Optimizing Gut Homeostasis:

Challenges and Evidences with

Probiotic Use
March 3, 2017
PICC Pasay
DISCLOSURES
Learning Outcomes:
• Determine the History and General Use of Probiotics

• Define the Mechanism of Action of Probiotics

• Discuss the essential properties of Bacillus Clausii

• Discuss Clinical Evidence of B. Clausii in :

• Infectious and Antibiotic Related Diarrhea
• H.Pylori treatment Adverse Effect
Defining a Probiotic
• Latin “Pro” –Before
and Greek “Bios” –Life

• Live micro-organisms which, when administered in adequate

amounts, confer a health benefit on the host

WHO, 2001
History of Probiotics

Louis Pasteur (
Henry Tissier (1889)
1857)Discovered
Discovered
Lactic Acid Bacteria (
Bifidobacterium Spp.
lactobacillus Species)

Elie Metchnikoff (1907) Linked

regular consumption of lactic Minoru Shirota
acid bacteria in fermented daily (1935)
products (sour milk) lead to Lactobacillus Casei
health and longevity in Bulgarian st. Shirota (yakult)
Peasants

The term “Probiotic” is used for the first time

in 1965 by Lilly and Stillwell
Why are Probiotics
Important for Human
Health?
 The balance of Intestinal Flora
and its changes with age
Classification Representative
Bacteria
Beneficial Bifidobacteria
Lactic Acid
Bacteria

Harmful Clostridium
Perfringes
Staphylococcus
E.Coli (toxic strain)

Opportunistic Bacteroidetes
Ecoli (nontoxic
strain)
Streptococcus

The Key for Healthy Longevity, Biogenics Therapy

Tomatori Mitsuoka, Emeritus Professor of the Univ of Tokyo
Gut Microbiota Homeostasis
and Dysbiosis
• Homeostasis: Property of Gut Ecosystem to maintain a
balance among the Bacterial Groups, Epithelial Tissue of the
Intestine and Immune System of the Host

• Dysbiosis : imbalance in the ecosystem due to several factors:

• Xenobiotics (antibiotics and anti cancer drugs)

• Immune Imbalance ( IBS)
• Stress
• Change in Nutrient Intake
• Early Colonization ( birth in hospitals)
Role of the gut microbiota in
defining human health

The Key for Healthy Longevity, Biogenics Therapy

Tomatori Mitsuoka, Emeritus Professor of the Univ of Tokyo
PROBIOTIC-RICH
FOODS
Characteristics of Effective Probiotics:

• Able to survive the passage through the digestive system

• Able to attach to the intestinal epithelium and colon

• Retain stability during the intended shelf life

• Are are nonpathogenic, nontoxic, and free of significant

adverse side effects

• Contain an adequate number of viable cells to confer the

health benefit
Probiotic Agents Used as Therapeutic
Agents
I. Lactobacillus species
L. acidophilus, L. casei, L.fermentum, L. crispatus, L. gasseri, L. paracasei

II. Bifidobacterium species

B. bifidum, B. breve, B. lactis, B. adolescents, B. lactis, B. longan

III. Other Species

B. subtilis, B.clausi, Saccharomycoses boulardti, E. faecium
Mechanism of Action of
Probiotics:

Bermudez et al, Probiotics Mechanisms

Of Action, Annals of Nutrition and
Metabolism,2012
Mechanism of Action of Probiotics:
Defenses of the Intestinal
Barrier: mucous layer,
antimicrobial peptides,
secretory IgA and the epithelial
junction adhesion complex

Mechanisms:
1. Gene expression
enhancement to promote
integrity of tight junction
2. Repair barrier after damage
3. Promote Mucus secretion
(mucins)
Mechanism of Action of Probiotics:
- Adhesion to intestinal mucosa is
regarded as a prerequisite for
colonization and is important for
the interaction between
probiotic strains and the host and
for modulation of the immune
system

- Inhibition includes passive forces,

electrostatic and hydrophobic
interactions, steric forces ,
lepoteichoic acids
Mechanism of Action of Probiotics:
- “one species of bacteria more vigorously
competes for receptor sites in the
intestinal tract than another species”

- Mechanisms:
1. Modification of environment, production
of antimicrobial substances (
bacteriocins) such as lactic and acetic
acid which has strong inhibitory effect
against Gram-Negative bacteria
2. Production of de-conjugated bile acids
(bile salts)
3. Produce metabolites that inhibit growth
of fungi (L. coryniformis)
Mechanism of Action of Probiotics:
- Ability to interact with epithelial and dendritic
cells (DCs) and with monocytes/macrophages and
lymphocytes.
Probiotic Impact on Human Health and Disease
Probiotic Impact on Human
Health and Disease
Probiotic: Bacillus Clausii

- Rod-Shaped, Gram-Positive, Motile, Aerobic, Spore- Forming

Bacteria

- -Identified in 1995 by German bacteriologist Dieter Claus

- Only Probiotic registered as a DRUG and not as a supplement

PhFDA recognizes 2 types of Probiotics:

1. Pharmaceutical probiotics (Rx, OTC) – Efficacy + Safety
2. Nutritional probiotics (FS) – Safety
 Properties of B. Clausii

ANTIMICROBIAL IMMUNOMODULATORY
PROPERTY PROPERTY
Case
• M.A. a 5/M was seen in the Ambulatory Clinic for loose stools
of 1 day duration. He had approximately 5 bowel movements
with the last one 30 mins prior to this consult. Physical
Examination was essentially normal. Mother claims he has
slight decrease in appetite, no vomiting and no fever.

• Management of this case will focus on:

• Check for General Danger Signs
• Prevention of Dehydration (ORS)
• Diagnostics (if warranted)
• Zinc Supplements
• Probiotics ??
Causes of Diarrhea
ACUTE
• Viruses ( Rotavirus, Norovirus)
• Bacteria ( salmonella, E.coli…)
• Parasites ( E. histolytica,
Giardia)
• Food Poisoning ( Staph, B.
cereus, C. perfringes)
• Drugs (antibiotics,
laxatives,antineoplastics…)
Chronic
• Drugs
• Functional ( IBS)
• Inflammatory Bowel disease (
Ulcerative colitis, chron
disease)
• Malabsorption Syndrome (
Lactose Intolerance, celiac
disease)
• ‘
• Tumors ( colon, lymphoma)
• Endocrine ( Hyperthyroidism)
Going back to our management of
the case:
• Provide the Ideal ORS
• Low Osmolarity
• SODIUM : 60 mmol/L (60-90)
• GLUCOSE: 84 mmol/L (NOT EXCEED 111)
• OSMOLARITY: 224 mmol/L (200-311)
• CITRATE : 8-12 mmol/L
• CHLORIDE : 50-80 mmol/L

• Zinc Supplementation
• 20 milligrams per day for children older than six months or 10 mg
per day in those younger than six months, for 10–14 days -WHO
 Diarrhea is the Top 2 cause of Child mortality for
those who are 1 – 4 years old and it remains to
be a top concern that moms have towards their
children.

Top Five (5) Concerns moms

have towards their Children

Five (5) Leading Causes of Child Mortality

By Age-Group (1-4, 5-9, 10-14) & Sex
No. & Rate/100,000 population
Philippines, 2010

Cause
1. Pneumonia
2. Diarrheas and gastoenteritis of presumed infectious origin
3. Congenital anomalies
4. Septicemia
5. Other diseases of the nervous system

SOURCE: RP Department of Health (2010 is latest data) http://www.doh.gov.ph/node/1488 | 2015 Project

Flora (Market Research) | 25
How can Probiotics
help my patient?
 B.clausii as an Adjuvant Therapy for Acute Childhood Diarrhea

Age Group: 6 months

to 12 years

Acute diarrhea:
Lahiri K et al. J Harmonized Res Med Health Sc.2015; 2:26-30
a prospective, randomized, open label, comparative | 27
study Lahiri K, et al. J Harmonized Res Med Health Sci 2015;2:26-30
 Improvement of Diarrhea with Probiotics

Without probiotics

With probiotics

Acute diarrhea:
| 28
Lahiri K et al. J Harmonized Res Med Health Sc.2015; 2:26-30
Lahiri, K et al. Bacillus Clausii As An Adjuvant Therapy In Acute Childhood Diarrhoea. IOSR
Journal of Dental and Medical Sciences (IOSR-JDMS) e-ISSN: 227 -0853, p-ISSN:
2279-0861.Volume 14, Issue 5 Ver. I (May. 2015), PP 74-76.
 Improvement of Diarrhea with Probiotics

Acute diarrhea:
Lahiri K et al. J Harmonized Res Med Health Sc.2015; 2:26-30
| 29
Lahiri, K et al. Bacillus Clausii As An Adjuvant Therapy In Acute Childhood Diarrhoea. IOSR
Journal of Dental and Medical Sciences (IOSR-JDMS) e-ISSN: 227 -0853, p-ISSN:
2279-0861.Volume 14, Issue 5 Ver. I (May. 2015), PP 74-76.
Probiotics for ADULTS with
Acute Gastroenteritis
OBJECTIVES:
Evaluate the Efficacy of B. Clausii: Duration of Diarrhea, Frequency of defecation,
abdominal pain and stool consistency

METHODOLOGY:
27 (OPD) patients with Acute Diarrhea (15-males and 12 females)
AGE: 35 +/- 8
| 30

Efficacy of Bacillus clausii strain UBBC-07 in the treatment of patients suffering

from acute diarrhea. Sudha MR, Bhonagiri S, Asin MK (2013) Beneficial Microbes
4: 211-216.
Probiotics for ADULTS with
Acute Gastroenteritis
RESULTS
Without Probiotics With Probiotics
Mean Duration of 34.81+/- 4.69 9.26+/- 3.05
Diarrhea/ day (P<0.0001)
Frequency of Defecation/ 6.96 +/- 1.05 1.78 +/- 0.0.50
day (<0.0001)
Abdominal Pain (<0.0001) 3.22 +/- 0.38 (severe) 0.74 +/- 0.71 (absent)
Stool Consistency 3.93 +/- 0.38 (watery) 1.22+/- 0.42 (soft)
(<0.0001)

| 31
Efficacy of Bacillus clausii strain UBBC-07 in the treatment of patients
suffering from acute diarrhea. Sudha MR, Bhonagiri S, Asin MK (2013)
Beneficial Microbes 4: 211-216.
Case
• M.A. a 5/M was seen in the Ambulatory Clinic for loose stools
of 1 day duration. He had approximately 5 bowel movements
with the last one 30 mins prior to this consult. Physical
Examination was essentially normal. Mother claims he has
slight decrease in appetite, no vomiting and no fever.

• On further history: Patient has no allergies and had just

completed a 7 day course of a penicillin based antibiotic for a
respiratory tract infection
Antibiotic-Associated Diarrhea
(AAD)
• AAD is defined as diarrhea associated with antibiotic exposure,
either while on antibiotics or for up to eight weeks after antibiotics
have been discontinued

• Causes:

• Pediatric: Viruses ( 25%) or C. difficile ( 22%-33%)

• Adults: C. difficile ( 13%-28%), C. perfringes ( 3%-21%) and S. aureus

(1-28%)

• McFarland LV, Goh S. Preventing Pediatric Antibiotic-Associated Diarrhea and Clostridium difficile Infections with Probiotics: a meta-analysis. World J
Meta-analysis. 2013;1:102–120.
• Alam S, Mushtaq M. Antibiotic associated diarrhea in children. Indian Pediatr. 2009;46:491–496
 Most Common Medications
Prescribed for Children

Grace Chai et al. Pediatrics 2012;130:23-31

Lots of Antibiotics for Little Kids

Analysis of NAMCS & NHAMCS US Antibiotic Prescribing 2010-2011.

The Pews Charitable Trust 2016
Possible Causes of
Antibiotic-Associated Diarrhea?
Antibiotic therapy

Direct effect of antibiotics on Alteration of the gut flora

the gut system

Bacterial population with Overgrowth of

specific functions pathogens

Intestinal Infection
Functional/Osmotic
diarrhea
Beaugerie, BP&RCG 2004 Gorkiewicz G, Int J Antimicrob Agents 2009
 How can Probiotics help in AAD?
• Meta-analysis of 9 RCTs
• Probiotics can be used to prevent AAD
• OR for pooled data from all 9 trials 0.37 (0.26 to 0.53; P<0.001)

D’Souza LA, BMJ 2002

How can Probiotics help in AAD?
•Meta-analysis of 7 RCTs

•strong benefit of probiotic administration on AAD

•Combined RR 0.39 (95% CI: 0.27-0.57)

Cremonini and Gasbarrini, Alim Pharm Ther 2002

 How can Probiotics help in
Antibiotic-associated Clostridium Difficile
Diseases?

OR for pooled data from the 6 trials

Active treatment over placebo in the Tx of the infection
McFarland L. Am J Gastroenterol. 2006;101:812-822.
Bacillus Clausii and its reduction of anti-
H.Pylori treatment adverse effects
• BACKGROUND: Helicobacter pylori eradication fails in about 10% of patients, particularly
because of the occurrence of resistance to antibiotics and side-effects.

• OBJECTIVES: To evaluate the effect of Bacillus clausii, a probiotic, on incidence (primary

variable) and severity of antibiotic-associated side-effects during anti-H. pylori therapy

• METHODOLOGY: 120 H.Pylori Patients (43-58 years old)

• Treatment Group: Triple Therapy + Probiotic 14 days plus 1 week of Probiotic after treatment
• Placebo: Triple Therapy without Probiotics

• PARAMETERS STUDIED: Validated Daily Diary for 4 weeks. The diary contains a
questionnaire evaluating onset, intensity and frequency of gastrointestinal side-effects:
taste distortion, loss of appetite, nausea, vomiting, epigastric pain, bloating, diarrhoea,
constipation and skin rash. The intensity of symptoms was rated using a scale.

Nista EC, Candelli M, Cremonini F, Cazzato IA, Zocco MA, et al. (2004) Bacillus clausii therapy to reduce side-effects of anti-Helicobacter pylori
treatment: randomized, double-blind, placebo controlled trial. Aliment Pharmacol Ther 20: 1181-1188.
| 40
Bacillus Clausii and its reduction of anti-
H.Pylori treatment adverse effects
There was a significant difference
between the B. clausii treated group
and placebo in the incidence of
nausea, diarrhoea and epigastric pain.

A greater reduction in the risk of

diarrhoea was observed in the B. clausii
group compared with the placebo group
after one and 2 weeks.

| 41
Nista EC, Candelli M, Cremonini F, Cazzato IA, Zocco MA, et al. (2004) Bacillus clausii
therapy to reduce side-effects of anti-Helicobacter pylori treatment: randomized,
double-blind, placebo controlled trial. Aliment Pharmacol Ther 20: 1181-1188.
Adverse Effects: Should I worry?
• When ingested orally, probiotics are generally considered safe
and well tolerated.

• The most common adverse effects include bloating and

flatulence; however, these are typically mild and subside
with continued use

Probiotics. Med Lett Drugs Ther. 2007; 49:66–8

• Kligler B, Cohrssen A. Probiotics. Am Fam Physician. 2008; 78:1073–8
In summary:
PROBIOTICS: Bacillus Claussi

• Positive effect on the development of the mucosal immune

system

• Helps restore the natural balance of Gut bacteria

• Benefit in the management of Infectious and Antibiotic

Associated Diarrhea

• Proven benefit in the reduction of H.Pylori treatment Adverse

Effect
| 43
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