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Prebiotics, Probiotics,

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Title: Prebiotics, Probiotics,


1
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

2
Disclosure
  • Investigator Initiated Research Support
    AstraZeneca, GlaxoSmithKline, Medtronics,
    Novartis, Prometheus
  • Speakers Bureau Novartis, Takeda

3
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

4
Functional Foods
  • Functional foods substances or supplements
    administered to obtain a specific result
  • Also called nutriceuticals or biotherapeutics
  • Examples
  • Prebiotics
  • Probiotics

5
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)

6
Prebiotics
  • Fructooligosaccharide (aka oligofructose)
  • Isomaltooligosaccharide
  • Xylooligosaccharide
  • Inulin
  • Fiber
  • Oligomate
  • Palatinose
  • Pyrodextrin
  • Raftiline

7
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

8
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

9
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

10
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

11
Intestinal Microecology
Foods that enter the GI Tract
12
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

13
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

14
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

15
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.

16
Conditions that can disrupt normal gut flora
homeostasis
  • Medications
  • Antibiotics
  • Surgery
  • Radiation
  • Diet
  • Co-morbid diseases
  • Crohns
  • Scleroderma

17
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18
Probiotics An Overview
  • Key properties
  • Mechanisms of action
  • Potential uses

19
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

20
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

21
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

22
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)

23
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)

24
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)

25
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)

26
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)

27
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

28
Probiotics Potential Uses
  • IBS
  • IBD
  • Infectious diarrhea in children (i.e., rotavirus)
  • Travelers diarrhea
  • Antibiotic associated diarrhea
  • Clostridium difficile

29
Genetic Predisposition
Stress
Environmental Influences
History Of Abuse
Parental Modeling
Development Of IBS
Infection/ Inflammation/ SIBO
Other Factors
Anxiety
Stress
Somatization
Poor Coping Skills
Depression
Manifestation Of IBS symptoms
30
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)

31
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

32
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

33
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 (n21) were found to have
    increased
  • mucosal permeability
  • number of lymphocytes in the lamina propria
  • number of intra-epithelial lymphocytes at 1 year
    FU

34
Pathogenesis of IBS Inflammation
  • Tornblom et al (Gastro. 2002) Full thickness
    jejunal biopsies of IBS patients (n10) 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)

35
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

36
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

37
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)

38
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)

39
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

40
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)

41
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

42
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 lt 0.05)

43
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

44
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

45
Probiotics IBS
  • Saggioro et al (J Clin Gastro 2004)
  • Lactobacillus plantarum bifidobacteria vs.
    Lactobacillus plantarum Lactobacillus
    acidophilus vs. placebo
  • Dose 5 x 109 cfu for each agent
  • Route - oral
  • Randomized, ? DB, PC
  • 70 subjects entered and completed mean age 40
  • Rome II criteria
  • 4 weeks
  • Pain severity decreased by 20 in both groups
    compared to placebo (no statistics performed)

46
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

47
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

48
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

49
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 lt 0.02)

50
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

51
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?

52
Probiotics Whats needed
  • Standardized protocols
  • Larger studies
  • Defined outcomes
  • Correlation with symptoms? Or cytokine levels? Or
    rectal biopsies? Or

53
Antibiotics and IBS
54
IBS Cured by AntibioticsAntibiotics Cure
IBS SymptomsIBS Symptoms Improve on
Antibiotics
55
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

56
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 lt 0.05)

57
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, plt0.04) and at 10 day follow-up
    (28.6 vs. 11.5 p 0.02)

58
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
  • Rifaximin 400 mg tid vs. placebo
  • LBT performed but not reported
  • Composite scores used

59
IBS SIBO
  • Pimental 2006, contd
  • At 10 week follow-up, overall symptoms improved
    (38.6 vs. 23.4 p lt 0.05), but no improvement
    in bowel habits, abdominal pain
  • Some improvement in bloating also noted (p
    0.010)

60
Summary
  • Confusing
  • Conflicting
  • Contradictory
  • Stimulating
  • Challenging
  • Exciting

61
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62
Pathogenesis of IBS
  • Genetic factors
  • Stress
  • Infections
  • Inflammation
  • Diet
  • Small intestine bacterial overgrowth

63
Probiotics and Immune Function
  • Probiotics have been shown to induce TNF activity
    in a murine model of NAFLD (Li et al,
    Hepatology, 2003)
  • In healthy volunteers, L. rhamnosus increased
    phagocytic activity and NK tumor cell killing
    activity (Sheih et al, J Am Coll Nutri 2001)

64
What is the role of genetics in IBS?
  • Familial aggregation studies
  • Twin studies
  • Genetic epidemiology studies
  • Reduced IL-10-levels
  • Alteration in SERT

65
Evidence of heredity in IBS Twin studies
0

FBD Functional Bowel Disorder
Morris-Yates A, et al. Am J Gastroenterol.
199893(8)13117 Levy RL, et al.
Gastroenterology. 2001121(4)799804 Lembo A, et
al. Gastroenterology. 2002120A636 Mohammed I,
et al. Am J Gastroenterol. 2005100(6)13404
66
Mechanisms in IBS
External influences Emotions
EnhancedPerception
Vagal Nuclei
5-HT
Sympathetic
AlteredMotility
VisceralHypersensitivity
Adapted from Camilleri and Choi. Aliment
Pharmacol Ther. 1997113.
67
Functions of the Gut Wall
  • Mechanical barrier
  • Absorption and secretion
  • Key component of normal immune function
  • Immune cells
  • Antibody production

68
GI Secretions
  • GI tract is exposed to 6 8 liters/day
  • Bile acids can inhibit indigenous flora
  • Gut flora maintains enterohepatic circulation of
    bile acids by deconjugation and transformation
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