1. Living Microorganisms
in
Therapy
-Dr CSN Vittal

2. Gut Flora

3. At birth ..
Gut is sterile

4. Intestinal colonization ..
– Begins with the process of
birth.
– Normal vaginal delivery
permits transfer of bacteria
from mother to infant.
– Breast Fed: >90% of
intestinal bacteria are
bifidobacteria.
– Top Fed: Enterobacteria
and gram –ve bacteria
predominate.

6. good
bad

7. Probiotics
Mode
of
Action
• Producing antimicrobial substances,
bacteriocins, peptides & Small Chain Fatty
Acids
• Producing volatile acids and lactic acid
which reduce the intestinal pH,
• Stimulating mucus secretion,
• Strengthening gut barrier function,
• Competing for adhesion sites,
• Competing for nutrients,
• Stimulating specific and non-specific
immune responses, etc.
• Reduction of bacterial translocation

8. L
APC
IgA
Tumors
Th0
Th1
B
IL-2 ↑
IFN- γ ↑
Th2
Antibody
mediated
response
Cell
mediated
response
Viruses
TGF-β↓
IL-4 ↓
IL-10 ↓
+
IL-2 ↑
IFN-γ ↑
TNF-α ↑
IFN-α ↑
Natural killer cells ↑
Macrophages ↑
Cytotoxic T-lymphocytes ↑
LL
L
Immune Response
M
Intestinal Epithelium
Microorganisms
B
IgG ↑
IgM ↑
IgE ↓
Non-adhesive Adhesive
M = M cells of intestinal epithelium
L = Lymphocytes
APC = Antigen presenting cells
Th = T-helper cells
IL = Interleukines
TGF = Tumour growth factor
IFN = Interferon
TNF = Tumour necrosis factor
Ig = Immunoglobulin

9. Eubiosis
Bifidobacteria
Lactobacillus
Assosiated
with health
Clostridia
Detrimental
to health

10. Dysbiosis
•Diarrhoea
•Radiation
•Steroids
•Chemotherapy
•Inflammation
•Chronic illness
•Postoperative stage
•Antibiotics

11. Restoration of Gut
Flora
Biotherapy :
The use of biological agents constitutes a purposeful attempt
to modify the relationship with our immediate microbial
environment, in ways that may benefit human health.
Using living microorganisms

12. • Fermentation – as ancient as
2500 BC – noticed in Sumerian
wall painting and Old
Testament (Genesis 18:8)
• Eli Metchinkoff credited long
life of certain races to
consumption of large amounts
of fermented milk products.
(1908)
• Lily & Stillwell coined the term
‘probiotics’. (1965)
• Professor Gibson & Dr Marcel
Roberfroid coined the term
"prebiotics" . (1995)
Historical Aspects

13. Probiotics
(Gk: for life)
“Live microbial feed supplement which
beneficially affects the host animal by
improving its intestinal microbial
balance”
- Fuller (1989)

14. Ideal Probiotic
• Contain viable microorgnisms which
naturally colonized in human gut.
• Should be safe with no pathogenic
effects.
• Able to survive in gastric transit and
can remain surviving in the intestine.
• Have beneficial effect and improve
health of the individual ingesting
them.
Gibson RG, Probiotics and prebiotics; gut microflora management for improved health,
Medicine Digest 2003;3:56-59

15. List of some Probiotics
1
Lactobacillus
reuteri
Lactobacillus GG
L casei
L bulgaricus
L plantarum
L rhamnosus
L salivarius
L acidophilus
L gasseri
L delbrueckii
L johnsonii
0
3
Streptococcus
thermophilus
S. faecalis
Saccharomyces
boulardii
S. cerevisiae
Enterococcus
faecium
Leuconostoc
mesenteroides
Propionibacterium
freudenreichii
2
Bifidobacterium
bifidus
B longuim
B infantis
B breve
B bifidum
B adolescentis
• (Gorbach, Goldin)

16. Food Sources
Yogurt
– L.acidophilus
– L.bulgaricus
– L.thermophilus
Bitter Milk
– L.lactus
– S.cremoris
Sour Cream
– S.cremoris
Yoghurt / Dahi consumption is folklore, many may not
know that 1 tsp of contains 6 billion organisms
sauerkraut
cheese
Miso soup
kimchi

17. Prebiotics
"Unlike probiotic bacteria, prebiotic carbohydrates are not destroyed when cooked."
Nondigestible food ingredients that
may beneficially affect the host by
selectively stimulating the growth
and/or
the activity of a limited number of
bacterial species already established
in the colon, and thus in effect
improve hosthealth’
(Gibson and Roberfroid, 1995)

18. Prebiotics
1 FRUCTO-OLIGOSACCHARIDES (FOS)
2 ISOMALTO-OLIGOSACCHARIDES
3 LACTOSUCROSE
4 LACTULOSE
5 INULINS
6 LACTILOL
7 PYRODEXTRINS
8 SOY OLIGOSACCHARIDES
9 XYLO-OLIGOSACCHARIDES
10 TRANSGALACTO-OLIGOSACCHARIDES

19. Prebiotics
Mechanism of Action
• Escape digestion in the upper
gastrointestinal tract and be used
by the microorganisms comprising
the colonic microflora.
• They mainly stimulate the growth of
bifidobacteria, for which reason
they are referred to as bifidogenic
factors.
• Primarily affect the large intestine.
• Increases short-chain fatty acid production in the colon, and
subsequent increased mucin production in the GI tract

20. A mixture of pro and
prebiotics with an
ability to improve
survival and
regeneration of GI
flora which in turn
will enhance the host
health
Synbiotics
Certain probiotic-
produced, soluble
factors, which were
sufficient to elicit
the desired
response
Postbiotics

21. Colonic
Cancer
Urogenital
infections
IBD / IBS
Atopic
Disorders
H Pylori
infection
Lactose
intolerance
Prevention / Tt
Of Diarrheas
NEC
ConstipationGingivitis /
Caries
Hypertension Cholesterol i
Ischemic Heart
Syndromes
Infantile
ColicRegurgitation
NAFLD
Hepatic
Encephalopathy

22. EVIDENCE BASED MEDICINE
• “The process of
systematically
finding, approving
and using
contemporaneous
research finding as
the basis for clinical
decisions.”
Archie Cochrane

24. LEVELS OF EVIDENCE
Level
1 A
Evidence from high quality randomized controlled
trials with statistically significant results and few
limitations in their design OR conclusions from
systematic reviews of the trials.
Level
1 B
Single high quality clinical trials that have clearly
shown positive or negative results with narrow
intervals of confidence, so that it is unlikely that
the trend would change in future studies
Level
2
Controlled trials without randomization.
Cohort studies or case control studies preferably from
more than one center or group Multiple time series with
or without intervention
Opinions of authorities based on clinical
experience and case reports
Level
3

25. Grade A
recommendation
(level 1A evidence)
• Treatment of acute
infectious diarrhoea
in children.
• Prevention of
antibiotic associated
diarrhoea.
• Prevention of
nosocomial
diarrhoea in
children.
• Treatment of lactose
malabsorption.
Pro / Prebiotics in Therapeutics

26. Grade A
recommendation
(level 1B evidence)
• Prevention of pouchitis
and maintenance of
remission.
• Prevention of
postoperative
infections.
• Prevention and
management of
paediatric atopic
diseases.
Pro / Prebiotics in Therapeutics

27. • Prevention of
travellers’ diarrhoea.
• Prevention of sepsis
associated with
severe acute
pancreatitis.
• Maintenance of
remission of
ulcerative colitis.
• Lowering of blood
cholesterol.
Grade B
recommendation
(level 2 evidence)
Pro / Prebiotics in Therapeutics

28. ?? Living Microorganisms
in
Prophylaxis

29. Supplementation of Infant Formula With
Probiotics / Prebiotics
• PROBIOTICS:
– For healthy infants, the available scientific data
suggest that the administration of currently evaluated
probiotic - supplemented formula to healthy infants
does not raise safety concerns with regard to growth
and adverse effects.
– The administration of probiotic-supplemented infant
formula during early life (4 months of age) does not
result in any consistent clinical effects.
– In general, there is a lack of data on the long-term
effects of the administration of formula supplemented
with probiotics
– Considering the above, the Committee does not
recommend the routine use of probiotic-
supplemented formula in infants.
• A Systematic Review and Comment
by the ESPGHAN Committee on Nutrition (JPGN 2011;52: 238–250)

30. Supplementation of Infant Formula With
Probiotics / Prebiotics
• PREBIOTICS:
– the administration of formula supplemented with some
prebiotics is associated with some clinical effects, such
as increased stool frequency and stool softening,
the clinical relevance of which remains questionable.
– Only 1 RCT with methodological limitations
demonstrating that the administration of extensively
hydrolysed formula supplemented with GOS/FOS is
associated with a reduced risk of some allergic
reactions and some types of infections.
– There is a lack of data on the long-term effects of the
administration of formula supplemented with prebiotics.
– Considering the above, the Committee does not
recommend the routine use of formula
supplemented with prebiotics in infants.
• A Systematic Review and Comment
by the ESPGHAN Committee on Nutrition (JPGN 2011;52: 238–250)

31. How Safe are these
‘Living Drugs’ !
• Infection - Sepsis
• Deleterious
metabolic activities
• Immune déviation or
excessive immune
stimulation
• Microbial resistance

32. Proposed risk factors for probiotic sepsis
Major risk factors
1) Immune compromise, including a debilitated state or
malignancy
2) Premature infants
Minor risk factors
1) Central Venous Catheter
2) Impaired intestinal epithelial barrier
3) Administration of probiotic by jejunostomy
4) Concomitant administration of broad spectrum antibiotics
which probiotic is resistant
5) Probiotics with properties of high mucosal adhesion or
known pathogenicity
6) Cardiac valvular disease (Lactobacillus probiotics only)
The presence of a single major or more than one minor risk
factor merits caution in using probiotics.
Am J Clin Nutr June 2006 vol. 83 no. 6 1256-1264

33.  Paucity of information regarding the
mechanisms through which probiotics
act, probiotic interactions, strain-specific
utility
 Lack of appropriate administrative
regimens,
 Dosage uncertainty,
 Possible adverse effects in prematurely
or with immune deficiency
AREAS OF UNCERTAINTY IN THE USE OF
PROBIOTICS
Probiotic use in clinical practice: what are the risks?
Boyle RJ, Robins-Browne RM, Tang ML. Am J Clin Nutr. 2006 Jun;83(6):1256-64;quiz1446-7

34. Conclusion
Avoiding an excessive optimism and
the thought that an efficacious panacea for all troubles
has been found,
there are sound reasons to believe that probiotics & prebiotics,
can influence human health, through the prevention and therapy of
many diseases,
although
Further studies are needed to explore mechanistic issues and probiotic
interactions. In view of the increasing use of probiotics as health supplements
and therapeutic agents, clinicians need to be aware of the risks and benefits
of these treatments.

35. • C.S.N. Vittal
Than Q