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 IBSBacteria and 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
Bacteria and IBSBacteria and IBS
- 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
Bacteria and IBSBacteria and IBS
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
Bacteria and IBS- Epidemiological DataBacteria and IBS- Epidemiological Data
Post Infectious IBS (PI-IBS)Post Infectious IBS (PI-IBS)
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
Bacteria and IBS- Epidemiological DataBacteria and IBS- Epidemiological Data
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
Bacteria and IBS- Epidemiological DataBacteria and IBS- Epidemiological Data
Post Infectious IBS (PI-IBS)Post Infectious IBS (PI-IBS)
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
Bacteria and IBS- Epidemiological DataBacteria and IBS- Epidemiological Data
Post Infectious IBS (PI-IBS)Post Infectious IBS (PI-IBS)
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
Bacteria and IBSBacteria and IBS
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 IBSBacteria and IBS
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
Bacteria and IBSBacteria and IBS
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
Bacteria and IBSBacteria and IBS
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
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)
Bacteria and IBSBacteria and IBS
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
Bacteria and IBSBacteria and IBS
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
Bacteria and IBSBacteria and IBS
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
Intestinal bacteria and gut function
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
Bacteria and IBSBacteria and IBS
Intestinal bacteria and gut function
Bacteria and IBSBacteria and 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…
Intestinal bacteria and gut function
Bacteria and IBSBacteria and IBS
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
Intestinal bacteria and gut function
Bacteria and IBSBacteria and IBS
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
Bacteria and IBSBacteria and IBS
Implications for Clinical ManagementImplications for Clinical Management
Data from probiotics trials
Data from antibiotics trials
Bacteria and IBSBacteria and IBS
Implications for Clinical ManagementImplications for Clinical Management
“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
Bacteria and IBSBacteria and IBS
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
Probiotics - Clinical trials in IBSProbiotics - Clinical trials in IBS
Clinical trials in IBS – a negative study
Kim HJ, Aliment Pharmacol Ther. 2003
Probiotics - Clinical trials in IBSProbiotics - Clinical trials in IBS
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
Clinical trials in IBS – a negative study
Kim HJ, Neurogastroenterol Motil 2005
Probiotics - Clinical trials in IBSProbiotics - Clinical trials in IBS
Weekly scores of flatulence and bloating
VSL#3 vs. placebo twice daily for 8 weeks
Decrease in flatulence
No effect of bloating
Clinical trials in IBS – a negative study
Probiotics - Clinical trials in IBSProbiotics - Clinical trials in IBS
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)
Probiotics - Clinical trials in IBSProbiotics - Clinical trials in IBS
(Likert scale)
O’Mahony et al., Gastroenterology 2005
Intestinal bacteria and gut function
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
Probiotics - Clinical trials in IBSProbiotics - Clinical trials in IBS
Intestinal bacteria and gut function
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
Normalization of IL10:IL12 ratiowith B. infantis
=> Probiotic strains can normalize immunologic alterations in IBS and this is associated with clinical response
Probiotics - Clinical trials in IBSProbiotics - Clinical trials in IBS
Data from probiotics trials
Data from antibiotics trials
Bacteria and IBSBacteria and IBS
Implications for Clinical ManagementImplications for Clinical Management
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
Implications for Clinical ManagementImplications for Clinical Management
Bacteria and IBSBacteria and 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
Bacteria and IBSBacteria and IBS
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
Bacteria and IBSBacteria and IBS
Ongoing Research – Clinical Trials
Bacteria and IBSBacteria and IBS
• 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
Bacteria and IBSBacteria and IBS
Balfour Sartor
Bill Whitehead
Tope Keku
Young-Hyo Chang
Jiwon Kim
Sarah Causey
Sarah Yaskel
Jenifer Juhl
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