NZ615973B2 - Use of bacterial endotoxins and lipoteichoic acids to improve postpartal health and productivity of dairy cows and their newborns - Google Patents
Use of bacterial endotoxins and lipoteichoic acids to improve postpartal health and productivity of dairy cows and their newborns Download PDFInfo
- Publication number
- NZ615973B2 NZ615973B2 NZ615973A NZ61597312A NZ615973B2 NZ 615973 B2 NZ615973 B2 NZ 615973B2 NZ 615973 A NZ615973 A NZ 615973A NZ 61597312 A NZ61597312 A NZ 61597312A NZ 615973 B2 NZ615973 B2 NZ 615973B2
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- New Zealand
- Prior art keywords
- endotoxin
- treatment
- lipoteichoic acid
- trt
- effect
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
- A61K2039/552—Veterinary vaccine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/70—Multivalent vaccine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/739—Lipopolysaccharides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/025—Enterobacteriales, e.g. Enterobacter
- A61K39/0258—Escherichia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/07—Bacillus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
Disclosed is a method for treating or preventing a metabolic disorder in a nonhuman subject, the method comprising administering to the non-human subject a bacterial endotoxin and a lipoteichoic acid, separately, simultaneously or sequentially, with the proviso that when the endotoxin is LPS, the metabolic disorder is not Laminitis. tabolic disorder is not Laminitis.
Description
USE OF BACTERIAL ENDOTOXINS AND LIPOTEICHOIC ACIDS TO IMPROVE
POSTPARTAL HEALTH AND PRODUCTIVITY OF DAIRY COWS AND THEIR
NEWBORNS
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of and priority from United States
Provisional Patent Application No. 61/448,815 filed March 3, 2011, which is
incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The invention concerns the use of bacterial endotoxins and lipoteichoic
acids to improve postpartal health and productivity of dairy cows and their newborns.
BACKGROUND
The transition period is critical for the health and productivity of dairy
cows due to high incidence of metabolic disorders caused by various bacterial
infections. Metabolic disorders are diseases that involve changes in plasma
metabolites of sick animals or humans. Almost 50% of dairy cows are affected by
one or more metabolic diseases such as ketosis, fatty liver, laminitis, displaced
abomasum, milk fever, downer cow syndrome, udder edema, metritis, retained
placenta, infertility, or mastitis. The conventional view on metabolic disorders is that
these diseases are related to the disturbance of one or more blood metabolites.
These changes are generally interpreted as deficiencies or excesses of these
nutrients in the diet, especially, around parturition.
High-grain diets (i.e. a diet rich in starch) may be implicated in the
development of metabolic disorders. Feeding ruminant animals high-grain diets is a
human designed intervention to increase milk and meat production. However,
ruminants do not naturally consume high-grain diets; rather, they eat mostly grass or
forage diets. Since grain is rich in starch and poor in fiber content, feeding high-grain
diets is associated with major changes in the gastrointestinal (GI) microflora switching
from fiber-digesting bacteria into starch-digesting bacteria. Most of the starch-
digesting bacteria are Gram-negative bacteria. The latter degrade starch to use it for
their nutritional needs. During this process large quantities of acids are released into
the GI tract, changing the pH from normally alkaline into acidic pH. Furthermore,
abundant starch increases the number of Gram-negative bacteria in the GI tract.
This is associated with the release of great amounts (20-fold increase) of toxic
compounds such as endotoxin or lipopolysaccharide (LPS). Endotoxin translocates
into the host’s blood circulation and causes a variety of alterations in blood
metabolites, immunity, and health status.
Research work indicates that lipoteichoic acid (LTA) is able to induce an
inflammatory response and dysfunction of multiple organs, know as septic shock,
when administered intravenously (iv) in experimental animals. An early investigation
demonstrated that iv infusion of LTA was associated with the release of tumor
necrosis factor alpha and interferon gamma in the plasma, a decrease in the arterial
oxygen pressure in the lungs, and increases in the plasma concentrations of bilirubin,
alanine aminotransferase, creatinine and urea, lipase from pancreas, and creatine
kinase. In addition, LTA causes the release of nitric oxide in multiple organs,
circulatory failure, and 50% mortality in the experimental animals (De Kimpe S. J.
et al., 1995). Moreover, research from different groups has shown that even a single
dose of LTA, as little as 0.1 mg, is sufficient to produce enhanced concentrations of
free fatty acids (FFA) and triglyceride in the blood of experimental animals.
Lipoteichoic acid also has been shown to increase the concentration of cholesterol in
the plasma. Additionally, mounting evidence indicates involvement of LTA in the
pathogenesis of mastitis in dairy cows. Thus, recent work demonstrated that that
infusion of LTA alone in the mammary gland was sufficient to elicit a marked
inflammatory response in the mammary gland of dairy cows, characterized by a
massive influx of neutrophils into milk. This suggests that during infection, LTA
contributes to the recruitment of neutrophils.
There remains a need for effective combinations and methods to
improve postpartal health and productivity of dairy cows and their newborns.
It is an object of the present invention to go some way towards meeting
this need and/or to provide the public with a useful choice.
SUMMARY
In a first aspect, the invention provides a method for treating or
preventing a metabolic disorder in a non-human subject, said method comprising
administering to said non-human subject a bacterial endotoxin and a lipoteichoic acid,
separately, simultaneously or sequentially, with the proviso that when said endotoxin
is a lipopolysaccharide, said metabolic disorder is not laminitis.
In a second aspect, the invention provides a use of a bacterial
endotoxin and a lipoteichoic acid in the preparation of a medicament for treating or
preventing a metabolic disorder in a subject, wherein said bacterial endotoxin and
said lipoteichoic acid are for administration, separately, simultaneously or
sequentially, with the proviso that when said endotoxin is a lipopolysaccharide, said
metabolic disorder is not laminitis.
Also described is a combination comprising a bacterial endotoxin and a
lipoteichoic acid. In an embodiment, the combination is for separate, simultaneous or
sequential administration to a subject for treating or preventing a metabolic disorder
in said subject.
Also described is a use of a bacterial endotoxin and a lipoteichoic acid
in the manufacture of a medicament for treating or preventing a metabolic disorder in
said subject, wherein said bacterial endotoxin and said lipoteichoic acid are for
administration, separately, simultaneously or sequentially.
Also described is a method for treating or preventing a metabolic
disorder, for treating or preventing bacterial infection or for improving milk energy
efficiency in a subject, said method comprising administering to said subject a
bacterial endotoxin and a lipoteichoic acid, separately, simultaneously or sequentially.
BRIEF DESCRIPTION OF THE DRAWINGS
In drawings illustrating embodiments of the invention:
Figure 1 is a graph depicting weekly variations of overall beta-
hydroxybutyrate in plasma of multiparous and primiparous Holstein cows challenged
with oral and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM;
n = 16; Trt = effect of treatment; Week = effect of sampling week, Trt x Week = effect
of treatment by sampling week).
Figure 2 is a graph depicting weekly variations of overall non-esterified
fatty acids in plasma of multiparous and primiparous Holstein cows challenged with
oral and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM;
n = 16; Trt = effect of treatment; Week = effect of sampling week, Trt x Week = effect
of treatment by sampling week).
Figure 3 is a graph depicting weekly variations of overall lactate in
plasma of multiparous and primiparous Holstein cows challenged with oral and nasal
treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 16; Trt = effect
of treatment; Week = effect of sampling week, Trt x Week = effect of treatment by
sampling week).
Figure 4 is a graph depicting weekly variations of overall cholesterol in
plasma of multiparous and primiparous Holstein cows challenged with oral and nasal
treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 16; Trt = effect
of treatment; Week = effect of sampling week, Trt x Week = effect of treatment by
sampling week).
Figure 5 is a graph depicting weekly variations of overall glucose in
plasma of multiparous and primiparous Holstein cows challenged with oral and nasal
treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 16; Trt = effect
of treatment; Week = effect of sampling week, Trt x Week = effect of treatment by
sampling week).
Figure 6 is a graph depicting weekly variations of overall haptoglobin in
plasma of multiparous and primiparous Holstein cows challenged with oral and nasal
treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 16; Trt = effect
of treatment; Week = effect of sampling week, Trt x Week = effect of treatment by
sampling week).
Figure 7 is a graph depicting weekly variations of overall energy
corrected milk in multiparous and primiparous lactating Holstein cows challenged with
oral and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM;
n = 29; Trt = effect of treatment; Week = effect of sampling week, Trt x Week = effect
of treatment by sampling week).
Figure 8 is a graph depicting weekly variations of overall milk efficiency
in multiparous and primiparous lactating Holstein cows challenged with oral and nasal
treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 30; Trt = effect
of treatment; Week = effect of sampling week, Trt x Week = effect of treatment by
sampling week).
Figure 9 is a graph depicting weekly variations of overall fat percent in
multiparous and primiparous lactating Holstein cows challenged with oral and nasal
treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 30; Trt = effect
of treatment; Week = effect of sampling week, Trt x Week = effect of treatment by
sampling week).
Figure 10 is a graph depicting weekly variations of overall fat to protein
ratio in multiparous and primiparous lactating Holstein cows challenged with oral and
nasal treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 30;
Trt = effect of treatment; Week = effect of sampling week, Trt x Week = effect of
treatment by sampling week).
Figure 11 is a graph depicting weekly variations of overall fat yield in
multiparous and primiparous lactating Holstein cows challenged with oral and nasal
treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 29; Trt = effect
of treatment; Week = effect of sampling week, Trt x Week = effect of treatment by
sampling week).
Figure 12 is a graph depicting weekly variations of overall fat corrected
milk in multiparous and primiparous lactating Holstein cows challenged with oral and
nasal treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 29;
Trt = effect of treatment; Week = effect of sampling week, Trt x Week = effect of
treatment by sampling week).
Figure 13 is a graph depicting weekly variations of overall feed intake in
multiparous and primiparous lactating Holstein cows challenged with oral and nasal
treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 30; Trt = effect
of treatment; Week = effect of sampling week, Trt x Week = effect of treatment by
sampling week).
Figure 14 is a graph depicting weekly variations of overall lactose
content in multiparous and primiparous lactating Holstein cows challenged with oral
and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 29;
Trt = effect of treatment; Week = effect of sampling week, Trt x Week = effect of
treatment by sampling week).
Figure 15 is a graph depicting weekly variations of overall lactose yield
in multiparous and primiparous lactating Holstein cows challenged with oral and nasal
treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 30; Trt = effect
of treatment; Week = effect of sampling week, Trt x Week = effect of treatment by
sampling week).
Figure 16 is a graph depicting weekly variations of overall milk fat
efficiency in multiparous and primiparous lactating Holstein cows challenged with oral
and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 30;
Trt = effect of treatment; Week = effect of sampling week, Trt x Week = effect of
treatment by sampling week).
Figure 17 is a graph depicting day-to-day variations of overall milk
production in multiparous and primiparous lactating Holstein cows challenged with
oral and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM;
n = 30; Trt = effect of treatment; Day = effect of sampling day, Trt x day = effect of
treatment by sampling day).
Figure 18 is a graph depicting weekly variations of overall milk yield in
multiparous and primiparous lactating Holstein cows challenged with oral and nasal
treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 30; Trt = effect
of treatment; Week = effect of sampling week, Trt x Week = effect of treatment by
sampling week).
Figure 19 is a graph depicting weekly variations of overall milk urea
nitrogen in multiparous and primiparous lactating Holstein cows challenged with oral
and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 30;
Trt = effect of treatment; Week = effect of sampling week, Trt x Week = effect of
treatment by sampling week).
Figure 20 is a graph depicting weekly variations of overall milk solid not
fat in multiparous and primiparous lactating Holstein cows challenged with oral and
nasal treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 30;
Trt = effect of treatment; Week = effect of sampling week, Trt x Week = effect of
treatment by sampling week).
Figure 21 is a graph depicting weekly variations of overall milk protein
content in multiparous and primiparous lactating Holstein cows challenged with oral
and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 30;
Trt = effect of treatment; Week = effect of sampling week, Trt x Week = effect of
treatment by sampling week).
Figure 22 is a graph depicting weekly variations of overall milk protein
yield in multiparous and primiparous lactating Holstein cows challenged with oral and
nasal treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 30;
Trt = effect of treatment; Week = effect of sampling week, Trt x Week = effect of
treatment by sampling week).
Figure 23 is a graph depicting weekly variations of overall total solid
contents in multiparous and primiparous lactating Holstein cows challenged with oral
and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 30;
Trt = effect of treatment; Week = effect of sampling week, Trt x Week = effect of
treatment by sampling week).
Figure 24 is a graph depicting the effect of measurement time on
diurnal variations of rumen contractions per minute in multiparous and primiparous
lactating Holstein cows challenged with oral and nasal treatment of LPS-LTA
(TRT; ) or saline (CTR; ) (LSM ± SEM; n = 10; Trt = effect of treatment;
Time = effect of time measured before and after treatment, Trt x time = effect of
treatment by measurement time).
Figure 25 is a graph depicting diurnal variations of rumen contractions
per minute in multiparous and primiparous lactating Holstein cows challenged with
three different doses of oral and nasal treatment of LPS-LTA (TRT; ) or saline
(CTR; ) (LSM ± SEM; n = 10; Trt = effect of treatment; Time = effect of time
measured before and after treatment, Trt x time = effect of treatment by
measurement time).
Figure 26 is a graph depicting diurnal variations of rumen contractions
per minute in multiparous and primiparous lactating Holstein cows challenged with
first dose of oral and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; )
(LSM ± SEM; n = 10; Trt = effect of treatment; Time = effect of time measured before
and after treatment, Trt x time = effect of treatment by measurement time).
Figure 27 is a graph depicting diurnal variations of rumen contractions
per minute in multiparous and primiparous lactating Holstein cows challenged with
second dose of oral and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; )
(LSM ± SEM; n = 10; Trt = effect of treatment; Time = effect of time measured before
and after treatment, Trt x time = effect of treatment by measurement time).
Figure 28 is a graph depicting diurnal variations of rumen contractions
per minute in multiparous and primiparous lactating Holstein cows challenged with
third dose of oral and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; )
(LSM ± SEM; n = 10; Trt = effect of treatment; Time = effect of time measured before
and after treatment, Trt x time = effect of treatment by measurement time).
Figure 29 is a graph depicting the effect of measurement time on
diurnal variations of rectal temperature in multiparous and primiparous lactating
Holstein cows challenged with oral and nasal treatment of LPS-LTA (TRT; ) or
saline (CTR; ) (LSM ± SEM; n = 10; Trt = effect of treatment; Time = effect of time
measured before and after treatment, Trt x time = effect of treatment by
measurement time).
Figure 30 is a graph depicting diurnal variations of rectal temperature in
multiparous and primiparous lactating Holstein cows challenged with three different
doses of oral and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; )
(LSM ± SEM; n = 10; Trt = effect of treatment; Time = effect of time measured before
and after treatment, Trt x time = effect of treatment by measurement time).
Figure 31 is a graph depicting diurnal variations of rectal temperature in
multiparous and primiparous lactating Holstein cows challenged with first dose of oral
and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM; n = 10;
Trt = effect of treatment; Time = effect of time measured before and after treatment,
Trt x time = effect of treatment by measurement time).
Figure 32 is a graph depicting diurnal variations of rectal temperature in
multiparous and primiparous lactating Holstein cows challenged with second dose of
oral and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM;
n = 10; Trt = effect of treatment; Time = effect of time measured before and after
treatment, Trt x time = effect of treatment by measurement time).
Figure 33 is a graph depicting diurnal variations of rectal temperature in
multiparous and primiparous lactating Holstein cows challenged with third dose of
oral and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; ) (LSM ± SEM;
n = 10; Trt = effect of treatment; Time = effect of time measured before and after
treatment, Trt x time = effect of treatment by measurement time).
Figure 34 is a graph depicting the effect of measurement time on
diurnal variations of respiration rate per minute in multiparous and primiparous
lactating Holstein cows challenged with oral and nasal treatment of LPS-LTA
(TRT; ) or saline (CTR; ) (LSM ± SEM; n = 10; Trt = effect of treatment;
Time = effect of time measured before and after treatment, Trt x time = effect of
treatment by measurement time).
Figure 35 is a graph depicting diurnal variations of respiration rate per
minute in multiparous and primiparous lactating Holstein cows challenged with three
different doses of oral and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; )
(LSM ± SEM; n = 10; Trt = effect of treatment; Time = effect of time measured before
and after treatment, Trt x time = effect of treatment by measurement time).
Figure 36 is a graph depicting diurnal variations of respiration rate per
minute in multiparous and primiparous lactating Holstein cows challenged with first
dose of oral and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; )
(LSM ± SEM; n = 10; Trt = effect of treatment; Time = effect of time measured before
and after treatment, Trt x time = effect of treatment by measurement time).
Figure 37 is a graph depicting diurnal variations of respiration rate per
minute in multiparous and primiparous lactating Holstein cows challenged with
second dose of oral and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; )
(LSM ± SEM; n = 10; Trt = effect of treatment; Time = effect of time measured before
and after treatment, Trt x time = effect of treatment by measurement time).
Figure 38 is a graph depicting diurnal variations of respiration rate per
minute in multiparous and primiparous lactating Holstein cows challenged with third
dose of oral and nasal treatment of LPS-LTA (TRT; ) or saline (CTR; )
(LSM ± SEM; n = 10; Trt = effect of treatment; Time = effect of time measured before
and after treatment, Trt x time = effect of treatment by measurement time).
DETAILED DESCRIPTION
Metabolic disorders are a group of diseases that affect dairy cows
immediately after parturition. There are several metabolic disorders identified in dairy
cows during the first month after parturition, the most significant of which are the
following:(1) sub-acute and acute ruminal acidosis; (2) laminitis; (3) ketosis, (4) fatty
liver, (5) left displaced abomasum (LDA), (6) milk fever; (7) downer cow; (8) retained
placenta; (9) metritis, (10) mastitis, (11) udder edema; and (12) bloat. Dairy farmers
lose approximately $142/cow per year for treatment of metabolic disorder in addition
to milk loss in the first 30 days of lactation. More than half of dairy cows are affected
by at least one metabolic disorder. This makes metabolic disorders of great
economic importance.
The reason that these diseases are called metabolic disorders is related
to the fact that they are associated with the disturbance of one or more blood
metabolites in sick cows. For example, ketosis is associated with enhanced ketone
bodies in the blood; fatty liver is associated with enhanced nonesterified fatty acids
(NEFA) in the blood and their accumulation in the liver; acidosis is associated with
increased production of volatile fatty acid (i.e., acetate, propionate, and butyrate) and
organic acids (e.g., lactic acid) in the rumen and low rumen and blood pH; and milk
fever is associated with decreased blood calcium. There is not yet a blood metabolite
identified for some of the metabolic disorders such as downer cow, LDA, metritis,
mastitis, or bloat. However, these diseases are associated with alteration of multiple
blood metabolites.
The most interesting observation with regards to the occurrence of
metabolic disorders is that they are highly associated with each other. For example,
cows affected by milk fever are more prone to mastitis, retained placenta, metritis,
LDA, dystocia, udder edema, and ketosis; cows affected by acidosis are more prone
to laminitis, LDA, milk fever, mastitis, and fatty liver. Those affected by retained
placenta are more prone to metritis, LDA, and ketosis. Ketosis and fatty liver are
common findings in cows affected by milk fever, mastitis, laminitis, displaced
abomasum, metritis, retained placenta and udder edema. Although these
associations have been known for years by animal scientists, the reason behind this
association is not very well understood. One speculation is that there might be a
common etiological factor that initiates the cascade of metabolic disorders.
Therefore, scientists are searching to identify such a common causal agent of
metabolic disorders; however, no such an agent has been identified so far.
Modern dairy cows have been selected by continuous genetic
improvement and rigorous selection to achieve high milk production. Since high milk
production cannot be maintained by forage alone grain-based diets which are very
rich in energy are fed to the cows. The ruminal digestive system is not developed to
digest high amounts of grain and feeding grains which are rich in starch is associated
with a decline in ruminal and colonic pH, change in osmotic pressure and shift in
bacterial populations from cellulolytic to amylolytic bacteria. Most of the known starch
digesters are Gram-negative bacteria and this shift in population is associated with a
20-fold increase in the amount of endotoxin in the ruminal fluid. Several
epidemiological studies have shown that endotoxin from rumen Gram-negative
bacteria has been implicated in diseases that are related to feeding high concentrate
diets such as sudden death syndrome, ruminal acidosis, fatty liver, left displaced
abomasum and laminitis. Ruminal epithelium lacks in mucus secretion and exposure
to acidotic environment leads to inflammation and tissue degeneration. The acidotic
environment, change in osmotic pressure and endotoxin may affect the permeability
of the rumen and colon resulting in translocation of endotoxin in the circulation.
Although the presence of endotoxin in the ruminal fluid has been documented, prior
to the present invention there has been no convincing evidence of translocation into
the circulation.
The main objective of this investigation was to apply repeated oral
administration of lipopolysaccharide (LPS) a cell wall component of Gram-negative
(GN) bacteria and lipoteichoic acid (LTA) a cell wall component of Gram-positive
(GP) bacteria around parturition to prevent metabolic disturbances induced by those
compounds and development of inflammatory states related to both GN and GP
bacteria as well as improve general health, and productivity of dairy cows.
Pregnant Holstein dairy cows were blocked by parity and the
anticipated day of calving, and were randomly allocated to 2 groups, 28 d before the
expected day of parturition. Cows were orally administered saline solution (Control
group), or saline solution containing 3 increasing doses of LPS (Treatment group)
form Escherichia coli 0111:B4 along with a LTA from Bacillus subtilis with the same
dose pre-partum. The dose of LTA was determined from a preliminary dosage study.
Blood, urine, saliva, and vaginal mucus samples were collected 4 weeks before and
4 weeks after calving, whereas milk samples were collected starting from calving until
4 weeks after calving for all cows in the experiment to be analyzed for different
variables. Cows were observed daily for presence of clinical disease during the
4 weeks before and 4 weeks after calving and rectal temperatures were taken during
3 weeks before and 2 weeks after calving. Blood samples were also obtained from
the newborns during the 4 weeks after birth in order to measure the immunity
transmitted to the newborn calves from the dam. Calves were also observed for
incidence of diarrhea until 4 weeks after birth.
To investigate the diurnal blood and health responses in treated cows,
blood and health records were taken at -15 min before as well as 1, 3 and 5 h after
application of the oral vaccine. Results of this study demonstrated that oral
administration of LPS and LTA was associated with lower incidence of metritis,
laminitis, retained placenta, and improved uterine horn fluctuation in the treated cows.
Furthermore, the severity of laminitis was lowered in treated multiparous cows, where
it tended to be lower in the treatment group. Moreover, treated cows tended to
require lower overall number of medications as well as have lower number of days
with more than one disease versus control cows. Blood data showed lower plasma
lactate in treated cows and a tendency for higher plasma cholesterol, which is an
indication of better energy status in those cows.
Treatment did not influence plasma BHBA, NEFA, and glucose.
Interestingly, data indicated that the oral vaccination of cows with LPS and LTA
increased their milk energy efficiency, which was associated with a trend for greater
feed intake in that group. Furthermore, the analysis of milk data demonstrated a
higher fat to protein ratio, as well as greater milk fat efficiency for the treated cows.
No effect of treatment was observed on other milk components as well as on the
overall milk production. Calf data indicated a tendency for lower calf diarrhoea score
in the treatment group for both multiparous and primiparous cows compared to
controls.
Overall, administration of oral LPS and LTA improved metabolic and
productive performance as well as general health status of the treated cows
suggesting application of this novel vaccine during the transition period is a very
promising intervention to improve general health, productivity, and wellbeing of dairy
cows and the newborns.
Endotoxin
Any bacterial endotoxin may be used in the practice of the methods
described herein. Endotoxins are cell-associated bacterial toxins. They generally
compose part of the outer membrane of the cell wall of Gram-negative bacteria,
whether pathogenic or not, such as Escherichia coli, Salmonella, Shigella,
Pseudomonas, Neisseria, or Haemophilus. Many endotoxins are lipopolysaccharides
(LPS), comprising a lipid component and a polysaccharide component. Toxicity of the
endotoxin is associated with the lipid component (lipid A) and immunogenicity is
associated with the polysaccharide component. Both lipid A and the polysaccharide
components of LPS act as determinants of virulence in Gram-negative bacteria.
The structure of the lipid A component is highly conserved amongst
Gram-negative bacteria. The polysaccharide component contains two regions. The
first is known as the core (R) antigen or (R) polysaccharide. The core polysaccharide
remains relatively constant within a bacterial genus but is structurally distinct amongst
genera of bacteria. The second polysaccharide region is the somatic (O) antigen or
(O) polysaccharide. The (O) polysaccharide varies substantially between species
and even amongst strains of Gram-negative bacteria.
Endotoxins described herein may be used in purified or unpurified form.
For example, in certain applications, it may be sufficient to provide the endotoxin in
the form of killed bacteria, such as lysed bacteria or even as live bacteria. In other
applications, purified endotoxins (for instance in crystalline form) may be used and
are available from commercial sources such as Sigma-Aldrich. Synthetic endotoxins,
such as synthetic LPS or LPS analogs may be used in practice of the invention.
Truncated endotoxins, or portions or fractions of endotoxins comprising only the lipid
A or core polysaccharide or (O) polysaccharide of LPS may be used as may be
chimeric endotoxins comprising an altered or heterologous lipid A or polysaccharide
components.
Lipoteichoic Acid
Any lipoteichoic acid may be used in the practice of the methods
described herein. Lipoteichoic acids are a major constituent of the cell wall of Gram-
positive bacteria such as Bacillus subtilis. Lipoteichoic acids consist of teichoic acids,
long-chain ribitol phosphate and glyceride lipid membrane anchor. One function of
lipoteichoic acids is as regulators of autolytic cell wall enzymes called muramidases.
Lipoteichoic acids also have potent antigenic properties and can stimulate an immune
response when released from bacterial cells, for instance, after bacteriolysis induced
by lysozyme, cationic peptides from leucocytes, or beta-lactam antibiotics.
Lipoteichoic acids described herein may be used in purified or
unpurified form. For example, in certain applications, it may be sufficient to provide
the lipoteichoic acid in the form of killed bacteria, such as lysed bacteria or even as
live bacteria. In other applications, purified lipoteichoic acids (for instance in
crystalline form) may be used and are available from commercial sources such as
Sigma-Aldrich. Synthetic lipoteichoic acid, such as synthetic LTA or LTA analogs
may be used in practice of the invention. Truncated lipoteichoic acids, or portions or
fractions of lipoteichoic acids may be used as may be chimeric lipoteichoic acids
comprising an altered or heterologous teichoic acids, ribitol phosphate chains
glyceride components.
Combinations and Compositions
The endotoxin and lipoteichoic acid may be administered to a subject in
the form of, without limitation, a combination comprising a bacterial endotoxin and a
lipoteichoic acid, said combination being for separate, simultaneous or sequential
administration. The combinations may comprise one or more pharmaceutical
compositions. Pharmaceutical compositions may be for mucosal, oral, nasal, rectal,
intravaginal or other modes of administration. The composition comprises the
endotoxin and/or the lipoteichoic acid in combination with one or more physiologically
acceptable ingredients, such as carriers, excipients and/or diluents. Compositions
and formulations for oral administration are particularly preferred.
Pharmaceutical compositions may be prepared, for example, in unit
dose forms, such as tablets, sachets, capsules, dragees, suppositories or ampoules.
They may be prepared in a conventional manner, for example by means of
conventional mixing, granulating, confectioning, dissolving or lyophilising processes.
Preferred are pharmaceutical compositions formulated for
administration to the gastrointestinal tract, such as by oral or rectal administration.
Oral administration is particularly preferred as a convenient and economical mode of
administration. Pharmaceutical compositions of the present invention in the form of
dosage units for oral administration may take the form of, for example, granules,
tablets, capsules, liquids or dragees prepared together with physiologically
acceptable carriers, excipients and/or diluents. Pharmaceutical compositions of the
present invention may be applied to or incorporated into, for example, animal feed,
fodder, silage, foodstuffs and drinking water.
Typical physiologically acceptable ingredients include:
(a) binding agents such as starch (e.g. pregelatinised maize starch, wheat
starch paste, rice starch paste, potato starch paste), polyvinylpyrrolidone,
hydroxypropyl methylcellulose, gum tragacanth and/or gelatin;
(b) fillers such as sugars (e.g. lactose, saccharose, mannitol, sorbitol),
amylopectin, cellulose preparations (e.g. microcrystalline cellulose), calcium
phosphates (e.g. tricalcium phosphate, calcium hydrogen phosphatelactose) and/or
titanium dioxide;
(c) lubricants such as stearic acid, calcium stearate, magnesium stearate,
talc, silica, silicic acid, polyethylene glycol and/or waxes;
(d) disintegrants such as the above-mentioned starches, carboxymethyl
starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof (e.g.
sodium alginate) and/or sodium starch glycollate;
(e) wetting agents such as sodium lauryl sulphate; and/or,
(f) stabilizers.
Soft gelatin capsules may be prepared with capsules containing a
mixture of the bacterial endotoxin and/or lipoteichoic acid together with paraffin oil,
liquid polyethylene glycols, vegetable oil, fat and/or another suitable vehicle for soft
gelatin capsules. Plasticizers such as glycerol or sorbitol may also be used. Hard
gelatin capsules may contain granules of the composition. Hard gelatin capsules
may also contain the endotoxin and/or lipoteichoic acid in combination with solid
powdered ingredients such as those listed above.
Liquid formulations for oral administration may be prepared in the form
of solutions, syrups or suspensions. Liquid formulations typically comprise the
bacterial endotoxin and/or the lipoteichoic acid together with an excipient such as
sugar or sugar alcohols, and a carrier such as ethanol, water, glycerol, propylene
glycol, polyethylene glycol, almond oil, oily esters or mixtures thereof. If desired,
such liquid formulations may also contain coloring agents, flavoring agents,
saccharine, thickening agents (e.g. carboxymethyl cellulose), suspending agents
(e.g. sorbitol syrup, methyl cellulose, hydrogenated edible fats), emulsifying agents
(e.g. lecithin, acacia), and/or preservatives (e.g. methyl p-hydroxybenzoates, propyl
p-hydroxybenzoates, sorbic acid). Liquid formulations for oral administration may
also be prepared in the form of a dry powder to be reconstituted with water or another
suitable vehicle prior to use.
Also described are kits or commercial packages comprising a
composition as described above together with printed matter comprising instructions
for using the composition for treating or preventing a metabolic disorder, for treating
or preventing bacterial infection or for improving milk energy efficiency in a subject.
The pharmaceutical composition will generally contain a therapeutically
effective amount of the bacterial endotoxin and/or the lipoteichoic acid, i.e. an amount
that is effective, at dosages and for periods of time necessary, to achieve a desired
prophylactic or therapeutic result, such as a reduction, inhibition, or prevention of
disease onset or progression. A therapeutically effective amount may vary according
to factors such as the disease state, age, sex, and weight of the individual, and the
ability of the compound to elicit a desired response in the individual. Dosage
regimens may be adjusted to provide the optimum therapeutic response. A
therapeutically effective amount is also one in which any toxic or detrimental effects
of the compound are outweighed by the therapeutically beneficial effects.
For any particular subject, specific dosage regimens may be adjusted
over time according to the individual need and the professional judgement of the
person administering or supervising the administration of the compositions.
In some embodiments wherein the subject is a pregnant animal such as
a dairy cow, the composition is administered to the subject from a time no more than
four weeks prior to parturition to a time no more than four weeks after parturition.
During this period the composition may preferably be administered about two times
per week. The composition may be administered in a dose of from 0.01 to 1 μg
endotoxin/kg body weight of the subject, more preferably from 0.01 to 0.05 μg
endotoxin/kg body weight of the subject, even more preferably at a dose of about
0.01, about 0.05 or about 0.1 μg endotoxin/kg body weight of the subject.
In other embodiments, the composition may be administered in a dose
comprising from 0.1 to 1000 μg lipoteichoic acid, more preferably from 1 to 500 μg
lipoteichoic acid, more preferably from 100 to 250 μg lipoteichoic acid, and even
more preferably about 100, about 120 or about 250 μg lipoteichoic acid.
Subjects
Compositions described herein may be used in prevention of metabolic
disorders in a wide range of subjects including mammals and birds, including, without
limitation: humans; livestock such as cattle, horses, goats, sheep, and pigs;
companion animals such as dogs and cats; and domesticated fowl such as chickens,
ducks and geese.
In one embodiment, the subject is a ruminant mammal, such as, without
limitation, a cow, goat, sheep, llama, bison or deer. In an embodiment, the subject is
a pregnant or has recently given birth, such as a ruminant mammal within about
4 weeks before or after parturition.
Disorders
The compositions described herein are useful for treating or preventing
metabolic disorders and bacterial infections. As used herein, “treating or preventing”
is intended to encompass curing as well as ameliorating at least one symptom of the
metabolic disorder or bacterial infection, as well as obtaining beneficial or desired
results including and preferably clinical results, delaying the development or
progression of or decreasing symptoms of a metabolic disorder or bacterial infection,
increasing the quality of life of those suffering from the metabolic disorder or bacterial
infection, decreasing the dose of other medications required to treat the metabolic
disorder or bacterial infection, prolonging survival of a subject suffering from the
metabolic disorder or bacterial infection, causing the clinical symptoms of the
metabolic disorder or bacterial infection not to develop by administration of a
protective composition prior to the induction of clinical symptoms, and/or preventing
recurrence of the metabolic disorder or bacterial infection.
A metabolic disorder may be caused by or associated with parturition in
the subject and/or the feeding of a diet containing an elevated proportion of grain-
based feed or easily digestible carbohydrates. The metabolic disorder may be
associated with or caused by increased permeability of the colon or rumen,
particularly increased permeability that permits bacterial endotoxins or lipoteichoic
acids to escape the rumen or colon and infiltrate the bloodstream. Metabolic
disorders that may be treated or prevented in animals, particularly ruminant mammals
include without limitation ruminal acidosis, laminitis, ketosis, fatty liver, left displaced
abomasum, milk fever, downer cow, retained placenta, metritis, mastitis, udder
edema or bloat. Metabolic disorders that may be treated or prevented in humans
include, without limitation abdominal obesity, impaired glucose regulation, raised
triglycerides, decreased high-density lipoprotein cholesterol, elevated blood pressure,
hyperinsulinemia with underlying insulin resistance, atherosclerosis, cardiovascular
disease or rheumatic inflammatory disease.
Bacterial infections that may be treated or prevented include, without
limitation, bacterial infections caused by endotoxin-producing Gram-negative
bacteria, including, without limitation Escherichia coli, Salmonella, Shigella,
Pseudomonas, Neisseria, or Haemophilus or by lipoteichoic acid-producing Gram-
positive bacteria, inlcuding, without limitation Bacillus subtilis, Staphylococcus,
Streptococcus, or Enterococcus.
Improving Milk Energy Efficiency
The compositions described herein are also useful for improving milk
energy efficiency in a subject. In one embodiment, improvement of milk energy
efficiency comprises increased fat to protein ratio. In other embodiments,
improvement of milk energy efficiency comprises increased milk fat efficiency. As
used herein, “milk energy efficiency” (MEE) is intended to encompass the amount of
milk fat in grams per kilogram of dry matter intake, and may be calculated with the
following formula:
MEE (Mcal/kg milk) = 0.0929 * % fat + 0.0547 * % Crude
Protein + 0.0359 * % lactose.
The invention is further illustrated by the following non-limiting
examples.
EXAMPLE 1
In an experiment conducted at Dairy Research and Technology Centre
(DRTC; University of Alberta), thirty primiparous and multiparous Holstein dairy cows
were selected for this experiment from the Dairy Research and Technology Centre
(DRTC), University of Alberta.
Materials And Methods
Half of the cows were treated orally with lipopolysaccharide (LPS) from
Escherichia coli 0111:B4 and lipoteichoic acid (LTA) from Bacillus subtilis to prevent
development of periparturient diseases related to LPS and LTA. At approximately
28 d before the expected day of calving thirty pregnant primiparous and multiiparous
cows were equally assigned into two groups (n = 15 per each group) including
subgroups of n = 10 cows and n = 5 heifers for post vaccination sampling. Based on
their parity, body condition score, and milk production from previous year cows were
assigned to one of the two groups.
Cows n = 15 per each group) were orally administered either 2 mL of
saline solution (Control group), or 2 mL of saline solution containing LPS from E. coli
strain 0111:B4 at three increasing concentrations as follows: 1) 0.01 µg/kg BW on
d -28 and -24, 2) 0.05 µg/kg BW on d -21 and -18, and 0.1 µg/kg BW on d -14 along
with a flat dose of LTA from Bacillus subtilis (i.e. 120 µg/animal) twice per week for
3 consecutive weeks starting from 4 wk pre-partum (Treatment group). The initial
crystalline Escherichia coli LPS (Lipopolysaccharide-FITC from E.coli strain 0111:B4
purchased from Sigma-Aldrich Canada Ltd.) containing 10 mg of purified LPS was
dissolved in 10 mL of distilled water as suggested by the manufacturer and stored a
refrigerator at +4°C. For administration to the animal the daily dose was dissolved in
2 mL of saline and then introduced into the oral cavity of the cows using 5 mL
disposable syringes. Similarly, the same amount of carrier (i.e., 2 mL saline) was
orally sprayed to all cows in the control group.
All experimental procedures were approved by the University of Alberta
Animal Care and Use Committee for Livestock, and animals were cared for in
accordance with the guidelines of the Canadian Council on Animal Care (1993).
Veterinary supervision was provided to the animals throughout the experiment.
Sampling And Analyses
Blood, saliva, vaginal mucus, and milk samples were collected twice per
week on day 1 and 3 of wk -4, -3, and -2 before the expected day of calving. All
samples were collected before the administration of vaccine. Blood samples from
both the daily and post vaccination sampling were analyzed for the following
metabolites: beta-hydroxybutiric acid (BHBA; Wako Chemicals, Inc., Richmond, VA,
USA), cholesterol (Diagnostics Chemicals Ltd., Charlottetown, PE, Canada), cortisol
(Diagnostic Chemicals Ltd., Charlottetown, PE, Canada), glucose (Diagnostic
Chemicals Ltd., Charlottetown, PE, Canada), non-esterified fatty acids (NEFA; Wako
Chemicals, USA, Inc., Richmond, VA), and insulin (Mercodia Inc., Winston Salemm,
NC, USA). Additionally, acute phase proteins (APP) including haptoglobin (Hp;
Tridelta Diagnostics Ltd, Morris Plains, NJ, USA; finished) were analyzed, whereas
two more APP including C-reactive protein (ALPCO Diagnostics Ltd., Morris Plains,
NJ, USA), and lipopolysaccharide-binding protein (HBT, Canton, MA, USA) will be
analyzed in the near future. Plasma is analyzed for anti-LPS antibodies including
immunoglobulin A (IgA), IgG, and IgM (HBT Endocab test kit HK504, Canton, MA,
USA). Plasma and milk samples are tested for content of endotoxin by the
chromogenic LAL test (CapeCode Inc., MA, USA) and for LTA. Milk samples were
also analyzed for fat, protein, lactose, somatic cell counts (SCC), and milk urea
nitrogen (MUN) at CanWest, Dairy Herd Improvement laboratory (DHI), Edmonton,
Alberta, Canada.
All treated cows were observed clinically for up to 6 h after vaccination
by measuring their rectal temperature, rumen contraction rate, and respiration rate. A
dose study was conducted to determine the dose of LPS to be used for oral treatment
without causing clinical symptoms to the animals. Blood samples from dose study
were collected several hours after oral treatment with LTA. Those samples were also
analyzed for various plasma metabolites. Disease incidence, dry matter intake (DMI),
body condition score (BCS), manure score, and milk production records were
collected for all dairy cows during 4 wk before and 4 wk after parturition.
Reproduction records were followed until conception or until a cull decision was
taken.
Statistics
Data were analyzed using the MIXED procedure of SAS (SAS Institute
Inc., Cary, NC, USA Version 9.1.3) as describe by the following model:
Y = m + t + w + tw + e
ijkl i j ij ijkl
where Y is the observations for the dependent variables, m represent the
ijkl
population mean, t is the fixed effect of treatment, w is the fixed effect of week, tw is
i j ij
the interaction between treatment and week, and e is the residual error assumed to
ijkl
be normally distributed. The PDIFF option of SAS was used to compare the LSM.
Measurements on the same animal were considered as repeated measures. The
covariance structure of the repeated measurements for each variable was modeled
separately according to the lowest values of fit statistics based on the BIC (Bayesian
information criteria). The significance limit was declared at P < 0.05.
EXAMPLE 2
The main objective of this investigation was to apply repeated oral
administration of lipopolysaccharide (LPS) a cell wall component of Gram-negative
(GN) bacteria and lipoteichoic acid (LTA) a cell wall component of Gram-positive
(GP) bacteria around parturition to prevent metabolic disturbances induced by those
compounds and development of inflammatory states related to both GN and GP
bacteria as well as improve general health, and productivity of dairy cows.
Thirty pregnant Holstein dairy cows were blocked by parity and the
anticipated day of calving, and were randomly allocated to 2 groups (n = 15 cows per
group), 28 d before the expected day of parturition. Cows were orally administered 2
mL of saline solution (Control group), or 2 mL of saline solution containing
3 increasing doses of LPS (Treatment group) form Escherichia coli 0111:B4 as
follows: 1) 0.01 µg/kg BW on d -28 and -24, 2) 0.05 µg/kg BW on d -21 and -18, and
0.1 µg/kg BW on d -14 along with a LTA from Bacillus subtilis with the same dose
(i.e. 120 µg/cow) pre-partum. The dose of LTA was determined from a preliminary
dosage study (see Example 3). Blood, urine, saliva, and vaginal mucus samples
were collected 4 weeks before and 4 weeks after calving, whereas milk samples were
collected starting from calving until 4 weeks after calving for all cows in the
experiment to be analyzed for different variables.
Cows were observed daily for presence of clinical disease during the
4 weeks before and 4 weeks after calving and rectal temperatures were taken during
3 weeks before and 2 weeks after calving. Blood samples were also obtained from
the newborns during the 4 weeks after birth in order to measure the immunity
transmitted to the newborn calves from the dam. Calves were also observed for
incidence of diarrhea until 4 weeks after birth. To investigate the diurnal blood and
health responses in treated cows, blood and health records were taken at -15 min
before as well as 1, 3 and 5 h after application of the oral vaccine.
Blood Metabolites Results
A indicated in Figure 3, blood data showed lower plasma lactate in
multiparous and primiparous Holstein cows challenged with oral and nasal treatment
of LPS-LTA, as well as a tendency for higher plasma cholesterol (Figure 4), which is
an indication of better energy status in those cows. Treatment did not influence
plasma BHBA, NEFA, or glucose (see Figures 1, 2 and 5).
Milk Composition Results
Interestingly, data indicated that the oral vaccination of cows with LPS
and LTA increased their milk energy efficiency (see Figures 7 and 8), which was
associated with a trend for greater feed intake in that group (see Figure 13).
Furthermore, the analysis of milk data demonstrated a higher fat to
protein ratio (see Figures 9 and 10), as well as greater milk fat efficiency for the
treated cows (see Figures 11 and 12).
No effect of treatment was observed on other milk components as well
as on the overall milk production (see Figures 14-23). Calf data indicated a tendency
for lower calf diarrhoea score in the treatment group for both multiparous and
primiparous cows compared to controls.
Clinical Results
Results of this study demonstrated that oral administration of LPS and
LTA was associated with lower incidence of metritis, laminitis, retained placenta, and
improved uterine horn fluctuation in the treated cows (see Figures 24-38).
Furthermore, the severity of laminitis was lowered in treated multiparous cows, where
it tended to be lower in the treatment group. Moreover, treated cows tended to
require lower overall number of medications as well as have lower number of days
with more than one disease versus control cows.
EXAMPLE 3
Preliminary LTA dosage study
This study aimed at establishing metabolic and clinical responses to
increasing oral doses of LTA and the oral dose that will initiate clinical symptoms in
dairy cows. Seven late lactating Holstein dairy cows of an average BW of 800 ± 30
kg were randomly allocated to an oral administration of 2 mL saline solution
containing one of the following LTA doses 20, 40, 70, 100, 120, 150, and 200 µg to
each cow, respectively. Blood samples were collected from the tail vein at -15 min, 1,
3, and 5 h, whereas clinical responses were observed at -15 min, 1, 2, 3, 4, 5, and 6
h after the oral administration of each dose of LTA.
Blood data demonstrated that oral administration of LTA increased
concentration of glucose in the plasma with the highest doses (150 and 200 µg)
having the highest plasma glucose (P<0.01). Furthermore, plasma glucose linearly
increased with time after oral administration of LTA (P<0.01). Interestingly, cows also
showed greater concentrations of plasma cholesterol at the highest doses of 150 and
200 µg (P<0.01). Also, concentrations of non-esterified fatty acid in the plasma were
found higher at 150 and 200 µg doses (P < 0.01). No effect of any of the doses of
LTA used was observed on the concentration of beta-hydroxybutyric acid in the
plasma (P>0.05). On the other hand, clinical data indicated that oral LTA influenced
rectal temperatures and respiration rates, although the variations were within the
normal ranges (P<0.01 and P<0.01, respectively).
Interestingly, the highest doses of LTA (150 and 200 µg) lowered rumen
contractions (P<0.01), whereas all other doses did not have an effect on this variable.
Overall, oral administration of increasing doses of LTA modulated plasma patterns of
selected metabolites and clinical responses of late lactating dairy cows. It was also
determined that the clinical safe dose of oral LTA to be used in future experiments
was 120 µg dose.
All publications and patent applications cited in this specification are
herein incorporated by reference as if each individual publication or patent application
were specifically and individually indicated to be incorporated by reference. The
citation of any publication is for its disclosure prior to the filing date and should not be
construed as an admission that the present invention is not entitled to antedate such
publication by virtue of prior invention.
Unless defined otherwise, all technical and scientific terms used herein
have the same meaning as commonly understood to one of ordinary skill in the art to
which this invention belongs. As used in this specification and the appended claims,
the singular forms "a", "an", and "the" include plural reference unless the context
clearly dictates otherwise.
The term “comprising” as used in this specification and claims means
“consisting at least in part of”. When interpreting statements in this specification, and
claims which include the term “comprising”, it is to be understood that other features
that are additional to the features prefaced by this term in each statement or claim
may also be present. Related terms such as “comprise” and “comprised” are to be
interpreted in similar manner.
Although the foregoing invention has been described in some detail by
way of illustration and example for purposes of clarity of understanding, it is readily
apparent to those of ordinary skill in the art in light of the teachings of this invention
that certain changes and modifications may be made thereto without departing from
the spirit or scope of the appended claims.
In the description in this specification reference may be made to subject
matter that is not within the scope of the claims of the current application. That
subject matter should be readily identifiable by a person skilled in the art and may
assist in putting into practice the invention as defined in the claims of this application.
Claims (30)
1. A method for treating or preventing a metabolic disorder in a non- human subject, said method comprising administering to said non-human subject a bacterial endotoxin and a lipoteichoic acid, separately, simultaneously or sequentially, 5 with the proviso that when said endotoxin is a lipopolysaccharide, said metabolic disorder is not laminitis.
2. The method according to claim 1, wherein said endotoxin is a lipopolysaccharide.
3. The method according to claim 1 or 2, wherein said bacterial endotoxin 10 is derived from a gram-negative bacterium.
4. The method according to claim 3, wherein said gram-negative bacterium is Escherichia coli.
5. The method according to any one of claims 1 to 4, wherein said endotoxin is a naturally-occurring, semi-synthetic or synthetic endotoxin and wherein 15 said lipoteichoic acid is a naturally-occurring, semi-synthetic or synthetic lipoteichoic acid.
6. The method according to any one of claims 1 to 5, wherein said lipoteichoic acid is derived from a gram-positive bacterium.
7. The method according to claim 6, wherein said gram-positive bacterium 20 is Bacillus subtilis.
8. The method according to any one of claims 1 to 7, comprising administering said bacterial endotoxin and said lipoteichoic acid to the mucosal tissues.
9. The method according to claim 8, when the mucosal tissues comprise 25 the gastrointestinal tract.
10. The method according to any one of claims 1 to 9, comprising administering said bacterial endotoxin and said lipoteichoic acid parenterally, orally, or nasally.
11. The method according to claim 10, wherein said bacterial endotoxin and 5 said lipoteichoic acid are formulated as a tablet, capsule or liquid formulation.
12. Use of a bacterial endotoxin and a lipoteichoic acid in the preparation of a medicament for treating or preventing a metabolic disorder in a subject, wherein said bacterial endotoxin and said lipoteichoic acid are for administration, separately, simultaneously or sequentially, with the proviso that when said endotoxin is a 10 lipopolysaccharide, said metabolic disorder is not laminitis.
13. The use according to claim 12, wherein said metabolic disorder is associated with parturition.
14. The use according to claim 12 or 13, wherein said metabolic disorder is metritis, laminitis, retained placenta, impaired uterine horn fluctuation or mastitis.
15 15. The use according to any one of claims 12 to 14, wherein said medicament is for administration to said subject from a time no more than four weeks prior to parturition to a time no more than four weeks after parturition.
16. The use according to any one of claims 12 to 15, wherein said medicament is for administration in an endotoxin dose of from 0.001 to 1 μg 20 endotoxin/kg body weight of said subject.
17. The use according to claim 16, wherein said endotoxin dose comprises about 0.01, about 0.05 or about 0.1 μg endotoxin/kg body weight of said subject.
18. The use according to any one of claims 12 to 17, wherein said medicament is for administration in a lipoteichoic acid dose of from 0.1 to 1000 μg 25 lipoteichoic acid.
19. The use according to claim 18, wherein said lipoteichoic acid dose comprises about 100, about 120 or about 250 μg lipoteichoic acid.
20. The use according to any one of claims 12 to 19, wherein said subject is a dairy cow. 5
21. The method according to any one of claims 1 to 11, wherein said metabolic disorder is associated with parturition.
22. The method according to claim 21, wherein said metabolic disorder is metritis, laminitis, retained placenta or impaired uterine horn fluctuation.
23. The method according to any one of claims 1 to 11, comprising 10 administering said bacterial endotoxin and said lipoteichoic acid to said non-human subject from a time no more than four weeks prior to parturition to a time no more than four weeks after parturition.
24. The method according to any one of claims 1 to 11, wherein the endotoxin dose is from 0.001 to 1 µg endotoxin/kg body weight of said non-human 15 subject.
25. The method according to any one of claims 1 to 11, wherein the endotoxin dose is about 0.01, about 0.05 or about 0.1 µg endotoxin/kg body weight of said non-human subject.
26. The method according to any one of claims 1 to 11, wherein the 20 lipoteichoic acid dose is from 0.1 to 1000 µg lipoteichoic acid.
27. The method according to any one of claims 1 to 11, wherein said lipoteichoic acid dose comprises about 100, about 120 or about 250 µg lipoteichoic acid.
28. The method according to any one of claims 1 to 11, wherein said non- 25 human subject is a dairy cow.
29. A method as claimed in claim 1, substantially as herein described or exemplified and with our without reference to the accompanying drawings.
30. A use as claimed in claim 12, substantially as herein described or exemplified and with our without reference to the accompanying drawings.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161448815P | 2011-03-03 | 2011-03-03 | |
US61/448,815 | 2011-03-03 | ||
PCT/CA2012/050120 WO2012116447A1 (en) | 2011-03-03 | 2012-02-29 | Use of bacterial endotoxins and lipoteichoic acids to improve postpartal health and productivity of dairy cows and their newborns |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ615973A NZ615973A (en) | 2015-12-24 |
NZ615973B2 true NZ615973B2 (en) | 2016-03-30 |
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