ibs抗生素治疗的争议（英文ppt）probioticsandibs课件

Prebiotics, Probiotics, & Antibiotics: Controversies in the Treatment of IBS,Brian E. Lacy, Ph.D., M.D. Associate Professor of Medicine Dartmouth Medical School Director, GI Motility Laboratory Dartmouth-Hitchcock Medical Center,Disclosure,Investigator Initiated Research Support: AstraZeneca, GlaxoSmithKline, Medtronics, Novartis, Prometheus Speakers Bureau: Novartis, Takeda,Goals,Define commonly used terms Review the microecology of the intestinal tract Discuss the mechanism of action of probiotics Review the available literature on probiotics and IBS Assess the role of antibiotics in the treatment of IBS,Functional Foods,Functional foods substances or supplements administered to obtain a specific result Also called “nutriceuticals” or “biotherapeutics” Examples: Prebiotics Probiotics,Prebiotics,Non-digestible food supplements or ingredients Not absorbed or degraded Alter the balance of intestinal flora and by acting as substrates stimulate the growth of beneficial bacteria (i.e., Lactobacillus and Bifidobacteria),Prebiotics,Fructooligosaccharide (aka oligofructose) Isomaltooligosaccharide Xylooligosaccharide Inulin Fiber Oligomate Palatinose Pyrodextrin Raftiline,Probiotics,Non-pathogenic live microbial food supplements Organisms that, when administered in adequate amounts, exert a positive influence on the health of the host animal Live organisms that benefit the host animal by improving intestinal microbial balance Usually administered in yogurt or capsules,A Brief History of Probiotics,Metchnikoff 1907 ingesting yogurt with Lactobacilli reduces toxic bacteria of the gut and prolongs life Kipeloff 1926 stressed importance of Lactobacillus acidophilus for good health Rettger 1930s early clinical application of Lactobacillus Parker 1974 1st to use the term probiotics Fuller 1989 defined probiotics,Probiotics,Lactobacilli anerobic, gram (+) rods casei plantarum acidophilus reuteri Bifidobacteria anerobic, gram (+) rods VSL #3 (8 separate organisms: 3 Bifidobacteria, 1 Streptococcus, 4 Lactobacilli) Enterococcus Streptococcus salivarius Saccharomyces,How is normal mucosal immune function maintained?,GI secretions (saliva, acid, bile) Mucus Normal peristalsis (presence of MMC) Barrier function (tight junctions) Intestinal proteolysis Intestinal immune cells IgA production and secretion,Intestinal Microecology,Foods that enter the GI Tract,Intestinal Flora: A symbiotic relationship with the host,Human GI tract contains 10x more bacteria (1014) than eukaryotic cells in the body Protects the host Stimulates immune function Produces antimicrobial substances Trophic effect on intestinal epithelium Maintains the enterohepatic circulation of bile acids Involved in metabolic processes (i.e., fermentation) in the colon,Intestinal Microflora: Location & Prevalence,Rare in the esophagus Uncommon in the stomach primarily gram (+) 102 - 104 105 in the jejunum primarily aerobes 1010 1012 in the colon primarily anerobes 1000x more anerobes than aerobes,Formation & Maintenance of Gut Flora (Microbiota),Genetic factors Age Gender Mothers microbiology Mode of delivery Feeding practices Breast-fed Bifidobacterium Bottle-fed - Lactobacillus Co-morbid conditions Medications Diet,Predominant human fecal flora,Aerobic organisms E. coli Enterococcus sp. Streptococcus sp. Bacillus sp. Citrobacter sp. Klebsiella sp.,Anaerobic species Anaerobic cocci Bacteroides sp. Eubacterium sp. Bifidobacterium sp. Lactobacillus sp. Fusobacterium sp. Clostridium sp.,Conditions that can disrupt normal gut flora homeostasis,Medications Antibiotics Surgery Radiation Diet Co-morbid diseases Crohns Scleroderma,Probiotics: An Overview,Key properties Mechanisms of action Potential uses,Key Properties of Probiotics,Bacteria of human origin Safe to use in large amounts in clinical practice Resist secretions of the upper GI tract Survive passage through the GI tract Adhere to human intestinal cells,Key Properties of Probiotics,Able to colonize the lumen of the GI tract Help to protect the cells against invasion by pathogens Produce antimicrobial substances hydrogen peroxide organic acids bacteriocins Antagonize carcinogenic and pathogenic flora,Probiotics: Mechanism of Action,Competitive inhibition Barrier protection Immune effects Anti-inflammatory effects Production of various substances (enzymes, SCFA, bacteriocidal agents) Ability to alter local pH and physiology Provides nutrition to colonocytes,Probiotics: Competitive Inhibition,Helps to restore the balance of “good” bacteria and “bad” bacteria Facilitates the growth of healthy bacteria i.e., Bifidobacterium and Lactobacillus Bifidobacterium infantis inhibits the growth of Salmonella (OMahony 2004; Gastro),Probiotics: Barrier Protection,Intestinal permeability to bacteria is increased with inflammation, i.e., Crohns, UC, ischemia (Nejdfors et al Scan J Gastroenterol 1998) Pretreatment with L. plantarum 299v inhibits E. coli intestinal permeability (Mangell et al Dig Dis Sci 2002) B. infantis prevents bacterial (Salmonella) translocation (OMahony Gastro 2004),Probiotics & Immune Function,Mononuclear cells incubated with Lactobacilli produce higher levels of IFN-gamma, TNF-alpha, and IL-1 (MacFarlane & Cummings, BMJ, 1999) Bifidobacteria suppressed the pro-inflammatory mediators (TNF-alpha, IFN-gamma, IL-12) in a murine model of IBD (IL-10 knockout) (McCarthy et al, Gut 2003) In healthy volunteers, L. rhamnosus increased phagocytic activity and NK tumor cell killing activity (Sheih et al, J Am Coll Nutri 2001),Probiotics & Immune Function,Borruel and colleagues assayed ileal specimens from Crohns patients (10) and compared to 5 controls (right hemicolectomy for colon cancer) Specimens cultured with various bacteria (L. casei, L. bulgaricus, L. crispatus) CD4 levels and TNF-alpha levels reduced in Crohns explants but not in normal volunteers Impression: probiotics interact with immunocompetent cells to modulate the production of pro-inflammatory cytokines from ileal tissue in Crohns patients (Borruel Gut 2002),Probiotics: Production of Other Substances,Intestinal bacteria play a key role in the production of short-chain fatty acids (SCFA) Butyric acid is the main fuel for colonocytes L. plantarum appeared to increase production of butyric acid in 36 healthy volunteers, leading to reductions in fibrinogen, leptin, and monocyte adhesive properties (Naruszewicz et al Am J Clin Nutr 2002),Probiotics: Impact on Local Physiology,Example - Antibiotic associated diarrhea Restores resident flora Increases production of SCFA SFCAs are absorbed by diffusion, leading to increased water and Na absorption Stimulates colonocyte proliferation, which may further improve water and Na reabsorption,Probiotics: Potential Uses,IBS IBD Infectious diarrhea in children (i.e., rotavirus) Travelers diarrhea Antibiotic associated diarrhea Clostridium difficile,Genetic Predisposition,Development Of IBS,Manifestation Of IBS symptoms,Stress,Infection/ Inflammation/ SIBO,Environmental Influences,Parental Modeling,Other Factors,History Of Abuse,Anxiety,Depression,Stress,Poor Coping Skills,Somatization,Pathogenesis of IBS: Stress,Animals models of stress demonstrate loosening of intercellular tight junctions Stress is associated with increased rate of post-infectious IBS Stress is associated with increased frequency and intensity of symptoms, and increased consulting behavior (Drossman et al, 2005),Pathogenesis of IBS: Infections,Chaudary & Truelove 1962 described onset of IBS after dysentery McKendall & Read 1994 Bowel dysfunction developed in 12/38 patients after salmonella infection Neal et al (1997) at 6 month follow-up, 7% of patients developed IBS symptoms after bacterial gastroenteritis Garcia-Rodriguez (1999) RR for developing IBS symptoms after bacterial gastroenteritis = 10,Pathogenesis of IBS: Infections,Gwee (1999) 94 patients with acute gastroenteritis compared to controls 23% had IBS symptoms at 3 months 64% were women Stress, hypochondriasis associated with increased likelihood Rectal biopsies at 3 months revealed an increased number of mucosal inflammatory cells,Pathogenesis of IBS: Inflammation,Gwee et al (Gut 1999) rectal biopsies revealed an increase in mucosal inflammatory cells in patients with post-infectious IBS Spiller et al (Gut 2000) After Campylobacter enteritis patients (n=21) were found to have increased: mucosal permeability number of lymphocytes in the lamina propria number of intra-epithelial lymphocytes at 1 year FU,Pathogenesis of IBS: Inflammation,Tornblom et al (Gastro. 2002) Full thickness jejunal biopsies of IBS patients (n=10) revealed low-grade infiltration of lymphocytes in the myenteric plexus in 9 patients, and neuronal degeneration in the myenteric plexus in 6/9 patients Experimental colitis alters myenteric nerve function and previous inflammation changes/sensitizes rats to stress (Jacobson et al, Gastro 1995; Collins et al, Gastro 1996),Pathogenesis of IBS: Altered Gut Flora,IBS patients may have different ratios of normal gut flora Reduced levels of Lactobacilli and Bifidobacterium Increased levels of Clostridium Balsari et al, Microbiologica 1982 Malinen et al, Am J Gastro 2005 Lin, JAMA 2004,Risk Factors for SIBO,Ileocecal resection Small intestinal stasis Diverticulosis, strictures Abnormal motility (scleroderma, CIP) Hypochlorhydria Immunodeficiency Gastroparesis Chronic diseases (cirrhosis, alcoholism, celiac) Pancreatitis, Parkinsons disease ? IBS,Pathogenesis of IBS: SIBO,78% of patients (157/202) referred for LHBT had bacterial overgrowth (Pimental et al, 2000) 84% of 111 IBS patients (Rome I criteria) had SIBO (Pimental et al, 2003) 65% of IBS patients have SIBO (Nucera et al, APT, 2005),Pathogenesis of IBS: SIBO,Walters & Vanner 10% of IBS Pts (Am J Gastroenterol 2005) Crowell et al 10% (ACG 2005) Olden et al 10% (ACG 2005) Jones et al 10% (ACG 2005) Ruff et al 6% of IBS patients had SIBO, using duodenal aspirates (ACG 2006),Probiotics & IBS,Halpern et al (Am J Gastroenterol 1996) L. acidophilus (Lacteol Fort) Dose 5 x 109 q day (heat killed) Route capsule Study randomized, double-blinded, cross-over Subjects entered 18 Criteria IBS symptoms 6 weeks; self-administered questionnaire Mean daily scores were better on Lactobacillus compared to placebo in 9 patients who responded,Probiotics & IBS,OSullivan et al (Dig Liver Dis 2000) Lactobacillus GG casei Dose - 1 x 1010 daily Route - tablet Randomized, double-blinded, placebo-controlled 24 Subjects entered; 19 completed Rome II criteria 20 weeks No significant benefits noted (? some relief of bloating),Probiotics & IBS,Sen et al (Dig Dis Sci 2002) Lactobacillus plantarum 2990 Dose - 6.5 x 109 daily (Pro Viva fruit drink) Route oral (approx. 125 cc) Double-blinded, PC, crossover study 12 subjects entered Rome criteria; 4 weeks No improvement in symptoms Decrease in breath H2 by LBT,Probiotics & IBS,Niedzielin et al (Eur J Gastro Hepatol 2001) Lactobacillus plantarum 299V Dose - 1 x 1010 twice daily (Pro Viva) Route liquid (approx. 250 cc) Randomized, double-blinded, PC 40 subjects total Rome criteria; 4 weeks Decreased symptoms with some improvement in abdominal pain compared to baseline in the L. plantarum group (p 0.05),Probiotics & IBS,Nobaek et al (Am J Gastroenterol 2000) Lactobacillus plantarum D5M9843 Dose - 2 x 1010 daily Route drink (approx. 400 cc) Randomized, double-blinded, placebo-controlled 60 subjects entered; 52 completed Rome criteria; 4 weeks Decrease in flatulence and abdominal discomfort (NS) Bacteria recovered from the stool,Probiotics & IBS,Kim et al (APT 2003) VSL #3 Dose 4.5 x 1011 daily Route powder 25 IBS subjects entered; 24 completed Parallel group, DB, placebo-controlled Rome criteria; diarrhea predominant 2 week run-in; 8 week trial Less bloating noted (p = 0.09); other Sx not improved No change in GI transit time,Probiotics & IBS,Saggioro et al (J Clin Gastro 2004) Lactobacillus plantarum mean age = 40 Rome II criteria 4 weeks Pain severity decreased by 20% in both groups compared to placebo (no statistics performed),Probiotics & IBS,OMahony et al (Gastroenterology 2005) Lactobacillus salivarius UCC4331 1 x 1010 Bifidobacterium infantis 35624 1 x 1010 Route: oral malted milk drink Randomized, double-blinded, PC 75 subjects entered, 68 eligible for analysis; mean age = 44; 1/3 men and 2/3 women Rome II criteria all subtypes included 8 weeks Sx, Qol, stool microbiologic studies, IL-10 and IL-12 serum levels,Probiotics & IBS,OMahony et al, cont. B. infantis improved global symptom scores and individual scores (pain/discomfort, bloating/distention, difficult defecation) significantly more than both Lactobacillus and placebo B. infantis improved QoL score for only domain of health worry B. infantis normalized IL-10/IL-12 ratios No change in stool frequency or consistency,Probiotics & IBS,Whorwell et al (Am J Gastro 2006) Bifidobacterium infantis 35624 Dose 106, 108, 1010 cfu daily x 4 weeks Route freeze-dried, encapsulated Randomized, double-blinded, PC; multi-center Rome II criteria all subtypes (55% D; 21% C) 362 female IBS patients (approx. 90 per group); 330 completed the study; 293 analyzed Primary endpoint abdominal pain score (6 point Likert scale); global IBS symptoms,Probiotics & IBS,Whorwell et al continued B. infantis at 108 cfu/day was significantly superior to placebo and to other B. infantis doses (p = 0.023) at improving abdominal pain as well as general composite scores (bloating, incomplete evacuation, straining, bowel dysfunction; p 0.02),Probiotics & IBS: Problems,In general, small studies Underpowered Most do not verify bacterial transit & survival Varying doses Varying strains/species/subspecies Varying compositions Varying endpoints,Probiotics: Questions to answer,Which species is best? Are combination agents better? What is the appropriate dose? What is the appropriate duration of treatment? What outcome measures are appropriate? What is the appropriate follow-up? What is the appropriate patient population?,Probiotics: Whats needed,Standardized protocols Larger studies Defined outcomes Correlation with symptoms? Or cytokine levels? Or rectal biopsies? Or,Antibiotics and IBS,“IBS Cured by Antibiotics” “Antibiotics Cure IBS Symptoms” “IBS Symptoms Improve on Antibiotics”,IBS & SIBO,Pimental et al Am J 2000 202 Pts underwent LBT and retrospectively diagnosed with IBS; 157 + (78%) 47 patients treated with antibiotics returned (70% dropout rate) (neomycin, metronidazole, ciprofloxacin, doxycycline, and unknown = 36%) 7-10 days later repeat LHBT and FU questionnaire 12/25 (48%) who had complete eradication no longer met Rome I criteria for IBS 22/47 = incomplete eradication (47%) and 13/25 had eradication but still met Rome I criteria,IBS & SIBO,Pimental et al - Am J Gastro 2003 111 IBS patients (Rome I; 37% C; 44% D) All had LHBT Randomized to neomycin (500 mg BID) or placebo At 7 day FU, 8/41 (19.5%) treated with neomycin normalized LHBT ITT analysis neomycin improved composite score 35% compared to placebo 11.4% (P 0.05),IBS & Bloating,Shahara et al (Am J Gastro 2006) 124 patients with bloating + excessive flatulence 56% met Rome II criteria for IBS (20% D, 38% C) Mean age = approx.40; 55% women Lactulose breath test (-) in all patients Rifaximin (400 mg bid; n = 63) vs. placebo x 10 days Rifaximin treated patients had a reduction in gas and bloating immediately following treatment (37.5% vs. 20.4%, p0.04) and at 10 day follow-up (28.6% vs. 11.5%; p = 0.02),IBS & SIBO,Pimental et al (Ann Int Med 2006) 87 IBS patients (Rome II) aged 18-65 Mean age = 39; 29 M: 58 W Randomized, DB, PC Rifax