Clinical Trials


• Clinical Efficacy of L. acidophilus NCFM and Bifidobacterium lactis Bi-07 in Patients with IBS, Functional Diarrhea, or Functional Bloating

• Clinical Efficacy of Yogurt Containing bifidobacterium lactis (BB12) in Subjects with Functional Gastrointestinal Symptoms (pending)

Probiotics Studies

Antibiotic Study

Genetic Study

• Genetic Surrogate Markers for Irritable Bowel Syndrome susceptibility, co-morbidity and disease characterization

• A phase 2, multicenter, randomized, double-blind, placebo controlled study to assess the efficacy and safety of Rifaximin in the treatment of patients with D-IBS

Thank you


Balfour Sartor

Bill Whitehead

Tope Keku

Young-Hyo Chang

Jiwon Kim

Sarah Causey

Sarah Yaskel

Jenifer Juhl

Documents

Probiotics and Antibiotics for IBS: Do Bacteria Matter? July 2, 2006 Yehuda Ringel, MD. Division of Gastroenterology and Hepatology University of North