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WO2018206573A1 - Composition comprenant des stilbènes appropriée pour améliorer la productivité en aquaculture - Google Patents

Composition comprenant des stilbènes appropriée pour améliorer la productivité en aquaculture Download PDF

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Publication number
WO2018206573A1
WO2018206573A1 PCT/EP2018/061864 EP2018061864W WO2018206573A1 WO 2018206573 A1 WO2018206573 A1 WO 2018206573A1 EP 2018061864 W EP2018061864 W EP 2018061864W WO 2018206573 A1 WO2018206573 A1 WO 2018206573A1
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Prior art keywords
resveratrol
fish
stilbene
composition
feed
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PCT/EP2018/061864
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English (en)
Inventor
Ernesto SIMON
A.S. Satish KUMAR
P.M. Murali
Shiriam RAGAVAN
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Evolva Holding SA
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Evolva AG
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Publication of WO2018206573A1 publication Critical patent/WO2018206573A1/fr
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/111—Aromatic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K10/00—Animal feeding-stuffs
    • A23K10/30—Animal feeding-stuffs from material of plant origin, e.g. roots, seeds or hay; from material of fungal origin, e.g. mushrooms
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/80—Feeding-stuffs specially adapted for particular animals for aquatic animals, e.g. fish, crustaceans or molluscs

Definitions

  • the present invention relates to compositions, methods and uses thereof to improve yield and quality of farmed or bred fish and decapod crustaceans.
  • Resveratrol and its derivatives are phytoalexin stilbenes found in very low concentrations in grapes, peanuts, cranberries, blueberries, strawberries, Polygonum cuspidatum and some other botanical sources.
  • Resveratrol is an antioxidant and has natural antibacterial properties, which can be used in both food preservation and medicinal use (Paulo et al. 2010), and may also be a potent antiviral molecule against DNA and RNA viruses (Campagna & Rivas 2010).
  • resveratrol is an antioxidant and has natural antibacterial properties, which can be used in both food preservation and medicinal use (Paulo et al. 2010), and may also be a potent antiviral molecule against DNA and RNA viruses (Campagna & Rivas 2010).
  • resveratrol Although there is much interest in the use of resveratrol in addressing a variety of issues, difficulties associated with producing the compound restrict its use in husbandry, the human environment and food-related industries. In the current market, the most common resveratrol production processes relies on extracting resveratrol from Japanese knotweed, a plant from the polygonaceae family grown commercially in China.
  • Table 1 shows the results of analysis using gas chromatography coupled to mass spectrometry performed on 40 g samples of commercially available resveratrol derived from knotweed plants grown in China (samples 1 , 2 and 3) when compared with fermentation derived resveratrol (samples 4 and 5).
  • Table 1 Polycyclic aromatic hydrocarbon content in resveratrol samples derived from knotweed grown in China (samples 1 , 2 and 3) and in resveratrol derived from recombinant microbial fermentation (samples 4 and 5).
  • PAHs Polycyclic aromatic hydrocarbons
  • Polynuclear aromatic hydrocarbons are chemicals released from incomplete combustion of organic matter, typically by the burning of fossil fuels in smelting, manufacturing, power stations, vehicles and home fires, as well as burning the by-products of agriculture such as crop residues and dung.
  • PAHs generally have low solubility in water, and are predominantly seen in solid form as particulate air pollution, soil or sediment pollution.
  • cancer is the primary health risk of exposure to PAHs, they have also been linked to cardiovascular disease and poor fetal development.
  • resveratrol extracts comprising environmental pollutants such as has been observed in knotweed-derived resveratrol may raise concerns from the ultimate human consumers of the resulting aquaculture products (such as fish, shellfish and products derived therefrom such as flesh or eggs).
  • a stilbene or a methylated or glycosylated derivative thereof (such as resveratrol or pinosylvin) is applied to feed or feed additive compositions suitable for administration to fish or decapod crustaceans.
  • the composition suitable for feeding a fish or decapod crustacean comprises 50 to 500ppm of a stilbene.
  • the composition further comprises at least one additional ingredient selected from natural or regenerated mineral material (such as calcium), solvent, surfactant, vegetable oil (such as a rapeseed oil), dispersant, carrier, vegetable mass (such as algae, soybeans, seaweed, barley, rice, peas, canola, lupine, wheat gluten, soy, corn or corn gluten), protein sources (such as insects, fish meal, fish trimmings from the fish industry, or small feeder fish stocks bred or harvested from the environment for incorporation in feed), lipids (such as fish oil), wetting agent, adhesive, thickener, binders, attractant, pigments (such as the carotenoids astaxanthin or canthaxanthin), vitamins, antioxidants, essential oil (thymol) or enzyme (such as phytase).
  • natural or regenerated mineral material such as calcium
  • solvent such as calcium
  • surfactant such as a rapeseed oil
  • dispersant such as a rapeseed oil
  • carrier such as algae
  • a method of enhancing weight gain and/or length in fish or decapod crustacean by feeding the fish or decapod crustaceans a feed composition comprising 50 to 500ppm of a stilbene applied once per day, once every two days, once per week, twice per week, once per two weeks, once per month, or once per two months, once per three months, or once per lifecycle of the cultured fish or decapod crustacean.
  • a method of enhancing weight gain and/or length in fish or decapod crustacean by feeding the fish or decapod crustaceans a feed composition comprising 100 to 300ppm of a stilbene applied once per day, once every two days, once per week, twice per week, once per two weeks, once per month, or once per two months, once per three months, or once per lifecycle of the cultured fish or decapod crustacean.
  • a stilbene in aquaculture to increase the productivity of fish or decapod crustacean, wherein productivity is measured as at least one of increased survival index, weight gain, gain in length, mass of harvestable flesh or mass of eggs compared to fish or decapod crustaceans from the same initial stock not fed compositions comprising stilbene.
  • the stilbene may be resveratrol, pinosylvin, or a methylated or glycosylated derivative thereof.
  • the fish is a carp, tilapia or salmonid
  • decapod crustacean is a crayfish, lobster, crab, shrimp or prawn.
  • Figure 1 provides the chemical structure of the stilbene trans-resveratrol.
  • Figure 2 provides a comparison of fish growth with and without the stilbene resveratrol.
  • Figure 3 provides photographs of vibrio biofilm formation following incubations with and without the stilbene resveratrol.
  • Figure 4 provides a comparison of fingerling gain in length with and without the stilbene resveratrol over an 82 day period.
  • Figure 5 provides a comparison of fingerling gain in weight with and without the stilbene resveratrol over an 82 day period.
  • Figure 6 provides a comparison of fingerling survival rates with and without the stilbene resveratrol over an 82 day period.
  • Figure 1 1 a Effect of resveratrol on biofilm of V. parahaemolyticus
  • Figure 1 1 e Effect of resveratrol on biofilm of V. vulnificus
  • Figure 12a Light microscopic analysis of V. parahaemolyticus biofilm grown in the absence and presence of resveratrol.
  • x, y, and/or z can refer to “x” alone, “y” alone, “z” alone, “x, y, and z,” “(x and y) or z,” “x or (y and z),” or “x or y or z.”
  • x, y, and/or z can refer to “x” alone, “y” alone, “z” alone, “x, y, and z,” “(x and y) or z,” “x or (y and z),” or “x or y or z.”
  • preferably “commonly,” and “typically” are not utilized herein to limit the scope of the claimed invention or to imply that certain features are critical, essential, or even important to the structure or function of the claimed invention. Rather, these terms are merely intended to highlight alternative or additional features that can or cannot be utilized in a particular embodiment of the present invention.
  • the term "isolating” or “separating” means any human intervention which change the relative amount of the compound compared to another selected constituent in a given matrix to a higher relative amount of the compound relative to the other constituent.
  • the compound may be isolated into a pure or substantially pure form.
  • a substantially pure compound means that the compound preparation contains less than 10%, such as less than 8%, such as less than 6%, such as less than 5%, such as less than 4%, such as less than 3%, such as less than 2%, such as less than 1 %, such as less than 0.5% by weight of other selected constituents.
  • an isolated compound is at least 50% pure, such as at least 60% pure, such as at least 80% pure, such as at least 90% pure, such as at least 91 % pure, such as at least 92% pure, such as at least 93% pure, such as at least 94% pure, such as at least 95% pure, such as at least 96% pure, such as at least 97% pure, such as at least 98% pure, such as at least 99% pure, such as at least 99.5% pure, such as 100 % pure by dry weight.
  • Synthetic or “non-naturally occurring” means that a compound is not normally found in nature or natural biological systems.
  • the term “found in nature or in natural biological systems” does not include the finding of a compound in nature resulting from releasing the compound to nature by deliberate or accidental human intervention.
  • Synthetic compounds may include compounds completely or partially synthetized by human intervention and/or compounds prepared by human modification of a natural compound.
  • aquaculture relates to the process of rearing a fish or decapod crustacean for at least part of the growth cycle in a semi-controlled environment (aquaculture facility) such that the rate of feeding and any medication may be controlled, and the fish or decapod crustacean is not able to escape into the surrounding environment.
  • The may be reared for fish or decapod crustacean meat for consumption as food or feed, for oil (such as omega 3 or omega 6 oil), eggs (such as caviar), sport, ornamental use, functional use (such as a biological control agent or a cleaner fish) or for breeding programs either for commercial sale or introduction into the wild.
  • Non-limiting examples of an aquaculture facility suitable for such growth of a fish or decapod crustacean may include a fish farm, crustacean farm, hatchery, breeding center, pond, lake, well, tank, enclosure (such as nets or a cage in a river or the sea), freshwater or saltwater aquarium.
  • fish refers to any fish farmed or cultured for at least part of the growth cycle.
  • the fish may be a freshwater or saltwater fish.
  • the fish may be a carp, catfish, eel, goldfish, tilapia or trout or salmon.
  • the fish is selected from carp, tilapia or salmonid.
  • the term "decapod crustacean” refers to crustaceans with 10 legs.
  • the decapod crustacean may be a penaeid.
  • the decapod crustacean be a crayfish, lobster, crab (such as the Chinese river crab), shrimp (such as the Pacific White shrimp) or prawn (such as the giant tiger prawn or the giant river prawn).
  • fish length and “decapod crustacean length” refer to the total length from front to rear. Figures provided herein are average values of fish length or decapod crustacean length for the whole batch being reared.
  • fish weight and “decapod crustacean length” refers to total mass of the fish or decapod. Figures provided herein are average values of fish weight or decapod crustacean weight for the whole batch being reared.
  • the term "survival index” refers to the proportion, frequently expressed as a percentage, of fish or decapod crustaceans in a batch surviving a specified growth phase; for example, the survival index for fry to fingerling, or the survival index from fingerling to maturity.
  • improved health refers to a general vitality, vigor and absence of disease relative to an equivalent batch of fish or decapod crustaceans from the same stock but not receiving feed supplemented with resveratrol.
  • Typical indications of improved health may include one or more of higher rates of activity, greater appetite for feed, a lack of blemishes or infections in the eyes, scales, shells, legs or fins.
  • Less empirical, but equally valuable perceived indicators of the health of ornamental or farmed fish and crustacean decapods is a more reflective or shinny appearance of scales or shells.
  • improved health may also be recognized as a lower incidence of the fish or decapod crustaceans exhibiting moribund characteristics, overt signs of illness, or apathy to external stimuli.
  • active ingredient refers to a chemical compound or mixture of chemical compounds capable of enhancing growth, reducing mortality, improving health, or improving the taste, colour or valuable oil content of fish or decapod crustaceans or products derived therefrom.
  • the stilbene or a methylated or glycosylated derivative thereof may be resveratrol (trans-resveratrol) or pinosylvin.
  • Resveratrol may be provided at suitable concentrations as purified extracts of Japanese knotweed, yucca, grapes, etc.
  • the resveratrol for inclusion in the feed, feed additives or water may be produced by recombinant microbial fermentation, including but not limited to fermentation extract, purified resveratrol, or dried fermentation cake from recombinant microbes capable of producing resveratrol.
  • Resveratrol derived from fermentation of recombinant microbes is preferred not least because it is inherently free of emodin and hazardous levels of Polycyclic Aromatic Hydrocarbons (PAHs).
  • PAHs Polycyclic Aromatic Hydrocarbons
  • stilbene and “stilbenoid” are interchangeable and refer to compounds based on the compound of formula (I):
  • substituents include, but are not limited to, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, C1-C6 alkoxy, thiol, C1-C6 alkylthio, amino, C1-C6 alkyl amino, di- C1-C6 alkyl amino, carboxyl, C1-C6 alkoxycarbonyl, amido, methyl, and glycosyl.
  • stilbenes, including resveratrol, and flavonoids are produced in plants and yeast through the phenylpropanoid pathway as illustrated by the reactions shown in Figure 1 .
  • phenylpropanoid refers to compounds based on a 3- phenylprop-2-enoate backbone. Examples of such compounds include, but are not limited to, cinnamic acid, coumaric acid, caffeic acid, ferulic acid, 5-hydroxyferulic acid, sinapinic acid, cinnamoyl-CoA, p-coumaroyl-CoA, and the like.
  • phenylpropanoid derivative refers to any compound derived from, synthesized from, or biosynthesized from a phenylpropanoid; i.e. a phenylpropanoid derivative includes any compound for which a phenylpropanoid compound is a precursor or intermediate.
  • phenylpropanoid derivatives include, but are not limited to, stilbenoid compounds and chalcone compounds.
  • Specific examples of phenylpropanoid derivatives include, but are not limited to, resveratrol, pinosylvin, pinocembrin chalcone, and pinocembrin.
  • dihydrophenylpropanoid refers to compounds based on a phenylpropanoate backbone. Examples of such compounds include, but are not limited to, dihydrocinnamic acid, phloretic acid, 3,4-dihydroxyhydrocinnamic acid, hydroferulic acid, dihydrocoumaroyl-CoA, dihydrocinnamoyl-CoA, and the like.
  • dihydrophenylpropanoid derivative refers to any compound derived from, synthesized from, or biosynthesized from a dihydrophenylpropanoid; i.e. a dihydrophenylpropanoid derivative includes any compound for which a dihydrophenylpropanoid compound is a precursor or intermediate. Examples of dihydrophenylpropanoid derivatives include, but are not limited to, dihydrostilbenoid compounds and dihydrochalcone compounds.
  • dihydrophenylpropanoid derivatives include, but are not limited to, phloretin, phlorizin, dihydropinosylvin, dihydropinosylvincarboxylate, 3-O-methyldihydropinosylvincarboxylate, 4-isoprenyl-3-0- methyldihydropinosylvincarboxylate (amorfrutin 1 ), 3-O-methyldihydropinosylvin, 4-isoprenyl-3- O-methyldihydropinosylvin (amorfrutin 2), 5-hydroxy-lunularic acid, and dihydroresveratrol.
  • phenylpropanoid pathway As used herein, the terms “phenylpropanoid pathway,” “phenylpropanoid derivative pathway,” “phenylpropanoid derivative synthesis pathway,” and “phenylpropanoid derivative biosynthesis pathway” are interchangeable and refer to any biosynthesis pathway in which a phenylpropanoid is a precursor or intermediate.
  • stilbene or a derivative thereof can be hydroxylated derivatives of stilbene and are thus encompassed by the term “stilbene” as used herein.
  • the term “stilbene” includes but is not limited to at least one of resveratrol, dihydroresveratrol, and pinosilvin; a glycosylated stilbene comprising piceid (3-resveratrol monoglucoside or 5-resverarol monoglucoside), resveratroloside (4'-resveratrol monoglucoside), Mulberroside E (3,4'-resveratrol diglucoside), 3,5- resveratrol diglucoside, and 3,5,4'-resveratrol triglucoside and their dihydro- reduced equivalents; a methylated stilbene comprising pterostilbene (3,5-dimethoxy-4'-hydroxy-trans- stilbene), 3,5,4'-trimethoxystilbene, pinostilbene, tetramethoxy
  • resveratrol refers to a compound seen in Figure 1 that may be synthesized, isolated, and purified from of a mixture of products produced in a host modified to express enzymes of the resveratrol biosynthetic pathway or that can be produced from natually occurring sources, such as grapes.
  • Resveratrol further refers to derivatives and analogs analogs thereof, including but not limited to forms of methylated and/or glucosylated resveratrol.
  • the resveratrol compound contemplated for use herein may be produced in vivo through expression of one or more enzymes involved in the resveratrol biosynthetic pathway in a recombinant yeast or in vitro using isolated, purified enzymes involved in the resveratrol biosynthetic pathway, such as those described in WO2006/089898, WO2008/009728, WO2009/016108, WO2009/124879, WO2009/124967, WO201 1/147818, which are incorporated by reference in their entirety.
  • Resveratrol derived from fermentation of recombinant microbes is preferred not least because it is inherently free of emodin and hazardous levels of Polycyclic Aromatic Hydrocarbons (PAHs). Therefore, resveratrol as defined herein can differ chemically from other sources of resveratrol, such as extracts from plants and derivatives thereof, or may include such plant extracts and derivatives thereof.
  • PAHs Polycyclic Aromatic Hydrocarbons
  • modified resveratrol can be used interchangeably to refer to a compound that can be derived from resveratrol or a compound with a similar structure to resveratrol.
  • modified resveratrol can refer to resveratrol- like molecules such as to glycosylated resveratrol molecules, methylated resveratrol molecules, or resveratrol molecules that are glycosylated and methylated.
  • glycosylation comprises covalently attaching one or a plurality of sugar or saccharide residues at one or more of the 3, 4', or 5 hydroxyl groups of resveratrol.
  • the saccharide moiety in each position can be independently zero, one, two, three, or multiple sugar residues, wherein all the sugar residues can be the same sugar residues or different sugar residues.
  • the active ingredients contemplated herein are used in the form of compositions.
  • the active ingredients can be applied to or incorporated into feed, to form a comestible composition suitable for ingestion by fish and/or decapod crustaceans.
  • the active ingredients can be applied, if desired, together with other carriers conventionally used in the formulation art of feed, feed additives, surfactants or other additives which aid application.
  • Suitable carriers and additives can be solid or liquid and are the substances expediently used in the art of formulation, for example natural or regenerated mineral materials, solvents, dispersants, wetting agents, adhesives, thickeners, binders or attractants.
  • Fish feed and decapod crustacean feeds typical comprise major nutrients such as protein, fat, carbohydrate, vitamins and minerals, and optionally one or more other feed additive that facilitates feed intake, digestion and absorption of nutrient.
  • the resveratrol-containing compositions may comprise the fermentation cake of microorganisms capable of producing resveratrol and/or carotinoids.
  • the microorganism engineered to produce resveratrol and/or carotinoids may be any food or feed-approved microorganism, preferably a yeast, such as baker's or brewer's yeast (Saccharomyces cerevisiae), Kluveromyces marxianus, Candida utilis, Rhodotorula glutinis.
  • Incorporation of fermentation cake comprising resveratrol-producing microorganisms into the feed or feed additives suitable administration to fish or decapod crustaceans has the advantage of providing additional nutrients, vitamins and minerals present in the fermentation broth or produced naturally by the microbes.
  • the resveratrol-producing recombinant microorganism is saccharomyces cerevisiae free of antibiotic markers and grown in a fermentation medium not comprising antibiotics. Saccharomyces cerevisiae has been included in feed for many years, and is sometimes known as "Feed yeast".
  • feed yeast an example of a "feed microorganism”
  • Bovine Spongiform Encephalopathy crisis in consequence of the demand for "clean” and sustainable protein sources which could not support the growth or reproduction of viruses or prions able to cross animal species barriers.
  • Saccharomyces cerevisiae are now appreciated to have a high Protein Efficiency Ratio, have a high lysine content, are an excellent source of vitamin D and further comprise significant concentrations of the nutrients glutathione, inositol and choline.
  • Yeast beta- glucans and mannans also help stimulate the immune system of many species. Yeast are considered by some to be probiotics for fish aquaculture.
  • the resveratrol-producing microorganisms may also be engineered to produce enzymes desirable for incorporation into feeds, additives or supplements suitable for administration to fish and/or decapod crustaceans, such as to improve the efficiency of feed utilization or the health of the fish and/or decapod crustacean.
  • the resveratrol-producing microorganisms are present as whole cells in "direct-fed microbial" compositions such as active dry yeast, yeast culture (such as molasses yeast condensed solubles).
  • the resveratrol-producing microorganisms are present as whole cells that are heat treated, irradiated, lysed (such as by sonication or by hydrolysis), pasteurized, or in another way rendered "non-fermentive" so that the viability of recombinant microorganisms in the resulting composition is significantly reduced, preferably reduced to the extent that no viable recombinant microbes may be detected.
  • the resveratrol optionally with saponins, thymol and/or recombinantly produced enzymes suitable for inclusion in fish feed or decapod crustacean feed, additive or supplement thereof, as a "yeast extract” comprising concentrated soluble materials recovered from lysed yeast cells following fermentative growth.
  • compositions contemplated herein can contain a carrier and at least about 0.0001 %, or at least about 0.001 %, or at least about 0.01 %, or at least about 0.1 %, or at least about 1 %, or at least about 2%, or at least about 5%, or at least about 7.5%, or at least about 10%, or greater than about 10%, or greater than about 15%, or greater than about 20%, or greater than about 25%, or greater than about 50% by weight stilbene, such as resveratrol.
  • stilbene can be present in an amount that is greater than about 60%, about 70%, about 80%, about 90%, about 95% or about 99% by weight of the composition.
  • the provided compositions contain stilbene in an amount at or about 0.0001 % to at or about 2%, or about 0.001 % to at or about 5%, or about 0.01 % to at or about 75% by weight of the composition.
  • a composition may contain stilbene in an amount of from at or about 1 % to at or about 50% by weight of the composition.
  • a composition may contain stilbene in an amount of from at or about 5% to at or about 40% by weight of the composition.
  • a composition may contain stilbene in an amount of from at or about 10% to at or about 30% by weight of the composition.
  • a composition may contain stilbene in an amount of from at or about 15% to at or about 25% by weight of the composition.
  • a composition may contain stilbene in an amount of from at or about 1 % to at or about 90% by weight of the composition. In another example, a composition may contain stilbene in an amount of about 10%, or about 15%, or about 20%, or about 25%, or about 30%, or about 50% by weight of the composition. In another example, a composition may contain stilbene in an amount of up to about 99% or more by weight of the composition.
  • a contemplated stilbene-containing composition such as a resveratrol-containing composition is provided as a concentrate.
  • a stilbene- containing composition may be provided as a 20X, or a 10X, or a 5X, or a 3X concentrate that can be diluted by an end user with an appropriate solvent to achieve a 1 X working concentration.
  • a stilbene-containing composition may be provided to an end user at a 1 X working concentration.
  • any concentration is contemplated for use herein.
  • compositions provided as concentrates can be used without dilution at all or may be diluted from a highly concentrated concentrate (e.g., about 20X to about 100X) to some multiple of concentration higher than 1X, such as 2X, 2.5X, 3X, etc. or can be used at a more dilute concentration, such as 1/2X, 1/4X, 1/10X, etc. While concentrates are more preferred as commercially available goods, the industry and end consumers typically apply dilute compositions to propagated plants, propagated plant material, materials and surfaces.
  • a contemplated composition may be seen in Table 2, where ingredients can be measured in percent volume per volume, percent weight per volume, or percent by weight.
  • the resveratrol is produced by fermentation of recombinant microbes, which is more cost effective.
  • Preferred production organisms include Saccharomyces cerevisiae or other yeasts.
  • the resveratrol employed in the compositions and methods described herein may be resveratrol derivatives or other forms of resveratrol, particularly more water- soluble derivatives including but not limited to acetyl-resveratrol or pinosylvin.
  • additional active ingredients include plant essential oil compounds or derivatives thereof.
  • examples include thymol, aldehyde C16 (pure), oterpineol, amyl cinnamic aldehyde, amyl salicylate, anisic aldehyde, benzyl alcohol, benzyl acetate, cinnamaldehyde, cinnamic alcohol, carvacrol, carveol, citral, citronellal, citronellol, p-cymene, diethyl phthalate, dimethyl salicylate, dipropylene glycol, eucalyptol (cineole) eugenol, is- eugenol, galaxolide, geraniol, guaiacol, ionone, menthol, methyl salicylate, methyl anthranilate, methyl ionone, methyl salicylate, nootkatone, opheliand
  • a contemplated composition may include a stilbene, such as resveratrol, to additional active ingredient ratio of about 1 :10, or about 1 :8, or about 1 :6, or about 1 :4, or about 1 :2, or about 1 :1 , or about 2:1 , or about 4:1 , or about 6:1 , or about 8:1 , or about 10:1.
  • the additional active ingredient is thymol.
  • Carriers may be added to a composition in an amount of about 10%, or about 15%, or about 20%, or about 25%, or about 30%, or about 50% by weight of the composition.
  • a carrier can be present in an amount that is at or greater than about 60%, about 70%, about 80%, about 90%, about 95%, or about 99% by weight of the composition.
  • carriers may be included as part of stilbene (such as resveratrol) comprising composition.
  • suitable carriers include an alcohol (such as ethanol), aqueous liquid carrier, water, a saline, a gel, an inert powder, a zeolite, a cellulosic material, a microcapsule, a hydrocarbon, a polymer, a wax, a fat, an oil, and the like.
  • Some carriers include time release materials where a stilbene-containing composition may be released over a period of hours, or days, or weeks.
  • Solvents suitable for incorporation into compositions according to some aspects of the current invention include but are not limited to alcohols and glycols and also their ethers and esters, such as ethanol, ethylene glycol, or strongly polar solvents. In some aspects, alcohol solvents are preferred for resveratrol.
  • one or more additional active ingredients efficacious against aquatic bacterial pathogens may also be included in compositions comprising stilbenes (such as resveratrol).
  • one or more of the active compounds listed in Table 3 may be added at concentrations of greater than 10 ⁇ g ml).
  • feed-additives are, when manufactured in their concentrated form on the basis of two or more elements, and both as regards insoluble and soluble variants be blended and packed at facilities using equipment approved of for also blending of vitamin and mineral premixes for animals.
  • feed and feed additives include:
  • stilbene such as resveratrol
  • stilbene such as resveratrol
  • Preferred inclusion rates of the stilbene (such as resveratrol or a derivative thereof) in the final feed are at concentrations of less than 700 PPM, 50 to 500 PPM, 100 to 400 PPM, or 100 to 300 PPM.
  • the composition further comprises at least one additional ingredient selected from natural or regenerated mineral material (such as calcium), solvent, surfactant, vegetable oil (such as a rapeseed oil), dispersant, carrier, vegetable mass (such as algae, soybeans, seaweed, barley, rice, peas, canola, lupine, wheat gluten, soy, corn or corn gluten), protein sources (such as insects, fish meal, fish trimmings from the fish industry, or small feeder fish stocks bred or harvested from the environment for incorporation in feed), lipids (such as fish oil), wetting agent, adhesive, thickener, binders, attractant, pigments (such as the carotenoids astaxanthin or canthaxanthin), vitamins, antioxidants, enzyme (such as phytase).
  • natural or regenerated mineral material such as calcium
  • solvent such as surfactant, vegetable oil (such as a rapeseed oil), dispersant, carrier, vegetable mass (such as algae, soybeans, seaweed, barley, rice, peas
  • compositions comprising active ingredients may be applied once per day, once every two days, once per week, twice per week, once per two weeks, once per month, or once per two months, once per three months, or once per lifecycle of the cultured fish or decapod crustacean.
  • Compositions according to aspects of the current invention may be employed as pure active ingredients or, preferably, together with the auxiliaries conventionally used in the art of formulation and are therefore processed in a known manner to give, for example, emulsion concentrates, spreadable pastes, ready-to-dilute solutions, dilute emulsions, wettable powders, soluble powders, dusts, granules, or encapsulations, for example in polymeric materials.
  • the methods of application such as spraying, atomizing, dusting, scattering, brushing on, submerging, coating, pouring or rubbing, and the type of composition are selected to suit the intended aims and prevailing circumstances.
  • compositions as described herein may be introduced to fish or decapod crustaceans at any time of the life cycle (i.e. to subjects of all ages), including but not limited to fry, fingerlings, maturing or finishing stages.
  • compositions as described herein are preferably used in the finishing of commercially reared fish or decapod crustaceans.
  • compositions as described herein are administered or incorporated into the feed, feed supplements or additives during the early growth cycle of commercially reared fish or decapod crustaceans, such as the growth phase from hatchlings to fry, and/or from fry to fingerlings.
  • compositions as described herein are administered or incorporated into the feed, feed supplements or additives during the entire growth cycle of commercially reared fish or decapod crustaceans.
  • the compositions described herein may be administered to fish every day from fry until slaughter.
  • the compositions described herein may be administered to fish every day from fry until end of fingerling stage.
  • the fish or decapod crustaceans may be caught or captured at a juvenile stage of growth in the wild, and transported to grow-out aquaculture facilities where they are fed with compositions as described herein until mature enough for harvest or re-release back into the wild.
  • the fish or decapod crustaceans may be fed feed or feed additive compositions as described herein from egg to fingerling stage in a hatchery, released into the wild and optionally recaptured at a later stage of growth.
  • compositions contemplated herein can be in the form of an aqueous liquid, an oil-based liquid, a concentrated liquid, a gel, a foam, an emulsion, a slurry, a paint, a clear coat, a wax, a block, a pellet, a puck, a granule, a powder, a capsule, a vesicle, an effervescent tablet, slow release tablet, an impregnated dissolvable sheet or film, an impregnated material, and combinations thereof.
  • feeding fish or decapod crustaceans such as, shrimp, prawn, crayfish, lobster or crab
  • feed compositions comprising 50 to 500 ppm of stilbene (such as resveratrol) results in the fish or decapod crustaceans reaching a higher live-weight and having a higher incidence of survival.
  • stilbene such as resveratrol
  • feeding fish or decapod crustaceans such as, shrimp, prawn, crayfish, lobster or crab
  • feed compositions comprising 4 to 320 mg/ml of a stilbene (such as resveratrol) inhibits or treats Vibrio biofilm formation without adverse effects on environmental microbes that do not form pathogenic biofilms.
  • feeds or feed additive compositions comprising greater than " ⁇ g/rml of a stilbene (such as resveratrol) inhibits or treats Vibrio biofilm formation without adverse effects on environmental microbes that do not form pathogenic biofilms.
  • feeds or feed additive compositions comprising greater than 20 ⁇ g ml of a stilbene (such as resveratrol) inhibits or treats Vibrio biofilm formation without adverse effects on environmental microbes that do not form pathogenic biofilms.
  • a stilbene such as resveratrol
  • EXAMPLE 1 Resveratrol tested for performance improvement in fish farming.
  • a typical feed for this species comprising a powdered mixture of groundnut oilcake and rice polish (1 :1 w/w) was used as a feed for the rearing of fry to fingerlings.
  • the feed additive resveratrol was incorporated into feed along with appropriate binders.
  • Large concrete tanks of 10 m x 5 m x1 m size in the seed rearing complex were used for the fingerling rearing study. Important water quality parameters were measured periodically (at 15 day intervals) in the tanks. Fish sampling was carried out at 20 day intervals. The experiment was conducted for a period of three months for Catla fingerling rearing.
  • resveratrol After 2 months of feeding, resveratrol resulted in a significant increase in body weight and length of the fingerlings compared to the negative control. This was especially the case for administration of feed comprising 300 PPM resveratrol. Without being bound by theory, this relative increase in growth and weight gain of fingerlings may reflect enhancement or efficiency of the metabolism and energy of fish body cells, efficient feed utilization and/or balanced immune response at high socking densities.
  • EXAMPLE 2 Resveratrol tested for activity against shrimp Acute Hepatopancreatic Necrosis Disease. Objective:
  • EMS/AHPND Acute Hepatopancreatic Necrosis Disease
  • Vibriosis may be caused by a number of vibrio species of bacteria, including: Vibrio aiginoiyticus, Vibrio harveyi, Vibrio vulnificus, Vibrio parahaemolyticus and Vibrio penaeicida.
  • Vibrio bacteria are transferred through the oral cavity and then localize in the shrimp gastrointestinal tract and create a poison that causes tissue devastation and invalidism of the shrimp digestive system (hepatopancreas).
  • the Food and Agricultural organization (FAO) of the UN has estimated that EMS leads to annual losses of more than USD 1 billion in shrimp aquaculture globally. Attempts in the art at prevention and cure using antibiotics and /or disinfectants have thus far not proved successful and there is no known cure.
  • Many bacteria, including vibrio require the formation of a biofilm in order to colonise a surface, for example during the early stages of infection.
  • Resveratrol standard preparation 50 mg of resveratrol solubilised in 1 ml of 100 % Ethanol (50 mg/ml Resveratrol).
  • 5ml_ marine broth liquid cultures were prepared from a streaked plate of stocks of Vibrio aiginoiyticus. The cultures were grown overnight at 37 degrees Celsius in a shaking incubator. 100 ⁇ of these overnight cultures were inoculated into 10 ml of marine broth (1 :100 dilutions) in test tubes. After inoculation, 20, 30, 40 and 50 PPM of Resveratrol was introduced into the duplicate culture broths in numbered test tubes. One broth comprising only media was inoculated with overnight culture and the same volume of ethanol (without resveratrol) was then incubated alongside the resveratrol-treated as a positive control for biofilm formation.
  • test tubes were incubated in static condition (not in a shaker) at 37 C for 6 days. Once visual inspection confirmed biofilm formation in the positive control tube, the test tubes were carefully removed from the incubator without disturbing any biofilm that had formed. All tubes were inspected for biofilm formation or inhibition, and the cultures then decanted into a beaker and autoclaved for proper disposal. After decanting the cultures, the test tubes were immersed three times into a larger beaker containing water. The test tubes were inverted and placed on tissue paper to drain any remaining liquid from the tubes. All of the test tubes were stained with 15 ml_ of 0.1 % crystal violet for 10 minutes.
  • the crystal violet solution was decanted into a large beaker of water. Any excess crystal violet in the test tubes was removed by gently rinsing, such that the only crystal violet remaining was that bound to a biofilm ring at the sides of the glass tubes. It was then possible to assess biofilm formation and inhibition by examining the depth and intensity of the crystal violet stained ring at the location of the meniscus of the culture broth.
  • Intensive aquaculture is associated with a high level of stress in farmed fish, shrimp or crustaceans, due to poor water quality and/or high amount of competing biomass. Stress can result in an impaired or reduced immunity, which results in increased rates of infections and severity of infections by pathogens.
  • the positive ability of resveratrol on Vibrio pathogenic bacteria was confirmed in the above study (Example 2).
  • the present study was performed to investigate the more general effects of a representative stilbene (resveratrol) on aquaculture productivity, using a shrimp farm as an example.
  • Vannamei Pacific White Leg Shrimp (Penaeus vannamei) was selected as a test subject. Vannamei is a variety of prawn native to the eastern Pacific Ocean and is considered to be one of the most important aquaculture crops worldwide. They are characterised by fast growth rate, good tolerance to high stocking density and efficient utilization of plant proteins in formulated diets. They are omnivorous scavengers and are less aggressive and less carnivorous than black tiger shrimp. The trial was conducted in a recirculating aquaculture system in fiberglass tanks (with a capacity of 100 litres) containing 70 litres of water and 15 ppm saline.
  • TG0 Negative control group: No inclusion beyond the commercial aquafeed.
  • TG1 Trial group I: Inclusion of resveratrol at 30 ppm final concentration.
  • TG2 Trial group II: Inclusion of resveratrol and thymol at final concentrations of 10 ppm resveratrol and 10 ppm thymol.
  • TG3 Trial group III: Inclusion of resveratrol and thymol at final concentrations of 15 ppm resveratrol and 15 ppm thymol.
  • ADG average daily weight gain
  • FCR feed conversion rate
  • Table 2 shows the aggregate results (i.e. totals across duplicate treatments) for survival and total weight gain at the end of the entire course of the 8 week trial for each treatment group.
  • the shrimp in the negative control group had the lowest total mass gain, whilst the shrimp fed aquaculture comprising resveratrol exhibited significantly improved mass gain representing an approximately 19% higher final biomass than untreated shrimp.
  • the shrimp in the negative control group had the lowest survival rate, whilst the shrimp fed aquafeed comprising resveratrol exhibited improved survival rates over untreated shrimp.
  • feed mixtures for application to different treatment groups were made containing 15mg (group T1 ), 30mg (groupT2), 100mg (group T3) and 300 mg (group T4) resveratrol per kilogram mixture.
  • the resveratrol in this study was present on a sodium caseinate carrier.
  • a negative control (NC) i.e, feed with addition of only sodium caseinate, was also included in the study to detect any effects attributable to the carrier.
  • the standard aquafeed without any supplements of sodium caseinate nor resveratrol was used as a control (C). Both control and negative control feeds were virtually iso- proteinous with the treatment feeds. All resulting feed mixtures were formulated as physically identical 3 mm diameter extruded floating pellets using the same feed mill.
  • the fingerlings also known as fry
  • the fingerlings were acclimatized to the new tank environment prior to stocking.
  • Each tank was stocked with 250 fingerlings (equating to an initial stocking density of 5 fingerlings/m 3 ) of Catla raised under standard conditions in the farm (all between 9.02- 9.73 cm, 1 1.2-1 1 .8 g).
  • the water quality in the tanks were maintained according to standard protocols in this farm, through periodic liming (CaCC at 1.0 kg/tank equivalent to 200 kg/ha) and fertilization (urea at 10 kg/ha and SSP at15 kg/ha).
  • the water loss due to evaporation in the tanks was replaced at week intervals.
  • Feed conversion ratio (FCR) Total feed intake/total biomass gain
  • Survival percentage (number of fish harvested/number of fish stocked) x 100 [001 16]
  • the data on length and weight increment, survival and biomass production were subjected to one way analysis of variance (ANOVA). Further, Duncan's multiple range test was performed to compare the mean growth and yield of the different treatments.
  • FIGS 4 and 5 depict the growth curves (length and weight gain respectively) of the juvenile Catla in the controls and treatments.
  • T1 to T4 a relative increase in average length in the treatments
  • T4 to T4 the relative increase in weight compared to control was most significant in T3 and T4 (P ⁇ 0.05) as compared to controls (C and NC) after 40 days.
  • a slight relative increase in weight in T-1 and T-2 compared to controls suggested that the enhanced weight gain effect of resveratrol may be dose dependent within the tested range.
  • Table 5 Yield attributes of the Catla juveniles reared with varied levels of resveratrol in feed.
  • Treatments T-3 and T-4 also resulted in significantly higher (P ⁇ 0.05) body weight at harvest (HBW), which was surprisingly achieved despite the significantly higher survival rates and hence more crowding in the tanks of these treatment groups compared to controls.
  • HWH body weight at harvest
  • the biomass production in the treatments was significantly higher in T-3 and T-4 (P ⁇ 0.05), compared to the NC control, which is a metric highly correlated with aquaculture profitability. This beneficial effect is replicated in the feed conversion ratio, which demonstrated a dose-dependent effect of resveratrol in treatments T-1 to T-4.
  • T-3 and T-4 show that resveratrol dosages of 100 ppm and higher were able to halve the Feed Conversion Ratio in densely stocked aquaculture when compared to control feed compositions already considered by local aquaculture practitioners to be optimized for highest growth and most efficient FCR.
  • the measured attributes improved from T-1 to T-3 and became highest in T4 (P ⁇ 0.05) revealing an especially strong influence on fish growth at the higher incorporation levels tested herein.
  • EXAMPLE 5 Testing the in vitro anti-QS and antibiofilm potentials of resveratrol against aquatic microbial pathogens.
  • QS Quorum Sensing
  • Als autoinducers
  • Many aquatic pathogens utilize the QS mechanism for the expression of various phenotypic characters, including biofilm formation and production virulence factors - both processes are critical to pathogenicity in aquaculture. Therefore, the below investigation evaluated the anti-infective and anti-biofilm potentials of resveratrol in reducing QS dependent pathogenicity of aquatic bacterial and fungal pathogens.
  • the bacterial strains used as test pathogens inculded V. parahaemolyticus (ATCC 17802), V. alginolyticus (ATCC 17749), V. arveyi (MTCC 3438), V. vulnificus (MTCC 1 145), A. hydrophila (ATCC 7966) and P. fluorescens were. All the test bacterial pathogens were cultivated in Luria-Bertani (LB) broth (pH 7.5 ⁇ 0.2) at 28°C. For experimental purposes, all the test bacterial pathogens were subcultured in LB until achieving an OD of 0.4 at 600 nm (-1 x10 8 CFU/ml). Chromobacterium violaceum, Serratia marcescens PS1 (GenBank accession number: FJ584421 ) and P. aeruginosa PAQ1 were used as QS biomarker strains.
  • the resveratrol stock solution was prepared by dissolving 50 mg of resveratrol in 1 mL of DMSO.
  • the MIC of resveratrol against test bacterial pathogens was determined as per the CLSI guidelines (2012). Briefly, 1 % of bacterial culture was added to 1 mL of LB broth supplemented with varying concentrations of resveratrol and incubated at 28°C for 24 hours in a shaker at 120 rpm. The MIC was recognized as the minimum concentration that completely prevents visible growth.
  • the anti-QS activity of resveratrol was assessed by violacein inhibition assay using C. violaceum (Zhu et al. 201 1 ). Briefly, 1 % of C. violaceum ( ⁇ OD 0.4 at 600 nm) cells were added to 1 ml of LB broth in a polystyrene micro-titre plate (MTP) and treated with various concentration of resveratrol. The plates were incubated at 30°C for 24 hours. After incubation, the cell pellets were collected from the control and resveratrol treated samples by centrifugation at 16,000 x g for 10 mins. Violacein pigment was then extracted from the collected cell pellets using DMSO and the OD was measured at 585 nm. ii) Prodigiosin quantification assay
  • 3 ⁇ _ (OD adjusted to 0.4 at 600 nm) of bacterial culture was stab inoculated at the center of swimming agar medium consisting of 1 % peptone, 0.5% NaCI, and 0.3% agar supplemented either with or without resveratrol.
  • resveratrol exhibited visible growth reduction at ⁇ 10 ⁇ g ml against the QS biomarker strain C. violaceum (Fig. 7a). At a concentration of 4 ⁇ g ml, resveratrol exhibited the inhibition of QS mediated violacein pigment production in C. violaceum without inhibiting cell growth. However, growth inhibition was observed with concentrations of 6 ⁇ g ml and greater.
  • Pseudomonas aeruginosa The anti-QS potential of resveratrol was further tested for an ability to reduce QS- dependent pyocyanin production in P. aeruginosa.
  • the P. aeruginosa cells were cultivated either in the presence or absence of resveratrol in the concentration range between 2.5 to 300 ⁇ g ml.
  • a significant decrease in pyocyanin production of P. aeruginosa to 77% of normal production was observed after treatment with resveratrol at 100 ⁇ g ml concentration (Fig. 9b).
  • Complete visible growth inhibition was not observed, even at the higher concentrations of resveratrol; an 80% growth inhibition of P. aeruginosa growth was seen at the highest tested concentration of 300 ⁇ g ml (Fig. 9a).
  • EXAMPLE 6 Testing the in vitro anti-QS and antibiofilm potentials of resveratrol against aquatic microbial pathogens.
  • Resveratrol demonstrated a complete visible growth inhibition at 50 ⁇ g ml and 100 ⁇ g ml concentration against Vibrio parahaemolyticus and V. alginolyticus respectively (Fig. 10a and 10b). At a concentration of 320 ⁇ g ml, resveratrol exhibited complete antibacterial activity against V. harveyi (Fig. 10c). However, resveratrol only displayed 20% growth inhibition of V. vulnificus, even at 640 ⁇ g ml (Fig. 10d). EXAMPLE 7: Antibacterial activity of resveratrol against fresh water pathogens
  • Resveratrol showed significant antibacterial activity at 50 ⁇ g ml against Aeromonas hydrophila. However no further significant increase in growth inhibition was observed even up to 200 ⁇ g ml.
  • EXAMPLE 8 Antibiofilm activity of resveratrol against aquatic bacterial pathogens
  • EPS exopolysaccharides
  • Flagellar-mediated motility plays an important role in QS mediated biofilm formation in several aquatic bacterial pathogens.
  • the anti-QS potential of resveratrol against the swimming and swarming motility of V. alginolyticus was studied.
  • This inhibition of swimming and swarming motility provides further evidence of the utility of resveratrol for QS-mediated anti-biofilm activity against bacterial aquatic pathogens.
  • Betulin inhibits virulence and biofilm of Streptococcus pyogenes by suppressing ropB core regulon, sagA and dltA. Pathogens and Disease 74(7).

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Abstract

L'invention concerne des compositions comprenant et des procédés d'administration de stilbènes dans une nourriture pour l'aquaculture, pour améliorer la survie, la santé, la croissance et/ou l'efficacité de conversion d'aliments en biomasse chez les poissons et les décapodes.
PCT/EP2018/061864 2017-05-08 2018-05-08 Composition comprenant des stilbènes appropriée pour améliorer la productivité en aquaculture Ceased WO2018206573A1 (fr)

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CN112314785A (zh) * 2020-10-14 2021-02-05 中国水产科学研究院淡水渔业研究中心 具有调节罗非鱼肠道免疫能力功能的饲料
CN116998636A (zh) * 2023-08-29 2023-11-07 贵阳倍隆生物科技有限公司 添加有五倍子单宁酸和鞣花酸的大口黑鲈饲料
WO2024151157A3 (fr) * 2023-01-10 2024-09-06 Universiti Putra Malaysia Levure exprimant de l'astaxanthine en tant qu'additif alimentaire pour l'aquaculture

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Title
DARIO R. VALENZANO ET AL: "Resveratrol Prolongs Lifespan and Retards the Onset of Age-Related Markers in a Short-Lived Vertebrate", CURRENT BIOLOGY, vol. 16, no. 3, 1 February 2006 (2006-02-01), GB, pages 296 - 300, XP055483790, ISSN: 0960-9822, DOI: 10.1016/j.cub.2005.12.038 *
KOWALSKA AGATA ET AL: "Dietary resveratrol improves immunity but reduces reproduction of broodstock medakaOryzias latipes(Temminck & Schlegel)", FISH PHYSIOLOGY AND BIOCHEMISTRY, KUGLER PUBLICATIONS, AMSTERDAM, NL, vol. 43, no. 1, 18 July 2016 (2016-07-18), pages 27 - 37, XP036151436, ISSN: 0920-1742, [retrieved on 20160718], DOI: 10.1007/S10695-016-0265-8 *
WILSON WHITNEY N ET AL: "Effects of resveratrol on growth and skeletal muscle physiology of juvenile southern flounder", COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART A, MOLECULAR AND INTEGRATIVE PHYSIOLOGY, ELSEVIER SCIENCE, NEW YORK, NY, US, vol. 183, 16 December 2014 (2014-12-16), pages 27 - 35, XP029124373, ISSN: 1095-6433, DOI: 10.1016/J.CBPA.2014.12.014 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112314785A (zh) * 2020-10-14 2021-02-05 中国水产科学研究院淡水渔业研究中心 具有调节罗非鱼肠道免疫能力功能的饲料
WO2024151157A3 (fr) * 2023-01-10 2024-09-06 Universiti Putra Malaysia Levure exprimant de l'astaxanthine en tant qu'additif alimentaire pour l'aquaculture
CN116998636A (zh) * 2023-08-29 2023-11-07 贵阳倍隆生物科技有限公司 添加有五倍子单宁酸和鞣花酸的大口黑鲈饲料

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