NZ620579B2 - Formulations comprising saccharomyces boulardii and superoxide dismutase for controlling obesity - Google Patents
Formulations comprising saccharomyces boulardii and superoxide dismutase for controlling obesity Download PDFInfo
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- NZ620579B2 NZ620579B2 NZ620579A NZ62057912A NZ620579B2 NZ 620579 B2 NZ620579 B2 NZ 620579B2 NZ 620579 A NZ620579 A NZ 620579A NZ 62057912 A NZ62057912 A NZ 62057912A NZ 620579 B2 NZ620579 B2 NZ 620579B2
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- reduction
- superoxide dismutase
- obesity
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- saccharomyces cerevisiae
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- 108010012715 Superoxide Dismutase Proteins 0.000 title claims abstract description 47
- 208000008589 Obesity Diseases 0.000 title claims abstract description 29
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Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/06—Fungi, e.g. yeasts
- A61K36/062—Ascomycota
- A61K36/064—Saccharomycetales, e.g. baker's yeast
-
- 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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/44—Oxidoreductases (1)
- A61K38/446—Superoxide dismutase (1.15)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
Abstract
composition contains Saccharomyces cerevisiae var boulardii and the superoxide dismutase enzyme where the superoxide dismutase enzyme is in gastro protected form is disclosed. The composition is useful as a diet supplement, in the prevention or reduction of the risk of developing metabolic dysfunctions related to obesity and the reduction of weight increase, for the reduction of food intake, for the reduction of body fat accumulation, and for the improvement of the systemic inflammatory condition connected with obesity. ctions related to obesity and the reduction of weight increase, for the reduction of food intake, for the reduction of body fat accumulation, and for the improvement of the systemic inflammatory condition connected with obesity.
Description
FORMULATIONS COMPRISING SACCHAROMYCES BOULARDII
AND SUPEROXIDE DISMUTASE FOR CONTROLLING OBESITY
The present invention relates to formulations useful as diet supplements
containing the probiotic yeast Saccharomyces boulardii and the antioxidant
enzyme superoxide dismutase. The formulations according to the invention are
useful to reduce the risk of developing the metabolic syndrome correlated with
obesity.
State of the art
Obesity is defined as a condition of excess body fat, and is associated
with a large number of dysfunctions, including cardiovascular disease (CVD)
and non-insulin-dependent diabetes mellitus (NIDDM).
The prevalence of obesity and excess weight in adults, children and
adolescents has grown rapidly in the last 30 years and continues to increase,
leading to high social costs.
Obesity is generally viewed as the result of a combination of an
excessive energy intake and a sedentary lifestyle, but although these factors
are naturally important, it has recently been suggested that sub-optimal
intestinal flora also has an influence (Tennyson CA, Friedman G. Curr Opin
Endocrinol Diabetes Obes. 2008 Oct;15(5):422-7), while systemic metabolic
complications are associated with the low-grade systemic inflammation that
arises in obese individuals (Fantuzzi G., J Allergy Clin. Immunol.
2005;115:911-919, Bàckhed F, Ding H, Wang T, PNAS 2004;101:15718-
15723).
Moreover, it has been demonstrated that some species of bacteria, such
as the lactic acid producing bacteria in the species L. gasseri, L. casei and
L. acidophilus, are able to reduce the weight increase in rats fed on a
carbohydrate-rich diet (Kang JH, Yun SI, Park HO, J Microbiol. 2010
Oct;48(5):712-4. Epub 2010 Nov 3).
In support of these studies, products containing probiotic bacteria
belonging to the genera Lactobacillus and Bifidobacterium have been
described which are able to prevent or cure metabolic dysfunctions deriving
from obesity (WO 2010146568; WO 2010091992; US 2008267933).
To date, in addition to the well described properties of probiotic
bacteria, many articles in the scientific literature have described some
beneficial effects on the health of a probiotic yeast, such as the inactivation of
Clostridium difficile toxin A by the yeast Saccharomyces boulardii
(Castagliuolo I, Riegler MF, Valenick L, LaMont JT, Pothoulakis C.-Infect
Immun. 1999 Jan;67(1):302-7) and the efficacy of Saccharomyces boulardii in
preventing diarrhoea caused by antibiotic treatments or by infections due to
intestinal pathogens (Surawicz CM, Elmer GW, Speelman P, McFarland LV,
Chinn J, van Belle G.-Gastroenterology. 1989 Apr;96(4):981-8; McFarland
LV- World J Gastroenterol. 2010 May 14;16(18):2202-22).
The enzyme superoxide dismutase (SOD), when administered
parenterally, has proved effective in a number of inflammatory disorders
(Carroll IM, et al. Am J Physiol Gastrointest Liver Physiol. 2007
Oct;293(4):G729-38; Oku T, et al. Inflamm Bowel Dis. 2006 Jul;12(7):630-
40) reducing free radical formation and tissue damage.
Despite the number and detail of these studies, a composition based on
probiotic yeasts which is able to prevent or counteract obesity and the
correlated disorders has never been studied or proposed.
Description of the invention
The present disclosure relates to a composition containing a probiotic
yeast and an antioxidant, which is useful to reduce the risk of developing
obesity and the metabolic syndrome correlated with it.
Specifically, in a first aspect, the invention provides a composition
containing Saccharomyces cerevisiae var boulardii and the superoxide
dismutase enzyme, wherein the superoxide dismutase is in gastroprotected
form.
In a second aspect, the invention provides a use of Saccharomyces
cerevisiae var boulardii and the superoxide dismutase enzyme in the
manufacture of a medicament, wherein the superoxide dismutase is in a
gastroprotected form.
In a third aspect, the invention provides a use of Saccharomyces
cerevisiae var boulardii and the superoxide dismutase enzyme in the
manufacture of a medicament for preventing or reducing the risk of
developing metabolic dysfunction related to obesity in a patient in need
thereof, wherein the superoxide dismutase is in a gastroprotected form.
In a fourth aspect, the invention provides a use of Saccharomyces
cerevisiae var boulardii and the superoxide dismutase enzyme in the
manufacture of a medicament for the reduction of weight increase, for the
reduction of food intake, for the reduction of body fat accumulation, and for
the improvement of the systemic inflammatory condition connected with
obesity, wherein the superoxide dismutase is in a gastroprotected form.
The probiotic yeast present in the composition, which is able to reduce
the risk of developing the metabolic syndrome correlated with obesity,
belongs to the genus Saccharomyces, and more preferably to the species
Saccharomyces cerevisiae var. boulardii (hereinafter called Sb).
The antioxidant substance used in combination with the probiotic yeast
Sb belongs to the class of antioxidant enzymes, and is more preferably the
enzyme superoxide dismutase (hereinafter called SOD).
SOD is preferably prepared in gastroprotected form by means of
conventional techniques and excipients. The effective dose of probiotic yeast
is between 10 and 10 colony-forming units (CFU) per daily administration,
preferably approx. 10 CFU, while the effective dose of SOD is between 1 and
100 mg, preferably between 2 and 50 mg, and more preferably between 5 and
mg a day. A dose of approx. 10 mg a day is particularly preferred.
The yeast and the SOD could also be administered simultaneously,
separately or sequentially: in such case, the two active ingredients need not be
associated in a single dose unit, and could optionally be used in a product in
kit form comprising separate dosage forms for the two active ingredients.
The efficacy of the diet supplement described herein has been evaluated
by monitoring physical properties such as weight, abdominal fat accumulation
and food intake, and measuring some biochemical parameters such as blood
glucose and the pro-inflammatory cytokine level.
The efficacy of the composition described herein as a diet supplement
was tested on a non-genetic murine obesity model obtained in male mice of
the C57BL/6 line, which had received from the age of 4 weeks a normal or
high-calorie diet supplemented daily with Sb and SOD or with the carrier
alone.
During the 9-week administration of the diet supplement, the body
weight and food intake were evaluated every week.
At the end of the administration period, the animals underwent the
glucose tolerance test after fasting overnight; other animals were sacrificed to
collect the peripheral blood needed to quantify the circulating cytokines and
measure the accumulated abdominal fat.
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.
The invention is described in greater detail in the examples below.
Example 1: Body weight, food intake and regulation of body fat.
In order to evaluate the efficacy of the diet supplement consisting of the
composition of Sb and SOD in regulating the physical properties influenced by
obesity, male C57BL/6 mice (15.2 + 0.3 g) aged 4 weeks were divided into
randomised groups to which a normal calorie diet (77% carbohydrate, 19%
protein and 4% fat) or a high-calorie diet (VHF, 21% carbohydrate, 19% protein
and 60% fat) was administered in the presence or absence of a daily supplement
consisting of 10 CFU of Sb (administered by gastric probe) and/or 10 mg of
SOD extracted from yeast, purified and made gastro-resistant by
microencapsulation up to a specific activity of 180000 U/g, and incorporated in
the food. However, other methods of gastroprotection, such as the gliadin film
medium or other equivalent techniques, would produce the same effect and can
therefore be considered equivalent for the purposes of the present invention.
Diet and food supplements were administered continuously for a total of
9 weeks.
The food intake of the animals (Table) and their body weight were
monitored weekly, while the accumulation of visceral fat was quantified after
9 weeks’ diet supplementation.
At the end of the experimental period the animals were sacrificed and
the abdominal fat was carefully collected, weighed and then fixed in formalin
for the subsequent histological tests (Figure 2a).
Diet supplementation with Sb + SOD, but not with Sb alone,
significantly reduces the weight increase associated with a high-calorie diet
(Figure 1). Moreover, the accumulation of adipose tissue at abdominal level
was significantly reduced in the animals that received Sb alone and in those
that received Sb in combination with SOD (Figures 2 and 2a).
Table
Food intake per Calorie intake per
Diet Supplement
mouse per day (g) mouse per day (kcal)
Normal
no 3,20 10,89
calorie diet
High-calorie
no 4,76 28,71
diet
High-calorie
Sb 2,00 12,08
diet
High-calorie
Sb + SOD 2,00 12,05
diet
Example 2: Regulation of biochemical parameters in obesity.
In order to evaluate the efficacy of the diet supplement consisting of the
composition of Sb and SOD in the metabolic complications associated with
obesity after 9 weeks of the experiment described in example 1, the mice were
subjected to an oral glucose loading test and a study of the cascade of signals
induced by insulin in a target organ (liver).
To perform the oral glucose tolerance test, the blood glucose was
determined after 18 hours’ fasting and before administration of an oral glucose
load (2 mg/g of body weight).
The blood glucose was then measured every 30 minutes for 120
minutes, and glucose tolerance was calculated as the area under the curve
(AUC) (Figure 3a and Figure 3b).
To evaluate the functional state of the cascade of signals induced by
insulin, an insulin load was administered intraperitoneally to the mice
(10 U/Kg of weight). In this case the animals were sacrificed 5 minutes later,
and liver samples were collected and frozen.
The total proteins were extracted from the liver samples and subjected
to the immunoblot test to evaluate the phosphorylation level of the IRS1
(Insulin Receptor Substrate 1) protein (Figure 4).
Under normal conditions, the bond between insulin and its receptor
causes phosphorylation of the IRS1 protein on the Tyr941 residue, whereas in
the case of the metabolic syndrome associated with obesity, this signal is
reduced.
Supplementation with Sb or Sb + SOD using the same preparations and
the same doses as in Example 1 reduced the extent of the post-glucose-load
hyperglycaemia associated with obesity (Figures 3a and 3b).
Co-administration of Sb and SOD caused a more marked reduction in
post-load hyperglycaemia. Diet supplementation in obese mice with Sb and
SOD restores the phosphorylation of IRS1 on the Tyr941 residue in response
to a blood glucose load, therefore correcting the insensitivity of the target
tissues to insulin (Figure 4).
Example 3: Systemic inflammation caused by obesity.
To evaluate the efficacy of the diet supplement consisting of the
composition of Sb and SOD on systemic inflammation, a common condition in
obese individuals, after 9 weeks’ diet supplementation a sample of circulating
blood was taken to measure the circulating levels of pro-inflammatory
cytokine (TNFα) and an adipokine (leptin). The assay was conducted on
serum using the ELISA assay (Figure 5 and Figure 6).
In the case of obese animals an increase in the circulating levels of
TNFα and leptin was observed, which contribute to the development of
systemic complications. Diet supplementation with Sb or Sb + SOD using the
same preparations and the same doses as in Example 1 significantly reduces
the circulating levels of TNFα and leptin (Figure 5 and Figure 6). In
particular, serum level of leptin, a pro-inflammatory adipokine derived from
adipose tissue with a role in food taking regulation, is reduced by the
supplementation with Sb + SOD at a significantly higher rate even if
compared to Sb and SOD single supplementations (Figure 6).
Example 4: Inflammatory state of the intestinal mucosa in obesity.
In order to evaluate the efficacy of the diet supplement consisting of the
composition of Sb and SOD on the inflammatory condition of the mucosa
associated with obesity after 9 weeks’ diet supplementation, the animals were
sacrificed so that a segment of ileum could be collected. The intestinal
segments were homogenised in phosphate buffer to which a cocktail of
protease inhibitors was added for the extraction of the total proteins. The
homogenate was centrifuged at 13000x rpm for 10 min at 4°C, and the
clarified supernatant was used to quantify the pro-inflammatory cytokines
IL1-β and TNF-α by ELISA assay and to quantify glutathione (GSH), the
most effective anti-oxidant natural compound. The cytokine levels were
normalised to the total protein levels determined by the Bradford assay.
In the case of obese individuals, an increase in the levels of IL1-β and
TNFα, which contribute to the development of systemic complications, is
observed in the intestinal mucosa. Diet supplementation with Sb or
co-administration of Sb and SOD using the same preparations and the same
doses as in Example 1 induces a significant reduction in both cytokines
(Figs. 7 and 8). Figures 7 and 8 clearly show that only co-administration of Sb
and SOD restores IL1-β and TNFα in the intestinal mucosa to comparable
values with the control mice.
Glutathione (GSH), which has a powerful anti-oxidant activity and that
can be related to an anti-inflammatory role at the mucosal level, shows a
significant decrease in the ileum of the obese animals. Its level is surprisingly
increased in case of a supplementation with Sb + SOD while single
supplementations with either Sb or SOD alone are not effective (Figure 9).
Claims (10)
1. A composition containing Saccharomyces cerevisiae var boulardii and the superoxide dismutase enzyme, wherein the superoxide dismutase is in 5 gastroprotected form.
2. A composition as claimed in claim 1 in kit form, suitable for the simultaneous, separate or sequential administration.
3. The composition of claim 1 or 2 for use as a diet supplement.
4. The composition of claim 1 for use in the prevention or reduction of the 10 risk of developing metabolic dysfunctions related to obesity.
5. The composition of claim 1 for use in the reduction of weight increase, for the reduction of food intake, for the reduction of body fat accumulation, and for the improvement of the systemic inflammatory condition connected with obesity. 15
6. A use of Saccharomyces cerevisiae var boulardii and the superoxide dismutase enzyme in the manufacture of a medicament, wherein the superoxide dismutase is in a gastroprotected form.
7. A use of Saccharomyces cerevisiae var boulardii and the superoxide dismutase enzyme in the manufacture of a medicament for preventing or 20 reducing the risk of developing metabolic dysfunction related to obesity in a patient in need thereof, wherein the superoxide dismutase is in a gastroprotected form.
8. A use of Saccharomyces cerevisiae var boulardii and the superoxide dismutase enzyme in the manufacture of a medicament for the reduction of 25 weight increase, for the reduction of food intake, for the reduction of body fat accumulation, and for the improvement of the systemic inflammatory condition connected with obesity, wherein the superoxide dismutase is in a gastroprotected form.
9. A composition as claimed in claim 1, substantially as herein described or exemplified and with or without reference to the accompanying figures.
10. A use as claimed in any one of claims 6 to 8, substantially as herein 5 described or exemplified and with or without reference to the accompanying figures.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT001488A ITMI20111488A1 (en) | 2011-08-03 | 2011-08-03 | FORMULATIONS INCLUDING SACCHAROMYCES BOULARDII AND SUPEROXIDE DISMUTASIS (SOD) TO CONTROL OBESITY |
PCT/EP2012/065119 WO2013017650A2 (en) | 2011-08-03 | 2012-08-02 | Formulations containing saccharomyces boulardii and superoxide dismutase (sod) to control obesity |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ620579A NZ620579A (en) | 2015-11-27 |
NZ620579B2 true NZ620579B2 (en) | 2016-03-01 |
Family
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