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Probiotics and Antibiotics for IBS: Do Bacteria Matter? Yehuda Ringel, MD. Division of Gastroenterology Probiotics and Antibiotics for IBS: Do Bacteria Matter? Yehuda Ringel, MD. Division of Gastroenterology and Hepatology University of North Carolina, Chapel Hill, NC. Tel Aviv Medical Center, Tel Aviv Israel July 2, 2006

Bacteria and IBS Intestinal Microflora • The intestine of an adult human contains approximately Bacteria and IBS 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 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

Bacteria and IBS and Intestinal Microflora • Very few studies • Results are not Bacteria and 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 FBD Is there a role for intestinal microflora in functional bowel disorders? Bacteria and FBD Is there a role for intestinal microflora in functional bowel disorders?

Brain-Gut Axis Research Psychosocial Factors • Stress/Anxiety/Depression • Abuse CNS Modulation • Cortex (S Brain-Gut Axis Research Psychosocial Factors • Stress/Anxiety/Depression • Abuse CNS Modulation • Cortex (S 1, Limbic system) • Brainstem Transmission Pathways • Autonomic Nervous System • Neuroendocrine System (HPA Axis) • Spinal pathways End Organ Sensation • Sensory receptors (5 HT, CCK) • “Silent” nociceptors • Bacteria/Inflammation Dysregulation Altered GI Function

Bacteria and IBS Presentation Outline Epidemiological Data - Post Infectious IBS (PI-IBS) - Small Bacteria and IBS Presentation Outline Epidemiological Data - Post Infectious IBS (PI-IBS) - Small Bowel Bacterial Overgrowth (SIBO) - Gas and Bloating Physiological Data/ Physiological effects - Animal studies - Human Studies Implications for clinical management - Treatment for PI-IBS - Treatment for SIBO - Data from probiotics trials Perspective and Conclusions

Bacteria and IBS Epidemiological Data (Evidence for bacterial effects on functional gastrointestinal symptoms) Post Bacteria and IBS Epidemiological Data (Evidence for bacterial effects on functional gastrointestinal symptoms) Post Infectious IBS (PI-IBS) Small Bowel Bacterial Overgrowth (SIBO) Gas and Bloating

Bacteria and IBS- Epidemiological Data Post Infectious IBS (PI-IBS) The term postdysenteric colonic irritability Bacteria and IBS- Epidemiological Data Post Infectious IBS (PI-IBS) The term postdysenteric colonic irritability was first used to describe persistent bowel symptoms following an episode of dysentery Chaudhary NA: “The irritable colon” 1962 A small series reported 12/38 (31%) of inpatients with Salmonella food poisoning had persistent symptoms of diarrhea and urgency at 1 year Mc. Kendrick et al, J Infect 1994 A prospective study demonstrated that 26% of patients admitted with acute GE had IBS symptoms at 6 months Gwee et al, Lancet 1996 Gwee et al, Gut 1999

Bacteria and IBS- Epidemiological Data Post Infectious IBS (PI-IBS) Author Follow-Up PI-IBS % Marshal, Bacteria and IBS- Epidemiological Data Post Infectious IBS (PI-IBS) Author Follow-Up PI-IBS % Marshal, et al, 2005 2 -3 yr 380/1137 33. 5 Mc. Kendrick, et al, 1994 12 m 12/38 31 Gwee, et al, 1999 3 m 22/100 22 Okhuysen, et al, 2004 6 m 6/60 10 Mearin, et al, 2005 12 m 24/271 10 Thornley, et al, 2000 6 m 9/93 9 Neal, et al, 1997 2003 6 m 6 yr 23/357 14/192 7 7. 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 1999 Parry et al, Am J Gastroenterol 2003

Bacteria and IBS- Epidemiological Data Post Infectious IBS (PI-IBS) A prospective, community-based, case-control study Bacteria and IBS- Epidemiological Data Post Infectious IBS (PI-IBS) A prospective, community-based, case-control study aiming to determine the frequency of FGIDs 6 months after bacterial gastroenteritis. 500 cases and 705 community controls were identified 128 cases and 219 controls were consented and eligible 108 cases and 206 controls returned the questionnaire/available data for analysis 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 FGIDs IBS functional dyspepsia functional diarrhea Parry et al, Am J Gastroenterol 2003

Bacteria and IBS- Epidemiological Data Post Infectious IBS (PI-IBS) At 3 months after bacterial Bacteria and IBS- Epidemiological Data Post Infectious IBS (PI-IBS) 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 GE FGIDs 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%) Functional GI Symptoms occur more frequently in people after bacterial GE compared to controls => PI-FBD is a real clinical entity Parry et al, Am J Gastroenterol 2003

Bacteria and IBS- Epidemiological Data Post Infectious IBS (PI-IBS) Diagnosis of PI-IBS Development of Bacteria and IBS- Epidemiological Data Post Infectious IBS (PI-IBS) Diagnosis of PI-IBS 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 Spiller et al, Gastroenterology 2003 Distinctive features • Mainly Diarrhea predominant • Psychological factors are less common • Intestinal inflammation is common • Better prognosis (? ) IBS subtypes in 103 patients with new onset of PI-IBS Dunlop et al, Am J Gastro 2003

Bacteria and IBS Epidemiological Data Evidence for bacterial effects on functional gastrointestinal symptoms Post Bacteria and IBS Epidemiological Data Evidence for bacterial effects on functional gastrointestinal symptoms Post Infectious IBS (PI-IBS) Small Bowel Bacterial Overgrowth (SIBO) Gas and Bloating

Bacteria and IBS Small Bowel Bacterial Overgrowth • A cohort of IBS patients referred Bacteria and IBS Small 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 IBS Small Bowel Bacterial Overgrowth Prevalence Breath test # Subjects Prevalence (%) Bacteria and IBS Small Bowel Bacterial Overgrowth Prevalence Breath test # Subjects Prevalence (%) Mc. Callum, 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 Author The large variation in the prevalence indicates the problematic state of this research Better data is needed

Bacteria and IBS Epidemiological Data Evidence for bacterial effects on functional gastrointestinal symptoms Post Bacteria and IBS Epidemiological Data Evidence for bacterial effects on functional gastrointestinal symptoms Post Infectious IBS (PI-IBS) Small Bowel Bacterial Overgrowth (SIBO) Gas and Bloating

Bacteria and IBS Bloating and Gas in IBS Gas Volume Score The production of Bacteria and IBS Bloating and Gas in IBS Gas Volume Score The production of gas in the intestine is a result of substrate (sugars) fermentation by intestinal bacteria • Complaints of bloating and gas are common in patients with IBS (80 -90%) Chami et al. Am J Gastroenterol 1991 Lin, Lancet 2005 • 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 • Abdominal girth is greater in IBS patients both at baseline and after eating Whorwell et al. Gastroenterol 2003

Bacteria and IBS Bloating and Gas in IBS Evacuation of intestinal gas in IBS Bacteria and IBS Bloating and Gas in IBS Evacuation of intestinal gas in IBS (n=20) and controls (n=20) Gas Volume Score Retained Gas and IBS symptoms Perception of bloating/gas Girth Change Patients with IBS have higher intestinal gas retention, increased perception and abdominal girth Serra et al. Gut 2001

Bacteria and IBS Physiological Data Evidence for bacterial effects on gut sensory and motor Bacteria and IBS Physiological Data Evidence for bacterial effects on gut sensory and motor functions

Bacteria and IBS Intestinal bacteria and gut function Main changes in intestinal functions in Bacteria and IBS Intestinal bacteria and gut 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 Barbara et al. , Am J Gastroenterol 2005 Þ Enteric microflora play an important role in maintaining normal intestinal function Þ Changes in intestinal microflora can lead to significant alterations in GI function

Bacteria and IBS Intestinal bacteria and gut function Alteration in intestinal motility and hyperalgesia Bacteria and IBS Intestinal bacteria and gut function Alteration in intestinal motility and hyperalgesia following intestinal inflammation with Tricinella spiralis in mice Bercik et al. , Gastroenterology 2004 Þ Certain pathogens have specific effects on gut functions that have direct relevance to the pathophysiology of IBS

Bacteria and IBS Intestinal bacteria and gut function Putative mechanisms for effects (1) Release Bacteria and IBS Intestinal bacteria and gut function 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…

Bacteria and IBS Intestinal bacteria and gut function Putative mechanisms for effects (animal model Bacteria and IBS Intestinal bacteria and gut function Putative mechanisms for effects (animal model studies) The effect of IV injected Lipopolysaccharide (LPS) on intestinal motility Bacterial LPS significantly reduced K+induced contractions in various intestinal segments: - in duodenum 68% - in jejunum 58% - in ileum 52% E. Rebollar, Acta Physiol Scand 2003

Bacteria and IBS Intestinal bacteria and gut function Putative mechanisms for effects (human studies) Bacteria and IBS Intestinal bacteria and gut function Putative mechanisms for effects (human studies) The effect of intestinal infusion of SCFA on intestinal motility Lipids SCFA saline SCFA Lipids SCFA significantly increases colonic motility and decreases gastric emptying Cherbut et al, 2003 Coffin et al, 1997

Bacteria and IBS Implications for Clinical Management Data from probiotics trials Data from antibiotics Bacteria and IBS Implications for Clinical Management Data from probiotics trials Data from antibiotics trials

Bacteria and IBS Implications for Clinical Management Data from probiotics trials Data from antibiotics Bacteria and IBS Implications for Clinical Management Data from probiotics trials Data from antibiotics trials

Bacteria and IBS Evolution of the use of probiotics in GI disorders “microbial balance” Bacteria and IBS Evolution of the use of probiotics in GI disorders “microbial balance” - probiotic microflora compete with pathogens for available substrate or binding sites on the intestinal mucosa Þ Probiotics were used mainly in context of infection and diarrheal diseases Immune modulating effects – both intestinally and systemically Þ Use of probiotics in context of chronic inflammation inflammatory bowel diseases (IBD), atopic dermatitis, asthma etc. Modulating intestinal functions – motility, sensation, secretion Þ Use of probiotics in context of functional GI disorders irritable bowel syndrome (IBS), bloating, functional diarrhea

Probiotics in GI Clinical use of probiotics in GI disorders Probiotics have been shown Probiotics in GI Clinical use of probiotics in GI disorders 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 may have beneficial effects in IBD: Pouchitis Ulcerative colitis (UC) Crohn’s Disease 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 Probiotics - Clinical trials in IBS • Several controlled trials • Results have been mixed • Methodological limitations

Probiotics - Clinical trials in IBS – a negative study Weekly proportions of responders Probiotics - 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 IBS – a negative study Post-treatment gastrointestinal transit measurements Probiotics - Clinical trials in IBS – a negative study 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 0. 86 Colonic filling 6 h (%) 72 ± 6 67 ± 5 0. 62 Post-treatment GC 24 3. 4 ± 0. 4 3. 2 ± 0. 3 0. 70 Post-treatment GC 48 4. 5 ± 0. 3 4. 4 ± 0. 2 0. 99 GC 24/48, geometric centre at 24 and 48 h; GE, gastric emptying There were no significant differences in GI transit measurements, between the two treatment groups, pre- or post-therapy Kim HJ, Aliment Pharmacol Ther. 2003

Probiotics - Clinical trials in IBS – a negative study Weekly scores of flatulence Probiotics - Clinical trials in IBS – a negative study Weekly scores of flatulence and bloating Decrease in flatulence No effect of bloating VSL#3 vs. placebo twice daily for 8 weeks Kim HJ, Neurogastroenterol Motil 2005

Probiotics - Clinical trials in IBS – a negative study Scintigraphic images of colonic Probiotics - Clinical trials in IBS – a negative study Scintigraphic images of colonic transit with VSL# 3 and placebo at baseline and after treatment GC 24, geometric centre at 24 h VSL# 3 was associated with slower colonic transit compared to placebo (P = 0. 05) Kim HJ, Neurogastroenterol Motil 2005

Probiotics - Clinical trials in IBS - a positive study Composite of IBS symptoms Probiotics - Clinical trials in IBS - a positive study Composite of IBS symptoms (Likert scale and VAS scores) Abdominal pain scores (Likert scale) Significant improvement in pain/discomfort score during most weeks of the treatment and into the washout phase with B. infantis (*P <. 05) 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) O’Mahony et al. , Gastroenterology 2005

Probiotics - Clinical trials in IBS Intestinal bacteria and gut function Mononuclear IL-10/IL-12 in Probiotics - Clinical trials in IBS Intestinal bacteria and gut function Mononuclear IL-10/IL-12 in IBS and controls pre- and post-treatment Evidence for abnormal immune function in IBS patients compared to controls O’Mahony et al. , Gastroenterology 2005

Probiotics - Clinical trials in IBS Intestinal bacteria and gut function Mononuclear IL-10/IL-12 in Probiotics - Clinical trials in IBS Intestinal bacteria and gut function 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 IL 10: IL 12 ratio with B. infantis O’Mahony et al. , Gastroenterology 2005 => Probiotic strains can normalize immunologic alterations in IBS and this is associated with clinical response

Bacteria and IBS Implications for Clinical Management Data from probiotics trials Data from antibiotics Bacteria and IBS Implications for Clinical Management Data from probiotics trials Data from antibiotics trials

Bacteria and IBS Implications for Clinical Management Antibiotics - Clinical trials in IBS Antibiotics Bacteria and IBS Implications for Clinical Management Antibiotics - Clinical trials in IBS 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 • Randomized, double-blind, placebo-controlled study • 87 outpatients Antibiotics - Clinical trials in IBS • 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 Results 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) Bloating was also improved No differences in the constipation group Pimentel et al. Am J Gastroenterol 2005 (abstract)

Antibiotics - Clinical trials in IBS Antibiotic Treatment for Bloating and Gas • Randomized, Antibiotics - Clinical trials in IBS Antibiotic Treatment for Bloating and Gas • 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 Results Symptomatic Relief: • After 20 days 41. 3% vs 22. 9% (p =0. 03) • After 40 days 28. 6% vs 11. 5% (p <0. 02) The best outcome was in the group in which neomycin was successful in normalizing the LBT Symptom improvement correlated with reduction in H 2 -breath excretion Sharara AI, et al. AJG 2006; 101: 326 -333.

Bacteria and IBS Conclusions 1. Anecdotal observations suggest alterations in int. microflora in patients Bacteria and IBS Conclusions 1. Anecdotal observations suggest alterations in int. microflora in patients with 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 However… • The few studies in this area have been small with methodological limitations • The enthusiasm for the use of probiotics or antibiotics in IBS has outpaced the scientific evidence

Bacteria and IBS We need • Better understanding of the normal intestinal microflora and Bacteria and IBS We need • Better understanding of the normal intestinal microflora and the alterations of intestinal microflora in specific GI conditions including IBS • Better understanding of the complex interactions between the host and intestinal microflora • More epidemiological data on the prevalence and role of SIBOG in IBS • Better understanding of the pathophysiology of PI-IBS, bloating and gas • Large, well-designed, controlled, clinical trials to investigate the effects of manipulation of intestinal microflora with probiotics, prebiotics, and antibiotics

Bacteria and IBS Ongoing Research – Clinical Trials Probiotics Studies • Clinical Efficacy of Bacteria and IBS Ongoing Research – Clinical Trials Probiotics Studies • 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 (BB 12) in Subjects with Functional Gastrointestinal Symptoms (pending) Antibiotic Study • 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 Genetic Study • Genetic Surrogate Markers for Irritable Bowel Syndrome susceptibility, comorbidity and disease characterization

Bacteria and IBS Thank you Balfour Sartor Young-Hyo Chang Bill Whitehead Jiwon Kim Tope Bacteria and IBS Thank you Balfour Sartor Young-Hyo Chang Bill Whitehead Jiwon Kim Tope Keku Sarah Causey Sarah Yaskel Jenifer Juhl