WHEN WERE BACTERIOPHAGES

DISCOVERED AND BY WHOM ?

1915
FREDERICK WILLIAM TWORT

ENGLISH BACTERIOLOGIST

QUESTION
WHO IS CREDITED WITH ISOLATING BACTERIOPHAGES
AND DISCOVERING THAT BACTERIOPHAGES ARE
RESPONSIBLE FOR KILLING BACTERIA AND
PROPOSED “PHAGE THERAPY” AND THE USE OF
“PHAGE COCKTAILS” TO TREAT DISEASE?

1917
FELIX d’ HERELLE

FRENCH-CANADIAN
MICROBIOLOGIST

QUESTION
AFLATOXIN B1 PENICILLIN

…SIMPLY STATED…
THEY ARE TOXIC MOLECULES PRODUCED BY FUNGI
…..WITH ONLY ONE PURPOSE…..

TO KILL
ANTI-BACTERIAL
ANTI-PROTOZOAN
ANTI-VIRAL
ANTI-INSECT
ANTI- FOOD ANIMAL
ANTI-HUMAN
 …SIMPLY STATED…
THEY ARE VIRAL ASSASSINS
WITH ONLY TWO PURPOSES
…..FOR THEIR EXISTENCE…..

TO KILL BACTERIA
AND
REPLICATE
 BACTERIOPHAGE
“LIFE CYCLE”
EXTRACELLULAR
PHASE
“INFECTIOUS VIRON”

INTRACELLULAR
PHASE
(LYTIC CYCLE OR LYSOGENIC CYCLE)
 WHERE CAN BACTERIOPHAGES
BE FOUND ?

BACTERIOPHAGES
ARE
UBIQUITOUS

WHERE YOU FIND BACTERIA

YOU WILL FIND
BACTERIOPHAGES
QUESTION
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 WHAT IS A MAJOR WAY THAT
BACTERIOPHAGES PROTECT
THE ANIMAL’S DIGESTIVE TRACT

PATHOGENS ENTER THROUGH MUCOSAL SURFACES

MUCUS MAINTAINS A HIGH PHAGE TO BACTERIA
RATIO WHICH PROTECTS THE UNDERLYING EPITHELIUM
AND PREVENTS INFECTION

THE BACTERIOPHAGE BINDS TO THE MUCIN GLYCOPROTEINS

AND ATTACHMENT TO THE MUCIN RESULTS WHICH
PROVIDES A “NON-HOST DERIVED IMMUNITY”
BY DECREASING BACTERIAL NUMBERS

QUESTION
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BACTERIOPHAGES

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BACTERIOPHAGE ANATOMY
HEAD
WITH

NECK DNA
&
COLLAR CENTRAL
TAIL TUBE
PLATE SHEATH
TAIL
FIBERS
 BACTERIOPHAGE
BINDING TO BACTERIA AND INJECTING DNA
 WHEN ONE BACTERIOPHAGE INJECTS
ITS DNA INTO A BACTERIAL CELL AND
CELL LYSIS OCCURS HOW MANY NEW
BACTERIOPHAGES CAN BE FORMED ?
THE NUMBER CAN VARY
BUT FROM 50-100(200) IS COMMON

QUESTION BACTERIAL CELL LYSIS

 WHAT LIMITS THE NUMBER OF NEW
BACTERIOPHAGES ? WHY NOT MORE,
LET’S SAY 200, 300, 400, +

THE DNA OF THE BACTERIOPHAGE

COMMANDS THE BACTERIAL CELL’S
METABOLIC MACHINERY TO PRODUCE
BACTERIOPHAGES AND EVENTUALLY
THE “BUILDING MATERIAL” WITHIN THE
BACTERIA REQUIRED FOR CONSTRUCTING
BACTERIOPHAGES IS DEPLETED

QUESTION
 IN COMPARISON TO BACTERIA
HOW BIG ARE BACTERIOPHAGES ?

QUESTION
 IN COMPARISON TO BACTERIA
HOW BIG ARE BACTERIOPHAGES ?
BACTERIOPHAGES ARE NORMALLY
ABOUT 100 TIMES SMALLER THAN BACTERIA

QUESTION ESTIMATED NUMBER ON EARTH 1031

 WHAT HAPPENS TO THE BACTERIOPHAGE
AFTER ITS DNA HAS BEEN INJECTED
INTO THE BACTERIA ?

QUESTION
 WHAT HAPPENS TO THE BACTERIOPHAGE
AFTER ITS DNA HAS BEEN INJECTED
INTO THE BACTERIA ?
THE BACTERIOPHAGE
IS THEN NOTHING BUT
AN EMPTY PROTEIN SHELL
WHICH WILL EVENTUALLY DECAY

EMPTY CAPSID

QUESTION
 DO BACTERIOPHAGE RESISTANT
BACTERIA EVER DEVELOP ?

YES
…HOWEVER…
THE RESISTANT BACTERIA ARE A MINORITY
AND THE BACTERIOPHAGES ARE CONSTANTLY
CO-EVOLVING AND WILL EVENTUALLY
DESTROY THE BACTERIA
3.5 BILLION YEARS WITHOUT
TOTAL RESISTANCE DEVELOPING
QUESTION
 BACTERIOPHAGE
“MAJOR ADVANTAGE”
THEY HAVE ENZYMES THAT ALLOW
FOR PENETRATION OF
COMPLEX BIOFILM ENVIRONMENTS
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 …SOMETHING TO REMEMBER…

ANTIBIOTICS HAVE BEEN SUCCESSFULLY USED

TO ENHANCE
ANIMAL PERFORMANCE FOR OVER 70 YEARS
AND
NO PERSON OR DOMESTIC ANIMAL
HAS EVER BEEN REPORTED TO BECOME
ILL OR DIE DUE TO THE USE OF ANY
GROWTH PROMOTING ANTIBIOTIC
IN AN ANIMAL’S DIET
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 …IN FACT…
DURING THE PAST 70 YEARS
HUNDREDS OF THOUSANDS OF TONS
OF GROWTH PROMOTING ANTIBIOTICS
HAVE BEEN SUCCESSFULLY USED WORLD-WIDE
AND THE SAME MAGNITUDE OF IMPROVEMENT
IN BODY WEIGHT AND FEED CONVERSION
IS BEING OBSERVED TODAY IN ANIMALS
AS WAS OBSERVED TO OCCUR 70 YEARS AGO
…THIS MEANS…
THAT THE BACTERIAL POPULATIONS IN THE ANIMAL’S
DIGESTIVE TRACT HAVE NOT DEVELOPED RESISTANCE
TO ANY OF THE GROWTH PROMOTING ANTIBIOTICS
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 …QUESTION…
WHAT “NEW TERM” ORIGINATED AS A RESULT OF THE
REMOVAL OF GROWTH PROMOTING ANTIBIOTICS IN
THE EUROPEAN UNION AND IS NOW COMMONLY USED
BY THE ANIMAL INDUSTRY TO DESCRIBE THE INCREASED
INCIDENCE OF ENTERITIS IN BROILERS AND
WET LITTER IN POULTRY HOUSES ?

“DYSBACTERIOSIS”
SOURCE: WOODWARD, P. (2005) , PROCEEDINGS OF THE 32nd ANNUAL CAROLINA POULTRY NUTRITION CONFERENCE
 “DYSBACTERIOSIS”

DESCRIBES A SITUATION WHERE

THERE IS A HUGE IMBALANCE IN THE
BACTERIAL POPULATION IN THE
BIRD’S INTESTINAL TRACT
“DYSBACTERIOSIS”
…CONSEQUENCES…

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ANTIBIOTIC GROWTH PROMOTERS
“MAJOR CURRENTLY ACCEPTED MECHANISMS OF ACTION”
1) INHIBITION OF ENDEMIC SUBCLINICAL INFECTION,
THUS REDUCING THE METABOLIC COSTS OF THE
INNATE IMMUNE SYSTEM

2) THEY REDUCE GROWTH-DEPRESSING METABOLITES

SUCH AS AMMONIA AND BILE DEGRADATION
PRODUCTS PRODUCED BY INTESTINAL MICROBES

3) THEY REDUCE MICROBIAL USE OF NUTRIENTS WHICH

ALLOWS THE ANIMAL TO USE MORE NUTRIENTS

4) THEY INCREASE THE UPTAKE AND USE OF NUTRIENTS

BECAUSE THE INTESTINAL WALL IS THINNER IN
ANIMALS FED GROWTH PROMOTING ANTIBIOTICS
 ANTIBIOTIC GROWTH PROMOTERS
“THE MOST RECENTLY PROPOSED MECHANISM OF ACTION”

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“THE MOST RECENTLY PROPOSED MECHANISM OF ACTION”

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 HOW DO CYTOKINES
REDUCE ANIMAL PERFORMANCE ?

INTESTINAL
MACROPHAGE

ACUTE
ANOREXIA PHASE PROTEIN
& 1,'#!&+
*$+ PRODUCTION
FEVER IN LIVER
(BIRDS DON’T EAT)
(REQUIRES ENERGY)
MUSCLE BREAKDOWN
(CATABOLISM)
GROWTH PROMOTING ANTIBIOTICS PREVENT THE RELEASE OF CYTOKINES
WHICH PREVENTS THE LOSS OF PERFORMANCE AND ALSO
REDUCES WASTED ENERGY ASSOCIATED WITH THE IMMUNE RESPONSE
AND THIS ENERGY CAN THEN BE USED TO PROMOTE PERFORMANCE
 AVERAGE EXPECTED PERFORMANCE RESPONSE
FROM GROWTH PROMOTING ANTIBIOTICS
USED IN THE DIET OF VARIOUS ANIMALS
IMPROVEMENT
WEIGHT GAIN (%) FCR (%)

BROILER + 3.6 - 3.4

LAYING HEN + 2.8 - 2.7
TURKEY + 3.1 - 2.2
STARTING + 15.7 - 8.6
PIG GROWING + 8.1 - 4.8
FINISHING + 3.2 - 2.0
SOUIRCE: Rosen, 1995, QUOTED BY Schwarz in Kraftfutter 9/97 pp.349
 MAJOR FACTORS KNOWN TO INFLUENCE THE
MAGNITUDE OF RESPONSE TO GROWTH PROMOTING
ANTIBIOTICS IN VARIOUS SPECIES OF ANIMALS
FACTOR
GERM FREE ENVIRONMENT (NO MICROBES)
FARM HYGIENE (CLEAN VS DIRTY)
AGE OF ANIMAL (YOUNG VS OLD)
FARM MANAGEMENT (STRESS LEVEL)
 MAJOR FACTORS KNOWN TO INFLUENCE THE
MAGNITUDE OF RESPONSE TO GROWTH PROMOTING
ANTIBIOTICS IN VARIOUS SPECIES OF ANIMALS
FACTOR
GERM FREE ENVIRONMENT (NO MICROBES)

GERM FREE ENVIRONMENT (NO RESPONSE IN PERFORMANCE

IS EXPECTED WHEN USING GROWTH PROMOTING ANTIBIOTICS)
THIS SHOULD ALSO BE TRUE WHEN USING BACTERIOPHAGES
 MAJOR FACTORS KNOWN TO INFLUENCE THE
MAGNITUDE OF RESPONSE TO GROWTH PROMOTING
ANTIBIOTICS IN VARIOUS SPECIES OF ANIMALS
FACTOR
GERM FREE ENVIRONMENT (NO MICROBES)
FARM HYGIENE (CLEAN VS DIRTY)

FARM HYGIENE (CLEAN) FARM HYGIENE (DIRTY)

“LOW MICROBIAL LOAD” “HIGH MICROBIAL LOAD”

THIS SHOULD ALSO BE TRUE WHEN USING BACTERIOPHAGES

 MAJOR FACTORS KNOWN TO INFLUENCE THE
MAGNITUDE OF RESPONSE TO GROWTH PROMOTING
ANTIBIOTICS IN VARIOUS SPECIES OF ANIMALS
FACTOR
GERM FREE ENVIRONMENT (NO MICROBES)
FARM HYGIENE (CLEAN VS DIRTY)
AGE OF ANIMAL (YOUNG VS OLD)

OLD ANIMAL YOUNG ANIMAL

THIS SHOULD ALSO BE TRUE WHEN USING BACTERIOPHAGES
 MAJOR FACTORS KNOWN TO INFLUENCE THE
MAGNITUDE OF RESPONSE TO GROWTH PROMOTING
ANTIBIOTICS IN VARIOUS SPECIES OF ANIMALS
FACTOR
GERM FREE ENVIRONMENT (NO MICROBES)
FARM HYGIENE (CLEAN VS DIRTY)
AGE OF ANIMAL (YOUNG VS OLD)
FARM MANAGEMENT (STRESS LEVEL)

LOW STRESS LEVEL HIGH STRESS LEVEL

“GOOD FARM MANAGEMENT” “POOR FARM MANAGEMENT”
THIS SHOULD ALSO BE TRUE WHEN USING BACTERIOPHAGES
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 CONSUMER DEMAND
HAS ALWAYS BEEN THE MAJOR DRIVING
FORCE IN THE POULTRY INDUSTRY
…AND NOW…
CONSUMERS ARE DEMANDING
ALL ANIMAL PRODUCTS BE PRODUCED
WITHOUT THE USE OF ANTIBIOTICS
 CONSEQUENCES
OF BANNING GROWTH PROMOTING
ANTIBIOTICS IN THE EUROPEAN UNION
INCREASED USE OF INCREASED
THERAPEUTIC LEVELS USE OF IMPROVED
OF ANTIBIOTICS DISINFECTANTS FARM
INCREASED MANAGEMENT
INTESTINAL PROBLEMS AND HYGIENE
(NECROTIC ENTERITIS)

DIET
DECREASED FORMULATION
PROFITS '&+)-&+ CHANGES
(NO ANIMAL PRODUCTS)
(MORE USE OF ENZYMES)

INCREASED
DECREASED
IMPROVED MORTALITY
ANIMAL HIGHER
FEED AND
PRODUCTION COSTS FOR
(BWT, F/G, UNIFORMITY) QUALITY MORBIDITY
CONSUMERS (HIGHER QUALITY INGREDIENTS)
 5 SPECIFIC MAJOR CONSEQUENCES
AS A RESULT OF ELIMINATING THE USE OF
GROWTH PROMOTING ANTIBIOTICS IN BROILER FLOCKS


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BROILERS CAN BE RAISED
WITHOUT GROWTH PROMOTING ANTIBIOTICS

…BUT…
-- TIME TO MARKET IS INCREASED BY 3 TO 6 DAYS --
-- LESS BIRDS ARE BEING PLACED IN HOUSES --
-- PRODUCTION EFFICIENCY IS NOT AS HIGH --
-- THE CONSUMER WILL PAY MORE --
POSSIBLE ALTERNATIVE REPLACEMENTS
FOR
GROWTH PROMOTING ANTIBIOTICS
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OF
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1) NON-TOXIC AND HAVE NO SIDE EFFECTS
2) EASY TO ELIMINATE FROM THE BODY
3) NO ENVIRONMENTAL RESIDUES
4) NO BACTERIAL RESISTANCE
5) STABLE IN THE FEED
6) STABLE IN THE DIGESTIVE TRACT
7) DOES NOT AFFECT PALATABILITY
8) WILL NOT DESTROY NORMAL MICROBES IN INTESTINE
9) ABILITY TO KILL PATHOGENIC BACTERIA
10) ENHANCE AN ANIMAL’S RESISTANCE TO DISEASE
11) IMPROVE FEED EFFICIENCY
12) PROMOTE GROWTH AND PROVIDE A CONSISTENT RESPONSE
 …FACT…
EVEN THOUGH THERE ARE SEVERAL
PROPOSED ALTERNATIVES TO
GROWTH PROMOTING ANTIBIOTICS
NO ALTERNATIVE PRODUCT
HAS EVER BEEN SHOWN TO BE AS
EFFECTIVE AS THE
GROWTH PROMOTING ANTIBIOTICS
FOR OVER 70 YEARS THE ANIMAL INDUSTRY HAS EXPERIENCED
A CONSISTENT POSITIVE PERFORMANCE RESPONSE FROM THE ADDITION OF
GROWTH PROMOTING LEVELS OF ANTIBIOTICS TO ANIMAL DIETS
 …ALSO…
EVEN THOUGH MANY ALTERNATIVES
TO GROWTH PROMOTING ANTIBIOTICS
SHOW PROMISE AND MIGHT BE USED
IN THE FUTURE THEIR MODE OF ACTION
IS TOTALLY DIFFERENT
…THAN THAT OF ANTIBIOTICS…
AND
THIS HELPS TO EXPLAIN WHY PERFORMANCE
RESULTS IN THE FIELD FROM USING
THESE PRODUCTS ARE NOT AS CONSISTENT
AS THE PERFORMANCE WITH ANTIBIOTICS
 “IDEAL CHARACTERISTICS”
OF
GROWTH PROMOTING ANTIBIOTIC
ALTERNATIVES
1) NON-TOXIC AND HAVE NO SIDE EFFECTS
2) EASY TO ELIMINATE FROM THE BODY
3) NO ENVIRONMENTAL RESIDUES
4) NO BACTERIAL RESISTANCE
5) STABLE IN THE FEED
6) STABLE IN THE DIGESTIVE TRACT
7) DOES NOT AFFECT PALATABILITY
8) WILL NOT DESTROY NORMAL MICROBES IN INTESTINE
9) ABILITY TO KILL PATHOGENIC BACTERIA
10) ENHANCE AN ANIMAL’S RESISTANCE TO DISEASE
11) IMPROVE FEED EFFICIENCY
12) PROMOTE GROWTH & PROVIDE A CONSISTENT RESPONSE
 …FACT…
IT IS VERY UNLIKELY THAT ANY NEW
GROWTH PROMOTING ANTIBIOTICS
WILL BE DEVELOPED AND APPROVED
IN THE NEAR FUTURE FOR USE
IN THE ANIMAL INDUSTRY
THE COST OF DEVELOPMENT AND TESTING ANTIBIOTICS
IS BECOMING COST PROHIBITIVE
AND
THE FUTURE TREND SEEMS TO BE NOT TO APPROVE
AS MANY NEW ANTIBIOTICS AS IN THE PAST
 NUMBER OF “SYSTEMIC” ANTIBACTERIAL
NEW DRUG APPLICATION APPROVALS
TO THE FDA SINCE 1980
20
NUMBER APPROVED

15

10

0 1980-84 85-89 90-94 95-99 2000-04 2005-09 2010-14

YEAR
DATA COURTESY OF THE FOOD AND DRUG ADMINISTRATION AND CENTER FOR DRUG EVALUATION AND RESEARCH
 CAN BACTERIOPHAGES BE
USED WITH ANTIBIOTICS ?

YES
VERY SUCCESSFULLY
…IMPORTANT FACTS TO REMEMBER…
ANTIBIOTICS
ARE NOT SPECIFIC FOR A CERTAIN BACTERIAL SPECIES
AND EVEN LESS SPECIFIC AGAINST CERTAIN STRAINS
OF BACTERIA WITHIN A SPECIES
(USUALLY KILL BACTERIA UNDERGOING A RAPID GROWTH PHASE)

BACTERIOPHAGES
ARE VERY SPECIFIC FOR ONLY ONE BACTERIAL SPECIES
AND SPECIFIC FOR CERTAIN STRAINS WITHIN A SPECIES
QUESTION (KILL BACTERIA INDEPENDENTLY OF THE GROWTH PHASE)
 …BACTERIOPHAGES…
FAVORABLE EXPECTED CONSEQUENCES
OF THEIR USE IN DIETS
GROWTH ENHANCEMENT
IMPROVED FEED CONVERSION
IMPROVED FLOCK UNIFORMITY
LESS SUBCLINICAL DISEASE
BETTER INTESTINAL “BACTERIAL STABILITY”
(PREVENT DYSBACTERIOSIS)
REDUCED IMMUNE STIMULATION
IMPROVED PRODUCT SAFETY & QUALITY
…AND…

OTHERS
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HOW DO I FEEL ABOUT THE FUTURE
WITHOUT GROWTH PROMOTING ANTIBIOTICS
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 Journal of Applied Poultry Research

…REPORTED FINDINGS…
1) BACTERIOPHAGES REDUCED CECAL & INTERNAL ORGAN SALMONELLA COUNTS*

2) BACTERIOPHAGES DECREASED THE TOTAL FECAL SHEDDING OF SALMONELLA

3) BACTERIOPHAGES DECREASED LIPOLYSIS CAUSED BY IMMUNE SYSTEM CYTOKINES

WHICH RESULTED IN LESS ENERGY UTILIZATION RELATED TO IMMUNE SYSTEM STIMULATION

4) BACTERIOPHAGES @ 0.2% DECREASED SE IN THE OVARY TO ZERO (0) CFU/GM

* 4 TRT. GROUPS (8 HENS/GROUP) (TRTS. -,+, .1,.2% BP): EYE/CLOACAL INOCULATION (108 CFU/ML SE )