A New Approach to Gastrointestinal Health and Disease

Douglas A. Jacobstein, MD Division of GI & Nutrition The Sinai Hospital of Baltimore

Probiotics:

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Objectives
Introduce the concept of probiotics, prebiotics, and synbiotics Give a brief history of probiotics List some of the potential uses
Infectious diarrhea Antibiotic associated diarrhea Inflammatory bowel disease

Give some insight to the practical considerations when using them

Probiotics
Definition
Nutritional supplement Contains 1 or more cultures of living organisms Typically bacteria or yeast Modify the endogenous microflora Have a positive effect on the host

Prebiotics
Definition
Nondigestible food ingredients
Fructo-oligosaccharides (chicory, inulin) Lactulose

Positively affect the endogenous flora Stimulate the growth of one or a limited number of bacterial species
FOSBifidobacteria LactuloseLactobacilli

Synbiotics
Definition
A probiotic organism in combination with its prebiotic food Providing both the organism and substrate at the time of ingestion may offer improved chance of survival in GI tract

Intestinal Flora
1012 viable bacteria/gram of large bowel content
More than total cells in the human body More than total humans who have ever lived

At least 17 families At least 50 genera 400-500 species in any single person 80-90% unculturable

19th Century
Pasteur (1877)
Observed antagonistic interaction between bacterial strains Suggested that non-pathogenic bacteria should be used to control pathogenic bacteria

Probiotics

Early 20th Century

Metchnikoff (1907)
Observed that lactic fermentation of milk arrested putrefaction Suggested that consumption of fermented products would offer the same benefit to humans Felt that longevity in Bulgarian peasants was due to ingestion of soured milks

Probiotics

Probiotics Mid to late 20th Century

1950s, Ferdinand Vergin publishes article discussing effects of antibiotics on beneficial intestinal bacteria
1980s Fuller establishes first definition of probiotics

Probiotics
Candidates
Lactobacillus
acidophilus, reuteri, casei, planatarum, rhamnosus GG

Bifidobacteria
bifidum, breve, infantis, longum

Streptococcus
thermophilus

Saccharomyces Several combinations on the market

Probiotics
Potential Mechanisms of Action
Inhibition of adhesion Immunomodulation Production of antimicrobial substances Modification of toxins or toxin receptors Competition for nutrients Reduction in bacterial translocation Anti-inflammatory signaling within the epithelium

Many Potential Uses

Infectious diarrhea and day care related illness Antibiotic Associated Diarrhea
Clostridium difficile

Probiotics

Inflammatory bowel disease Travelers diarrhea Prevention of NEC Allergy Irritable Bowel Syndrome

Many Potential Uses

Infectious diarrhea and day care related illness Antibiotic Associated Diarrhea
Clostridium difficile

Probiotics

Inflammatory bowel disease Travelers diarrhea Prevention of NEC Allergy Irritable Bowel Syndrome

U.S. Daycare Statistics

National Household Surveys Education Program (NHES), U.S. Department of Education, 2002

Day Care and Childhood Infection

It has long been suspected that early exposure to other children increases the risk of communicable diseases
I Diehl, The prevalence of colds in nursery

school children and non-nursery school children. J Pediatr 34:52-61, 1949

Impact of Day Care Center Illness

Children in day care 4.5 times more likely to be hospitalized1 Child illness accounts for up to 40% of adult absenteeism from work1

Cost of $2307 (1998 dollars) per diarrhea-associated hospitalization2

0.52 days lost per month for day care vs. 0.37 days for children in other childcare
1DM

Bell, et al. Am J Public Health 79:479-84, 1989 2CM Zimmerman, et al. Pediatr Infect Dis J 20(1):14-9, 2001

Day Care Means Increased Risk of Gastrointestinal Infections

Estimated crude incidence density of diarrhea among children in home care, family day care, and DCCs. From: Louhiala. J Pediatr 131(3):476-9, 1997

Potential Methods to Reduce Day Care Center Morbidities

Prevention of infections
Respiratory and gastrointestinal

Treatment of infections Reduce transmission of disease Probiotics may positively influence each of these methods
Stimulating the immune system Reducing viral shedding

Prevention of Diarrheal Illness

18 Week Therapy in French Children (6-24 months) in Day Care Yogurt (364)
Children with diarrhea Duration of diarrhea (days) Rotavirus positive stool

Yogurt+

P-value

L. casei
(360)

87 (22%) 61 (16%) 3.95 2.2% 3.53 0.3%

0.029 0.24

CA Pedone, et al. Int J Clin Pract 54(9):568-71, 2000

Prevention of Diarrheal Illness

12 Week Therapy in Israeli Infants (4-10 months) in Day Care

Controls (60)
Days with diarrhea Episodes of diarrhea Clinic visits Absences

B. lactis
(73)

L. reuteri
(68)

P-value

0.59 0.31

0.37 0.13

0.15 0.02

<0.001 <0.001

0.55
0.43

0.51
0.41

0.23
0.14

0.002
0.015

Z Weizman, et al. Pediatrics 115:5-9, 2005

Treatment of Acute Diarrhea

5 Day Therapy in Danish Children (9 to 44 months) in Day Care with Acute Diarrhea

Whole Study Group

Control (19)
Duration of diarrhea (hours) Duration of watery diarrhea Duration of fever (days) Diarrhea after 120 hours

L. reuteri/ L. rhamnosus
(24)

P-value

115.7 37 1.1 7

75.9 38.1 1.4 2

0.05 0.94 0.59 0.03

V Rosenfeldt, et al. Pediatr Infect Dis J 21:417-9, 2002

Treatment of Acute Diarrhea

5 Day Therapy in Danish Children (9 to 44 months) in Day Care with Acute Diarrhea

Early Intervention (<60 hours) Control L. reuteri/ (13) L. rhamnosus

(17)
Duration of diarrhea (hours) Duration of watery diarrhea Duration of fever (days) Diarrhea after 120 hours

P-value

138.9
52.3

78.8
36.6

0.02
0.34

1.3
6

1.5
1

0.75
0.03

V Rosenfeldt, et al. Pediatr Infect Dis J 21:417-9, 2002

Rotavirus Diarrhea
Affects 70% of children up to age 51 Approximately 50,000 hospitalizations annually in the U.S. in children under 5 years of age1 Most common cause of infectious diarrhea in community settings2
Symptoms typically last 3-8 days3
Highest proportion in children 12 to 36 months Viral shedding up to 21 days after onset of symptoms
1AW

Tucker, et al. JAMA 279(17): 1371-6, 1998 2V Waters, et al. Pediatr Infect Dis J 19(9): 843-8, 2000 3LK Pickering, ed. Red Book, 26th ed.: 534-6, 2003

Infectious Diarrhea
Children up to 2 years of age in chronic care facility Randomized to receive B. bifidum and S. thermophilus or placebo Statistically less diarrhea (7% vs 31%) Statistically less rotavirus shedding (10% vs 39%)
Saavedra et al, Lancet 1994

Probiotics

Antibiotic Associated Diarrhea

Common side effect of antibiotic therapy
Up to 40% of children receiving broad spectrum antibiotic therapy

Probiotics

Mechanism
Likely due to altered microbial flora Leads to altered metabolism of osmotically active substances

Antibiotic Associated Diarrhea

188 children 6 months to 10 years of age randomized to receive Lactobacillus GG versus placebo while receiving oral antibiotics Significant differences in patients who had diarrhea were seen (26% placebo vs 8% probiotic)
Vanderhoof J et al, J Pediatr, 1999

Probiotics

Vanderhoof J et al, J Pediatr, 1999

Vanderhoof J et al, J Pediatr, 1999

2 Week Therapy in Finnish Children (2 weeks to 12 years) Controls (58)

Children with diarrhea Duration of diarrhea (days) Stool frequency (per day)

(After Antibiotics for Respiratory Illness)

Lactobacillus GG
(61)

Prevention of Diarrheal Illness

P-value

9 (16%)

3 (5%)

0.05

4
5

4
5

NS
NS

T Arvola, et al. Pediatrics 104(5), 1999

Antibiotic Associated Diarrhea

S. boulardii
Reduced rate of diarrhea in 116 patients versus placebo

Probiotics

Lactobacillus GG
Decreased diarrhea in people treated with triple therapy for H. pylori Found to reduce days of diarrhea and side effects when coadministered with erythromycin in healthy volunteers

Clostridium difficile
Second most common cause of bacterial diarrhea (25% of cases) Commonly precipitated by antibiotic use or disruption of endogenous flora
Positive response to LGG in patients with recurrent infection Successful prevention of recurrence with S.

Probiotics

boulardii

Clostridium difficile
138 hospitalized adults receiving antibiotics randomized to receive probiotics (Lactobacillus and Bifidobacterium) or placebo Patients receiving probiotics were less likely to have C. difficile toxin (46% vs 78%) Patients who developed diarrhea were less likely to have C. difficile toxin (2.9% vs 7.25%)
Plummer S Int Microbiol, 2004

Probiotics

Many Potential Uses

Infectious diarrhea and day care related illness Antibiotic Associated Diarrhea
Clostridium difficile

Probiotics

Inflammatory bowel disease Travelers diarrhea Prevention of NEC Allergy Irritable Bowel Syndrome

Chronic Inflammation: Imbalance Between Mediators

IL-1b IFNg IL-12 IL-8 IL-1Ra IL-4/IL-13 TGFb

IL-10

TNFa

The Development of Inflammatory Bowel Disease

Initiating Event

Damage

Abnormal Immune Response

Ongoing Inflammation

What is the initiating event?

Bacteria in IBD
Normal intestinal bacteria may cause inflammation to start In people without IBD, the body turns off the inflammation In people with IBD, the body cannot turn off the inflammation The process continues until something stops it

Bacteria and IBD

The Evidence
Special mice bred to develop IBD Stay healthy in sterile (bacteria-free) conditions Get sick when given normal intestinal bacteria

Bacteria and IBD

The Evidence
Diversion (ostomy)
Healing occurs when stool is diverted Inflammation returns when bowel is put back together

Antibiotics
Certain antibiotics that work against the intestinal bacteria help improve IBD

The newly discovered IBD gene (Nod2)

Involved in the bodys response to bacteria

From Fedorak RN and Madsen KL Inflamm Bowel Dis, 2004

Probiotics in IBD: Pouchitis

J Pouch

Probiotics in IBD:
Pouchitis
People with a history of pouchitis after colectomy 20 people given VSL3 20 people given placebo After 9 months: 3 out of 20 on VSL3 had a flare of pouchitis P < 0.001 20 out of 20 who received placebo had a flare

Ginochetti et al, Gastroenterology, 2000

Probiotics in IBD:
Pouchitis
Remission of pouchitis with antibiotics 36 patients randomized to receive VSL#3 or placebo Followed for 12 months
85% of probiotic group in remission at 1 year versus 6% of placebo group (p < 0.001)
Mimura et al, Suppl to Gastroenterology, 2002

Probiotics in IBD
Preliminary Studies
Ulcerative colitis patients All given steroids
59 given mesalamine (Pentasa, Asacol) 57 given a probiotic

Remission rates similar (75% vs. 68%) Relapse rates similar (73% vs. 67%) Length of remission similar (206 days vs. 221 days)
Rembacken et al Lancet, 1999

Probiotics in IBD
Preliminary Studies
4 pediatric patients with active Crohns disease Given Lactobacillus GG for 6 months
Patients had improvement in disease activity Patients had improvement in intestinal permeability
Gupta et al, J Pediatr Gastroenterol Nutr, 2000

Probiotics in IBD
Preliminary Studies
Open-label trial in adults with active Crohns Received Lactobacillus salivarius instead of corticosteroids
25 patients enrolled
19 patients avoided other therapies for 3 months Disease activity score decreased from 217 to 150
McCarthy et al, Gut 2001

Lactobacilli and Bifidobacteria

Why They Are Safe

Many exposures in pediatrics

Fermented foods Probiotics The hosts own microflora
Oral cavity Ileum and colon Vagina

Lactobacilli and Bifidobacteria

Why They Are Safe
Cases of infection extremely rare Account for 0.05% to 0.4% of infective endocarditis and bacteremia Less than 1 case per million people Review of 143 human clinical trials from 1961-1988
Over 7500 subjects No reported adverse events

Lactobacilli and Bifidobacteria

Why They Are Safe
Increasing probiotic consumption has not led to increased opportunistic infections
National Public Health Institute-Finland 1995-1999
Increasing cases of bacteremia (all types) Increasing use of probiotics Constant level of Lactobacillus bacteremia

Safe, however...
Several reports of fungemia associated with use of yeast-based probiotics (S. boulardii) Difficult to determine pathogenicity
Virulence factors for pathogens (adherence, colonization) are common in probiotic bacteria When bacteremia occurs, often polymicrobial and in critically ill host

Probiotics

Invasive Lactobacillus Infection

Occasional reports of invasive infections
Bacteremia (rare) Endocarditis: 16 reported cases (19922001)
5 cases with yogurt or probiotic Only 1 confirmed to be identical to probiotic

Liver abscess (74 yo woman)

Daily consumption of probiotic drink Indistinguishable from probiotic strain

Practical Issues
Purified strains of bacteria Selected for ability to:
Survive acid/bile in upper GI tract Colonize Adhere

Probiotics

Must have shelf viability Should have quality control

Practical Issues
Not FDA regulated
Quality control is poor 80% of preparations tested had 1% or less of the bacterial concentration on the label

Probiotics

Numerous preparations on the market

Which strains work best? Do different strains work better for different diseases? Do combinations work better than single strains?

Practical Issues
Typically $1 to $3 per day
VSL3: $56 for 20 day supply Culturelle (LGG): $55 for 30 day supply Custom Probiotics CP-1: $40 for 30 day supply

Probiotics

May need several months of therapy to see an effect Likely stop working after discontinued Concentration (dose) highly variable

Probiotics
Summary
An old concept, with a new attitude Potential therapy for many GI related diseases Largely unproven, but growing body scientific evidence Patients will need guidance as to which ones to use, when to use them, how to use them

Probiotics Necrotizing Enterocoltis

Randomized, controlled trial in 367 VLBW infants Received breast milk with probiotic (Lactobacillus and Bifidobacterium) versus breast milk alone Incidence of NEC lower in probiotic group (1.1% versus 5.3%, p= 0.04) with cases of severe NEC in control group versus none in probiotic group
Lin et al, J Pediatr, 2005