Patient Education Event, 1/11/2015, "Probiotics: What Are They? What Can They Do for You?"

1. Probiotics: What Are They?
What Can They Do for You?
Elisabeth R. Evans, MSN, FNP-BC
UC San Diego Inflammatory Bowel
Disease Center

2. Outline
I. The Microbiome
II. Probiotics Defined
a. What are probiotics
b. How Probiotics work
c. Probiotic Effects
III. Clinical Applications
IV. Safety Concerns
2

3. 3
• 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

4. 4
• 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

5. 5
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

6. 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
6
-Isolauri 1991 and 1994
-Kaila 1995
-Majamaa 1995
--U.N. Food and Agriculture
Organization and WHO, 2001

7. 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.

8. The Epithelial Barrier
Lumen Lamina propria

9. Intestinal epithelium can distinguish
between pathogens and normal bacteria
No response
Activation of NF-kB
Release of IL-8

10. Probiotics enhance mucus production
•Mucus secretion via
cAMP
• Up-regulation of mucin-
producing genes
Microbes Induce:
Deplancke et al AJCN 2001
Otte et al Am J Phys 2004
Caballero-Franco et al Can J Gastro 2004

11. 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 repair
Anti-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-carcinogenic
Detoxification
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 invaders
Controls inflammation

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.
17
-McFarland, Anaerobe 2009
-Biller, JPGN 1995
-Surawicz, Clin Infect Dis 2000

17. 18
• 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.

18. 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

19. 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

20. 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

21. 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

22. 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).

23. 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.
24
-DiLorenzo et al ROME III -Baber et al JPGN 2008
-Ringel et al Clin Gastro Hepatol 2009 -Pimentel et al Ann Intern Med 2006

24. 25-Moayyedi, Gut 2008

25. 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).
26
-Guyonnet, Aliment Pharmacol Ther 2007

26. 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
27

27. 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.
28
- Boyle J, Am J Clin Nutr 2006 - Rayes, Am J Transplant 2005
- Anukam KC, J Clin Gastro 2008 - Madsen K, J Clin Gastro 2008

28. 29-Boyle J et al Am J Clin Nutr 2006

29. 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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30. 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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31. 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

32. 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

33. Selected References/Suggested Reading
1. 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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34. Thank You!
Questions?
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