Probiotics: What Are They?

What Can They Do for You?

Elisabeth R. Evans, MSN, FNP-BCUC San Diego Inflammatory Bowel

Disease Center

Outline

I. The Microbiome

II. Probiotics Defined

a. What are probiotics

b. How Probiotics work

c. Probiotic Effects

III. Clinical Applications

IV. Safety Concerns2

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• The human microbiome is the sum collection of all the microbes found in or on our bodies.

• “In a sense, you aren’t really you.”

• Your body is a ‘colony of creatures.’

Introducing: The Microbiome

-Colin Nickerson, Boston Globe 2/25/2008

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• The human body supports unique ecological niches in the skin, GI tract, genito-urinary tract, and ducts of exocrine glands.– 100 trillion (1014)

microbial cells.– 10 trillion (1013)

human cells.– Concentration

ranges:• 103/g in stomach• 108/g in colon

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The Microbiome• Digestion

– Fermentation of food residue– Assimilation of minerals and

trace metals– Modification of bile acids

• Immune system training– Stimulation of innate immunity

– Processing of antigens

– Recognition of self vs. foreign

What are Probiotics?• Defined as living microscopic organisms, or microorganisms, that

scientific research has shown to benefit your health.

– Probiotic – “for life”• Most often they are bacteria, but they may also be other

organisms such as yeasts. In some cases they are similar, or the same, as the “good” bacteria already in your body, particularly those in your gut.

• Clinical uses of probiotics were first reported in the 1970s.– Therapy for lactose intolerance.

• The first successful trial of probiotics was conducted in children.

– Treatment of rotavirus gastroenteritis

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-Isolauri 1991 and 1994-Kaila 1995-Majamaa 1995

--U.N. Food and Agriculture Organization and WHO, 2001

What are Probiotics?• The most common probiotic bacteria come from two groups,

Lactobacillus or Bifidobacterium.

• HOWEVER, many other types of bacteria are also classified as probiotics. Each group of bacteria has different species and each species has different strains. This is important to remember because different strains have different benefits for different parts of your body.

• For example, Lactobacillus casei Shirota has been shown to support the immune system and to help food move through the gut, but Lactobacillus bulgaricus may help relieve symptoms of lactose intolerance, a condition in which people cannot digest the lactose found in most milk and dairy products.

• In general, not all probiotics are the same, and they don’t all work the same way.

The Epithelial Barrier

Lumen Lamina propria

Intestinal epithelium can distinguish between pathogens and normal bacteria

No response

Activation of NF-kBRelease of IL-8

Probiotics enhance mucus production

•Mucus secretion via cAMP

• Up-regulation of mucin- producing genes

Microbes Induce:

Deplancke et al AJCN 2001Otte et al Am J Phys 2004Caballero-Franco et al Can J Gastro 2004

Effects of Probiotics

12-Ramakrishna BS, Trop Gastro 2009

Probiotic Influence Outcome Implication

Enzymes Improve digestion Prevent gas formation

Short-chain fatty acids(e.g. butyrate)

Sustenance for epithelium, improve energy harvest(increase proliferation, differentiation, vascular supply)

Mucosal repairAnti-carcinogenic

Lactate Decreased stool pH Protection from invaders

Bacteriocins Colonization resistance Protection from invaders

Mucins Prevent pathogen adherence to epithelium Protection from invaders

Tight junction proteins Improves epithelial integrity Protection from translocation

Metabolic alteration Nitrogen and sulfide breakdown, consumption of reactive oxygen species (i.e. free radicals)

Anti-carcinogenicDetoxification

Immune conditioning Oral tolerance Controls inflammation

Defensins Microcidal influence Prevent bacterial overgrowth

Secretory IgA Clearance of luminal antigens and systemic effect (e.g. UTIs)

Protection from invadersControls inflammation

Common Uses of probiotics• Irritable Bowel Syndrome (IBS) is a disorder of

movement in the gut. People who have IBS may have diarrhea, constipation or alternating bouts of both. IBS is not caused by injury or illness. Not a disease characterized by inflammation.

•  Probiotics, particularly Bifidobacterium infantis, Sacchromyces boulardii, Lactobacillus plantarum and combination probiotics may help regulate how often people with IBS have bowel movements. Probiotics may also help relieve bloating from gas. Research is continuing to determine which probiotics are best to help treat IBS.

 

Common Uses of probiotics• Irritable Inflammatory Bowel Disease (IBD) is a

life long chronic illness in which the intestines become inflamed. Unlike IBS, IBD is a disorder of the immune system. Symptoms include abdominal cramps, pain, diarrhea, weight loss and blood in your stools. There are two main types of IBD: Crohn’s disease and ulcerative colitis.

• Recent research indicates that your gut microbiota plays a role in developing IBD.

• It appears that E. coli Nissle, a mixture of several strains of Lactobacillus, Bifidobacterium and Streptococcus may be beneficial. Research is continuing to determine which probiotics are best to treat IBD.

Common Uses of probiotics• Infectious Diarrhea is caused by bacteria, viruses or parasites.

There is evidence that probiotics such as Lactobacillus rhamnosus and Lactobacillus casei may be particularly helpful in treating diarrhea caused by rotavirus, which often affects babies and small children. Several strains of Lactobacillus and a strain of the yeast Saccharomyces boulardii may help treat and shorten the course of infectious diarrhea. 

• Traveler’s Diarrhea is caused by ingesting pathogenic, disease-causing, bacteria that are often present in the food or water. Most studies show that probiotics are not very effective in preventing or treating traveler’s diarrhea in adults. Scientists face a challenge in determining which probiotics might be useful because of the number of destinations to which people travel and the number of different bacteria travelers may encounter.

Common Uses of probiotics • Antibiotic-Related Diarrhea caused by reducing the number of

good microorganisms in your gut.• One such bacterium is Clostridium difficile, which is a major

cause of diarrhea in patients with IBD. • The trouble with Clostridium difficile is that it can lay dormant

and spores may activate. • There is evidence that taking probiotics such as Saccharomyces

boulardii may help prevent this. • There is also evidence that taking probiotics when you first

start taking an antibiotic may help prevent antibiotic-related diarrhea in the first place.

• It is important to note that most antibiotic-associated diarrhea is NOT infectious but rather is a result of reducing the number of normal microbiota in your gut.

Clostridium Difficile• Probiotics reduced risk

of recurrent C. diff by 57% compared with placebo in a 2009 large meta-analysis.

• Moreover, probiotics improve treatment result when used in combination with antibiotic therapy compared to antibiotics alone.

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-McFarland, Anaerobe 2009-Biller, JPGN 1995-Surawicz, Clin Infect Dis 2000

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• An exaggerated and dysregulated immune response to normal gut flora.

• Familial distribution and genetic predisposition.– Genetic mutations discovered in

intracellular signaling.• A disease of developed countries,

possibly related to modern diet and reduced incidence of infectious disease. This is the “Clean Hygiene Hypothesis”

– Mouse models: Inflammation does not occur if mice are maintained germ-free.

• A compromised epithelial layer is sufficient to result in intestinal inflammation.

Inflammatory Bowel Disease

Overexpression of proinflammatory mediators in T cells.

Deficient protective and regulatory signals.

Abnormal antigen presentation.

Aberrant thymic education.

Inflammatory Bowel Disease• Six trials in Crohn’s patients from 1998-2008 studied

S. boulardii (1 g/d), L. johnsonii LA1 and L. rhamnosus GG (109 CFU bid).– All studies reported no significant beneficial effects.

• Ten trials in ulcerative colitis with 861 total patients using different strains yielded inconsistent results.– E. coli Nissle 1917 was noted to be equivalent to mesalamine

in maintaining remission after induction therapy.

– VSL#3 showed efficacy in maintenance therapy.

– L. rhamnosus GG failed to show a significant effect.

19-Haller D, J Nutr 2010

E. Coli Nissle 1917 in UC• Matthes et al recently reported beneficial effects in

a trial of rectally administered EcN in UC patients with distal colitis.– 10, 20, or 40 ml of EcN enemas (108 CFU/ml) were

administered to 90 patients in 10 centers in Germany (age range 18-70 years) in a double-blind RCT.

– Patients had confirmed diagnosis of mild UC proctitis/proctosigmoiditis (25-30 cm from anus).

– Enema administered prior to bedtime for 2, 4, and 8 weeks.

• Remission rates were 53% in 40 ml group, 44% in 20 ml group, 27% in 10 ml group, and 18% in placebo (dose-dependency efficacy p=0.0446).

20-Metthes H, BMC Comp Alt Med 2010

E. Coli Nissle 1917 in UC• Remission rates (dose-

dependency efficacy p=0.0446):

– 53% in 40 ml group– 44% in 20 ml group– 27% in 10 ml group– 18% in placebo group

• Histology improved in dose-dependent manner.

• Adverse events mostly related to gas.

– Intervention stopped in 18% (10 ml) to 30% (40 ml) of patients.

21-Metthes H, BMC Comp Alt Med 2010

Pouchitis• Double-blind RCT

– 40 adults with chronic relapsing pouchitis.

– Remission achieved by antibiotics administration.

– Randomized to receive VSL#3 or placebo.

– After 12 months, relapse rate of 10% in VSL#3 group (2/20) vs. 40% in placebo group (8/20).

22- Gionchetti P, Gastro 2003

Pouchitis• Patients with pouchitis

associated with PDAI > 7 (0-18).– ≥2 flares in previous year or

requiring continuous abx to maintain remission.

– Remission induced by 4 wks of Flagyl and Cipro.

23- Mimura T, Gut 2004

• Randomized to receive VSL#3 or placebo once daily x 1 year or until relapse.- Symptomatic, endoscopic, and histological eval made before, at 2 and

12 months, or at relapse.

• 36 pts randomized: 20 to VSL#3 group and 16 to placebo.- Remission maintained in 17/20 (85%) pts in VSL#3 group vs. 1/16 (6%)

in placebo group (p=.0001).

Irritable Bowel Syndrome• A common syndrome in the developed world.

– Up to 20% of general population– Higher incidence in females– Unknown etiology

• Characterized by irregular bowel movements, bloating, gaseousness, pain.– Defined by ROME III criteria

• Associated with bacterial overgrowth in the small intestine by breath-hydrogen studies.– Often responds to antibiotic therapy.

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-DiLorenzo et al ROME III -Baber et al JPGN 2008-Ringel et al Clin Gastro Hepatol 2009 -Pimentel et al Ann Intern Med 2006

25-Moayyedi, Gut 2008

Yogurt and IBS• Activia (Danone®) contains B.

animalis, S. thermophilus, and L. bulgaricus.

• Test vs. heat-treated control consumed twice daily:

– Improvement in bloating and abdominal pain.

– In subgroup of severely constipated subjects, stool frequency increased in the test group compared with control (p<0.05).

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-Guyonnet, Aliment Pharmacol Ther 2007

Other Conditions• Functional constipation• Chronic diarrhea• Helicobacter pylori infections• Steatohepatitis• Lactose intolerance• Pancreatitis• Colon cancer• Non-GI conditions

– Recurrent UTIs, vaginosis, AOM, sinusitis– Atopic disease and asthma

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Safety• Multiple reports of bacteremia and fungemia

associated with probiotic supplements in hospital setting.– Patients largely immunocompromised and/or had central

access/hardware.– Hand contamination suggested in many of cases.

• Probiotics are used in HIV and transplanted patients.• Benefit shown in critical care patients.

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- Boyle J, Am J Clin Nutr 2006 - Rayes, Am J Transplant 2005- Anukam KC, J Clin Gastro 2008 - Madsen K, J Clin Gastro 2008

29-Boyle J et al Am J Clin Nutr 2006

Conclusions• We are a complex ecosystem inhabited by a multitude of

organisms.• Probiotics are beneficial organisms that engage our

immune system and exert health benefits.• The human microbiome has tremendous therapeutic

potential.– How do we diagnose and treat dysbiosis?

• Probiotics as supplements are generally safe.– Severely Immunocompromised patients and those with indwelling

hardware must be cautioned.

• Further study is needed.– Which probiotic strains are the most effective? What is the best

dose? Do the bacteria need to be alive to exert health benefit?

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Trade Names• Most-studied strains:

– Lactobacillus rhamnosus GG (Culturelle®)

– L. acidophillus and L. bulgaricus (Lactinex®)– L. reuteri (Biogaia®)– Bifidobacterium lactis (Theralac®)

– Bifidobacterium breve (Bifiene®)

– B. infantis (Align®)

– Saccharomyces boulardii (Florastor®)

– E. coli subsp. Nissle 1917 (Mutaflor®)– VSL#3® (S. thermophilus, B. breve, B. infantis, B. longum, L.

acidophilus, L. plantarum, L. casei, and L. bulgaricus)

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VSL #3• High dose multi-strain probiotic, 450 billion

live bacteria per sachet. Most probiotics ~5-50 billion per dose.

• DS packets by prescription only• Results seen in 7 days, may take up to 1

months• Should be kept in refrigerator, but may be

kept at room temp for up to 7 days. • Kosher and gluten free

VSL #3 Dosing• IBS ½ -1 packet or 2-4

capsules /day• UC 1-2 packet/day• Pouchits 2-4 packets or

1 -2 DS packets/day• Active UC 4-8 packets

or 2-4 DS packets/day

• Capsules– 1 = 112.5 billion CFU

• Packets– 1 = 450 billion CFU

• Double Strength Packets – 1 = 900 billion CFU

Selected References/Suggested Reading1. Ramakrishna BS. Probiotic-induced changes in the intestinal epithelium: Implications in gastrointestinal

disease. Tropical Gastro 2009; 30(2):76-85.

2. Ramakrishna BS. The normal bacterial flora of the human intestine and its regulation. J Clin Gastro 2007; 41(Suppl 1):S2-6.

3. Matsumoto M, et al. Dynamics of fecal microbiota in hospitalized elderly fed probiotic LKM512 yogurt. Microbiol Immunol 2009; 53:421-432.

4. Hickson M, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ 2007; 14(335).

5. D’Souza AL, et al. Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis. BMJ 2002; 324.

6. Mattar AF, et al. Probiotics up-regulate MUC-2 mucin gene expression in a Caco-2 cell-culture model. Ped Surg Int 2002; 18:586-90.

7. Mazmanian SK, et al. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 2005; 122:107-18.

8. O’Hara AM, et al. Functional modulation of human intestinal epithelial cell responses by Bifidobacterium infantis and Lactobacillus salivarius. Immunology 2006; 118:202-15.

9. Sartor RB. Microbial influences in inflammatory bowel diseases. Gastro 2008; 134:577-594.

10. Asakura H, et al. Is there a link between food and intestinal microbes and the occurrence of Crohn’s disease and ulcerative colitis? J Gastro Hepatol 2008; 23:1794-1801.

11. Sokol H, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci 2008; 105:16731-6.

12. Kligler B, et al. Probiotics in children. Ped Clin N Am 2007; 54:949–967.

13. Guarner F, et al. Probiotics and Prebiotics: Practice Guideline. World Gastro Org, May 2008.

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Thank You!

Questions?

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