Methods, kits, and compositions for the evaluation and treatment of interstitial cystitis

Abstract

To provide methods and kits for identifying a companion animal having an increased risk of developing interstitial cystitis; along with compositions for treating the same.SOLUTION: A pet food composition comprises an effective amount of a fiber-bound polyphenol component, for use in increasing the level of a urinary cytokine selected from: Fms-like tyrosine kinase 3 (F1t3-L), a stem cell factor (SCF); and IL-12p40, in a companion animal.SELECTED DRAWING: Figure 1A

Description

Background Art

[0001] Cross - reference to related applications This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 129,088, filed on December 22, 2020, the content of which is incorporated herein by reference in its entirety.

[0002] Feline interstitial cystitis (FIC), also known as feline bladder pain syndrome (BPS), is a term used to describe a systemic condition characterized by bladder pain, frequent urination, lower urinary tract disease (LUTD), and nocturia in cats. FIC can be classified into two types: an acute form that resolves spontaneously within three to seven days regardless of treatment, and a chronic form that persists or recurs frequently over weeks or months. FIC is also seen in all ages, and felids between two and seven years of age are at higher risk. Various scientists have proposed pathophysiological mechanisms that may lead to FIC, but the exact causal relationship of FIC is not clear.

[0003] Clinical diagnosis of FIC typically includes urinalysis, urine culture, and abdominal ultrasound. However, the diagnosis depends on the situation. Typically, FIC is diagnosed by "ruling out" other possible causes, including urolithiasis, infection, neoplasia, or renal disease. Currently, there is no consistent or specific diagnostic molecular marker that can serve as a reliable marker for evaluating FIC. Furthermore, all clinical trials rely heavily on subjective pet owner observations, interpretations, and quantification of clinical signs that may confirm FIC. This produces unreliable results because the ability to consistently quantify the owner's urine patterns and behavior is inconsistent.

[0004] While several candidate biomarkers have been identified and evaluated in humans, few have been evaluated in cats with FIC. Therefore, there is a need in the art for non-invasive urinary biomarkers for diagnosing FIC and for food formulations that alleviate the condition by improving diagnostic biomarker levels and clinical symptoms. Specific embodiments of the present invention are designed to satisfy these and other objectives. [Overview of the project]

[0005] Some embodiments of the present invention provide a method for diagnosing or identifying a feline predisposition to developing interstitial cystitis. In certain embodiments, the diagnostic method includes analyzing cytokine biomarkers. Biomarker levels may be analyzed from any bodily fluid, and in preferred embodiments, biomarker levels are obtained from urine. Furthermore, preferred biomarkers to be tested include, but are not limited to, Fms-like tyrosine kinase 3 ligand (Flt3-L) and cytokine stem cell factor (SCF).

[0006] A particular embodiment of the present invention is directed toward the treatment of interstitial cystitis in felines, comprising administering a pet food composition containing high levels of antioxidants.

[0007] A further embodiment of the present invention provides a kit for diagnosing or identifying a tendency of felines to develop interstitial cystitis.

[0008] According to at least one embodiment, a method is provided for identifying companion animals at increased risk of developing interstitial cystitis (IC). The method typically includes analyzing a biological sample obtained from a companion animal to determine the concentration of urinary cytokines, analyzing a biological sample from a healthy companion animal to determine the concentration of urinary cytokines, and comparing the urinary cytokine concentration of the companion animal to that of a healthy companion animal, wherein if the biological sample obtained from the companion animal contains a lower concentration of urinary cytokines than that of a healthy companion animal, the companion animal has a higher risk of developing interstitial cystitis.

[0009] According to another embodiment, a method is provided for identifying companion animals that would benefit from a treatment that reduces the risk of developing interstitial cystitis, the treatment comprising administering to the companion animal a composition containing an effective amount of a fiber-bound polyphenol component. The method for identifying companion animals that would benefit from a treatment that reduces the risk of developing interstitial cystitis comprises analyzing a biological sample obtained from the companion animal to determine the concentration of urinary cytokines, analyzing a biological sample from a healthy companion animal to determine the concentration of urinary cytokines, and comparing the urinary cytokine concentration of the companion animal to the urinary cytokine concentration of a healthy companion animal, wherein a lower urinary cytokine concentration in the companion animal than in a healthy companion animal indicates that the companion animal would benefit from a treatment that reduces the risk of developing interstitial cystitis.

[0010] In yet another embodiment, a method for reducing the risk of developing interstitial cystitis in feline subjects includes the steps of: analyzing a biological sample obtained from a companion animal to determine the concentration of urinary cytokines; analyzing a biological sample from a healthy companion animal to determine the concentration of urinary cytokines; comparing the urinary cytokine concentration of the companion animal to the urinary cytokine concentration of a healthy companion animal, wherein a lower urinary cytokine concentration in the companion animal than in the healthy companion animal indicates that the companion animal will benefit from treatment; and administering to the companion animal a composition containing an effective amount of fiber-bound polyphenol component when the urinary cytokine concentration in the companion animal is lower than in the healthy companion animal.

[0011] According to additional embodiments, a kit is provided for identifying companion animals at higher risk of developing interstitial cystitis. The kit typically includes a container for collecting biological samples; a detection method selected from: ELISA, chromatographic analysis, quantitative assay of aptamer systems, fluorescent tags or stains specific to combinations of two or more of their metabolites; a point-of-care test device having pre-loaded chromophores / antibodies specific to one or more urinary cytokines described herein; and instructions for use.

[0012] According to certain embodiments, a method is provided for treating, inhibiting or improving symptoms associated with interstitial cystitis in companion animals, the method comprising administering a composition containing an effective amount of fiber-bound polyphenols to a companion animal in need thereof. [Brief explanation of the drawing]

[0013] [Figure 1A] Figure 1A shows the levels of specific urinary cytokines in healthy and diseased felines.

[0014] [Figure 1B] Figure 1B shows the levels of urinary cytokines before and after interstitial cystitis diagnosis.

[0015] [Figure 1C] Figure 1C shows the levels of urinary cytokines over several years.

[0016] [Figure 2A] Figures 2A and 2B show the relationships of various urinary cytokines in healthy and diseased feline animals. [Figure 2B] The same as above.

[0017] [Figure 3A] Figures 3A and 3B show the levels of two urinary cytokines in healthy and diseased feline animals. [Figure 3B] The same as above.

[0018] [Figure 4] Figure 4 shows the levels of serum cytokines in healthy and diseased feline animals.

[0019] [Figure 5A] Figure 5A shows the ROC curves of diseased and healthy feline animals generated from urinary cytokines. [[ID=~40]]

[0020] [Figure 5B] Figure 5B shows the ROC curves of diseased and healthy feline animals generated from blood CBC, chemistry and cytokines.

[0021] [Figure 6A] Figures 6A and 6B show the data on urinary cytokines, as well as blood CBC, chemistry and cytokines. [Figure 6B] The same as above.

Mode for Carrying Out the Invention

[0022] The following invention relates, in part, to a diagnostic method for assessing the tendency of feline animals to develop interstitial cystitis.

[0023] The following description of the preferred embodiments is merely exemplary in nature and is not intended to limit the invention in any way. The description of the exemplary embodiments is intended to be read in connection with the accompanying drawings, which should be considered a part of the entire written description. The following description of the preferred embodiments is merely exemplary in nature and is not intended to limit the invention in any way. The description of the exemplary embodiments is intended to be read in connection with the accompanying drawings, which should be considered a part of the entire written description.

[0024] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. The singular form of any class of components refers not only to one chemical species within that class but also to mixtures of those chemical species. For example, the term "protein" in the singular may refer to a mixture of compounds each of which is also considered a protein. The terms "a" (or "an"), "one or more," and "at least one" may be used interchangeably herein. The terms "comprising," "including," and "having" may be used interchangeably. The term "include" should be construed to mean "including but not limited to." The term "including" should be construed to mean "including but not limited to."

[0025] The term "range," used throughout, is a shorthand for describing any value within that range. Any value within the range can be selected as the end of that range. In addition, all references cited herein are incorporated herein by reference in their entirety. In the event of any conflict between a definition in this disclosure and a definition in a cited reference, this disclosure shall prevail.

[0026] Unless otherwise defined, all technical and scientific terms and acronyms used herein have the same meaning as those commonly understood by those skilled in the art. Furthermore, it goes without saying that the present invention is not limited to any specific methods, protocols, or reagents described herein. The methods, protocols, and reagents described are merely examples and are for illustrative purposes only.

[0027] As used herein, the term “biological specimen” may be used interchangeably with the terms “sample,” “specimen,” “biomaterial,” and “biological material.” A biological specimen refers to any organic material obtained from a pet, including bodily fluids such as blood, saliva, and urine, biopsy-derived or tissue samples such as fur, and other clinical specimens such as breath condensates. Biological specimens can be obtained in non-invasive and / or invasive manners. For example, a biological specimen may be provided in a non-invasive manner, such as by swabbing the mouth, via a fur collection, or via urine. In other embodiments, a biological specimen may be provided in an invasive manner, such as by needle biopsy or tissue removal via biopsy.

[0028] In certain embodiments, the biological sample may further contain one or more excipients. Excipients may be added to the biological sample at any point in time. For example, excipients may be added to the biological sample during sample collection, transport, preparation, and / or analysis.

[0029] The addition of excipients is well known in the art. Such excipients should be present in amounts that do not impair the purpose and effect provided by the present invention. Excipients may be included as stabilizers, preservatives, processing aids, pH buffers, fillers, diluents, colorants, or dyes. For example, ethylenediaminetetraacetic acid (EDTA) may be added to biological samples during collection to preserve them.

[0030] Examples of excipients include boric acid and its derivatives, dimethyl sulfoxide (DMSO), ethanol, polyethylene glycol, ethylenediaminetetraacetic acid (EDTA), formic acid and its derivatives, protease inhibitors, sodium salts such as sodium citrate and sodium metabisulfate, and other protease inhibitors.

[0031] Biological samples (e.g., blood, saliva, urine, breath condensate, tissue, etc.) can be used as diagnostic tools. For example, biological samples (e.g., biofluids) can be used as diagnostic tools due to their ability to correlate with the health status and / or condition of an animal (e.g., a human). Health status may be related to disease, disorder, or other conditions. For example, biofluids can be used to diagnose and / or determine the onset of disease, the progression of disease, and / or the treatment progress of disease. Biofluids can be used as diagnostic fluids in non-invasive and / or invasive ways. For example, in some embodiments, the biofluid may be provided in a non-invasive manner, such as by swabbing the mouth, spitting, or via urine. In other embodiments, the biofluid may be provided in an invasive manner, such as by blood collection via injection or tissue removal. Detection of antibodies in a biofluid (e.g., rapid detection) can be performed rapidly via a compact tool (such as a toothbrush, mouthguard, or patch). Detecting disease, disorder, or other conditions by a biofluid may enable point-of-care diagnosis of disease, disorder, or other conditions. While this disclosure may provide numerous embodiments relating to biofluids, these embodiments are, of course, for illustrative purposes only. The embodiments may extend to any biological sample, including biofluids and biological tissues, for example.

[0032] Detecting diseases, disorders, or other conditions in biological samples can enable point-of-care diagnosis of diseases, disorders, or other conditions. Methods for quantifying one or more biomarkers in biological samples are well known in the art (e.g., colorimetric analysis, nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy, mass spectrometry, etc.). This disclosure may provide numerous examples relating to urine, but naturally, these examples are for illustrative purposes only. The examples may be extended to any biological sample, including body fluids or biological tissues.

[0033] As used herein, the term “biomarker” may be used interchangeably with the term “biological marker” and is used to refer to any measurable substance that can be used to examine organ function or any other biological state or condition. In certain embodiments, biomarkers may include proteins such as immunoglobulins, polynucleotides such as DNA and RNA, and metabolites. In certain embodiments, biomarkers may also include cytokines, but are not limited to, colony-stimulating factors (CSF), interferons (IFN), interleukins (IL), and tumor necrosis factor (TNF). In preferred embodiments, the biomarker is an FMS-related tyrosine kinase 3 ligand biomarker. In other embodiments, the biomarker is a cytokine stem cell factor.

[0034] The detection and quantification of biomarkers in a sample (such as urine) may be performed at any point after collection. For example, the quantification of biomarkers in a biological sample may be performed within a short period (e.g., within 2 minutes, within 5 minutes, etc.) or after a longer storage, transport, preservation, or incubation stage (e.g., within 6 hours, within 72 hours, etc.). In certain embodiments, the biological sample is stored, transported, or kept at a temperature in the range of approximately -200°C to approximately 30°C, for example, -80°C. As another example, tissue biopsies are preferably stored at -20°C for short-term storage and -80°C for long-term storage. Naturally, these examples are for illustrative purposes only, and the appropriate temperature depends on the type of biological sample used in the present invention. Biological samples should be stored at an appropriate temperature for a particular type of biological sample, as is generally understood by those skilled in the art.

[0035] One or more biomarkers in a sample may be used as a diagnostic tool for any type of disease, disorder, or other condition. For example, one or more biomarkers may indicate a cat's predisposition to a disease, disorder, and / or condition (e.g., likelihood of developing the condition). In a preferred embodiment, one or more biomarkers are used to diagnose or identify a predisposition to interstitial cystitis in cats. In a more preferred embodiment, FLT3L or the cytokine SCF is used to diagnose or identify a predisposition to interstitial cystitis in felines.

[0036] As described herein, electronic assays can be used to quantify biomarkers in biological fluids (e.g., blood, saliva, urine, etc.). Biomarkers may be associated with diseases, disorders, and / or conditions. For example, a biomarker may indicate the presence of a disease, disorder, and / or condition. A biomarker may indicate the risk of a disease, disorder, and / or condition (e.g., the risk of developing it). Electronic assays may use impedance, such as impedance cytometry, to quantify biomarkers in biological fluids. The biomarker may include proteins. The biomarker may include immunoglobulin G (IgG) and / or immunoglobulin A (IgA). Quantification of biomarkers in biofluids can be performed in a short time (e.g., within 5 minutes, within 2 minutes, etc.) and via compact, lightweight, and / or inexpensive equipment. In embodiments, machine learning techniques (e.g., supervised machine learning techniques) may be used to determine (e.g., assist in determining) the quantification of biomarkers (e.g., immunoglobulins) in biofluids.

[0037] In some embodiments, the present invention is a pet food composition used to treat any of the pathological conditions or states described herein. In a preferred embodiment, the present invention is a method for treating interstitial cystitis in felines, comprising administering a pet food composition. Preferably, the pet food composition contains a high level of antioxidants. In a more preferred embodiment, the pet food composition contains a high level of antioxidants and is administered daily for at least 28 days.

[0038] The pet food composition may be in the form of kibble. In other embodiments, the pet food composition is in the form of multilayer kibble and / or multilayer kibble including a coating. Furthermore, the coating may include a flavor enhancer. As used herein, the term “flavor” encompasses all the various characteristics of food perceived by animals, such as texture, taste, and smell. For example, the coating may include a flavor enhancer to enhance the flavor of the pet food composition. In certain embodiments, the composition has a flavor equal to that of a control composition.

[0039] In certain embodiments, the kibble is formed by extrusion. In other embodiments, the composition is in a form selected from loaf, stew, "meat and gravy" form, porridge, shredded with a water content of more than 50%, and a product that can be extruded from a syringe. In another embodiment, the present invention contains 6% to about 12% by weight of moisture.

[0040] In some embodiments, the kibble may contain a binder. In certain embodiments, the binder may be monosaccharides such as glucose, fructose, mannose, and arabinose; disaccharides and trisaccharides such as sucrose, lactose, maltose, trehalose, and lactulose; corn and rice syrup solids; dextrins such as corn, wheat, rice, and tapioca dextrin; maltodextrin; starches such as rice, wheat, corn, potato, tapioca starch, or these starches modified by chemical modification; alginates, chitosan; gums such as carrageenan and gum arabic; glycerol, sorbitol, etc. Examples of polyols such as cinnitol, xylitol, and erythritol; esters of polyols such as sucrose esters, polyglycol esters, glycerol esters, polyglycerol esters, and sorbitan esters; sorbitol; molasses; honey; gelatin; peptides; whey liquid, whey powder, concentrated whey, whey isolate, whey protein isolate, high-lactose whey by-products; meat broth solids such as chicken broth and chicken broth solids; soy protein; and any or combinations thereof of proteins and denatured proteins such as egg white.

[0041] In certain embodiments, the binder includes, but is not limited to, lipids and / or lipid derivatives. Lipids can be used in combination with water and / or other binder components. Examples of lipids include vegetable fats such as soybean oil, corn oil, rapeseed oil, olive oil, safflower oil, palm oil, coconut oil, palm kernel oil and partially and fully hydrogenated derivatives thereof, animal fats and partially and fully hydrogenated derivatives thereof, and waxes.

[0042] In certain embodiments, the present invention may include, but is not limited to, additives, minerals, vitamins, carbohydrate sources, fats, proteins, additional fiber, amino acids, carotenoids, antioxidants, fatty acids, glucose mimics, probiotics, prebiotics, and others.

[0043] Pet food compositions may contain additives well known in the art. Such additives should be present in amounts that do not impair the purpose and effect provided by the present invention. Examples of additives include stabilizing substances, sensory stimulants, processing aids, and substances that provide nutritional benefits.

[0044] Stabilizing agents may extend the shelf life of a composition. Suitable examples include preservatives, antioxidants, cohesive and scavenging agents, packaging gases, stabilizers, emulsifiers, thickeners, gelling agents, and wetting agents. Examples of emulsifiers and / or thickeners include gelatin, cellulose ethers, starch, starch esters, starch ethers, and modified starch.

[0045] Additives for coloring, flavoring, and nutritional purposes include colorants, salts (including, but not limited to, sodium chloride, potassium citrate, potassium chloride, and other edible salts), vitamins, minerals, and flavorings. The amount of such additives in the composition is typically up to about 5% by weight (based on the dry weight of the composition). In some examples, pet food compositions contain additives in amounts up to about 4% by weight, up to about 3.5% by weight, up to about 3% by weight, up to about 2.5% by weight, up to about 2% by weight, up to about 1.5% by weight, and up to about 1% by weight, based on the total weight of the dry-weight pet food composition. Additionally or alternatively, pet food compositions may contain additives in amounts of about 1% or less by weight, up to about 0.5% or less by weight, or up to about 0.1% or less by weight, based on the total weight of the dry-weight pet food composition. Other additives include antioxidants, omega-3 fatty acids, omega-6 fatty acids, glucosamine, chondroitin sulfate, plant extracts, and herbal extracts.

[0046] In certain embodiments, the pet food composition contains vitamins and minerals in amounts necessary to avoid deficiencies and maintain health. These amounts are readily available in the art. The Association of American Feed Control Officials (AAFCO) provides recommended amounts of these ingredients for dogs and cats (see Association of American Feed Control Officials. Official Publication, pp. 126-140 (2003)). Minerals may be specifically maintained at optimal levels well known to those skilled in the art to reduce the incidence of stone formation.

[0047] Examples of vitamins include vitamin A, vitamin B1 (related sources such as thiamine or thiamine nitrate), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (related sources such as pantothenic acid or calcium pantothenate), vitamin B6 (related sources such as pyridoxine or pyridoxine hydrochloride), vitamin B8 (folic acid), vitamin B12, vitamin C (ascorbic acid), vitamin D (vitamin D3 supplements, etc.), vitamin E, vitamin H (biotin), vitamin K, acetate, choline-related sources such as choline and choline chloride, and inositol.

[0048] Examples of minerals and trace elements include calcium, phosphorus, sodium, potassium, magnesium, copper, zinc, choline, and iron salts. Examples of mineral sources include sodium selenite, monosodium phosphate, calcium carbonate, potassium chloride, ferrous sulfate, zinc oxide, manganese sulfate, copper sulfate, manganese oxide, potassium iodide, and / or cobalt carbonate.

[0049] As used herein, the term "carbohydrate" includes polysaccharides (e.g., starch, dextrin) and sugars (e.g., sucrose, lactose, maltose, glucose, fructose) that are metabolized for energy when hydrolyzed. Examples of high-carbohydrate ingredients suitable for inclusion in the compositions disclosed herein include, but are not limited to, corn, grain sorghum, wheat, barley, and rice.

[0050] In certain embodiments, the carbohydrate component comprises a mixture of one or more carbohydrate sources. Examples of carbohydrates or carbohydrate components may include cereals, grains, corn, wheat, rice, oats, cracked corn, sorghum, grain sorghum / milo, wheat bran, oat bran, amaranth, durum, and / or semolina.

[0051] By appropriately balancing the carbohydrate sources, those skilled in the art can manipulate the texture of the final product. For example, short-chain polysaccharides tend to produce a sticky or gooey texture, while long-chain polysaccharides do not. The desired texture of this hybrid food can be achieved by using long-chain polysaccharides and modified starches (such as natural or modified starches, cellulose, and similar substances).

[0052] The carbohydrate mixture may additionally contain any ingredients such as added salt, spices, seasonings, vitamins, minerals, flavorings, colorings, and similar substances. The amount of any additives will depend at least in part to the nutritional requirements of different life stages of animals.

[0053] In some embodiments, the present invention may contain about 5% to about 25% by weight of fat. For example, a pet food composition may contain, based on the total weight of the pet food composition, about 5% to about 25% by weight of fat, about 5% to about 20% by weight, about 5% to about 15% by weight, about 5% to about 10% by weight, about 10% to about 25% by weight, about 10% to about 20% by weight, about 10% to about 15% by weight, about 15% to about 25% by weight, about 15% to about 20%, or about 20% to about 25% by weight of fat. Sources of fat or fatty components may include chicken fat, chicken tallow, turkey fat, pork tallow, lard, animal fat, beef tallow, vegetable oil, corn oil, soybean oil, cottonseed oil, palm oil, palm kernel oil, linseed oil, canola oil, rapeseed oil, fish oil, herring oil, anchovy oil, and / or orestra.

[0054] In some embodiments, the present invention may contain about 5% to about 30% by weight of protein. For example, a pet food composition may contain, based on the total weight of the pet food composition, about 5% to about 30% by weight, about 5% to about 25% by weight, about 5% to about 20% by weight, about 5% to about 15% by weight, about 5% to about 10% by weight, about 10% to about 30% by weight, about 10% to about 25% by weight, about 10% to about 20% by weight, about 10% to about 20% by weight, about 10% to about 15% by weight, about 15% to about 30% by weight, about 15% to about 25% by weight, about 15% to about 20% by weight, about 20% to about 30% by weight, or about 20% to about 25% by weight of protein. The term "protein" means a polypeptide, peptide, or polymer of amino acids. This term encompasses naturally occurring and non-naturally occurring (synthetic) polymers, as well as polymers in which artificial chemical mimics are substituted for one or more amino acids. This term also encompasses fragments, variants, and homologs that have the same or substantially the same properties and perform the same or substantially the same functions as the original sequence. This term encompasses polymers of any length, including polymers containing approximately 2–1000, 4–800, 6–600, and 8–400 amino acids. This term includes synthesized, as well as amino acid polymers isolated and purified from natural sources. Under some embodiments, the terms “polypeptide,” “peptide,” or “protein” are used interchangeably.

[0055] Proteins may be supplied from any variety of sources well known to those skilled in the art, including plant sources, animal sources, microbial sources, or combinations thereof. For example, animal sources may include meat, meat by-products, seafood, dairy products, and eggs. Meat may include, for example, chicken, fish, and animal meat (including cattle, pigs, sheep, goats, and similar animals). Meat by-products may include, for example, lungs, kidneys, brains, livers, stomachs, and intestines. Plant proteins may include, for example, soybeans, cottonseed, and peanuts. Microbial sources may be used to synthesize amino acids (e.g., lysine, threonine, tryptophan, methionine) or intact proteins (such as proteins from the sources listed below).

[0056] Proteins or protein components may include, for example, chicken meal, poultry, poultry by-product meal, lamb, lamb meal, turkey, turkey meal, beef, beef by-products, offal, fishmeal, intestines, kangaroo, white fish, venison, soybean meal, soybean protein isolate, soybean protein concentrate, corn gluten meal, corn protein concentrate, distillation-dried grains and / or distillation-dried grain solutions, and single-cell proteins such as yeast, algae, and / or bacterial cultures.

[0057] Proteins may remain intact, be completely hydrolyzed, or be partially hydrolyzed. The protein content of food can be determined by several methods well known to those skilled in the art, such as Method 988.05 published by the Association of Official Analytical Chemists in the Official Methods of Analysis ("OMA"). The amount of protein in the compositions disclosed herein may also be determined based on the amount of nitrogen in the composition according to methods known to those skilled in the art.

[0058] Examples of amino acids may include 1-tryptophan, taurine, histidine, carnosine, alanine, cysteine, arginine, methionine, tryptophan, lysine, asparagine, aspartic acid, phenylalanine, valine, threonine, isoleucine, histidine, leucine, glycine, glutamine, taurine, tyrosine, homocysteine, ornithine, citrulline, glutamic acid, proline, and / or serine. Carotenoid sources may include lutein, astaxanthin, zeaxanthin, bixin, lycopene, and / or beta-carotene. Antioxidant sources may include tocopherol (vitamin E), vitamin C, vitamin A, plant-derived materials, carotenoids (as listed above), selenium, and / or CoQ10 (coenzyme Q10). In one preferred embodiment, the pet food composition contains high levels of arginine and its derivatives, and / or low levels of tryptophan and its derivatives. In another preferred embodiment, the pet food composition contains high levels of polyunsaturated fatty acids (e.g., alpha-linolenic acid, arachidonic acid, EPA, DHA).

[0059] Examples of fatty acid components may include arachidonic acid, alpha-linoleic acid, gamma-linolenic acid, linoleic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and / or fish oil (as a source of EPA and / or DHA). Sources of glucose mimetic compounds may include glucose antagonists (including 2-deoxy-D-glucose, 5-thio-D-glucose, and 3-O-methylglucose), anhydro sugars (including 1,5-anhydro-D-glucitol, 2,5-anhydro-D-glucitol, and 2,5-anhydro-D-mannitol), mannoheptulose, and / or avocado extract containing mannoheptulose.

[0060] Other ingredients include beef broth, dried brewer's yeast, eggs, egg products, split flax, DL-methionine, amino acids, leucine, lysine, arginine, cysteine, cystine, aspartic acid, polyphosphates, sodium pyrophosphate, sodium tripolyphosphate; zinc chloride, copper gluconate, stannous chloride, stannous fluoride, sodium fluoride, triclosan, glucosamine hydrochloride, chondroitin sulfate, green-lipped mussel, blue-lipped mussel. Mussel, methylsulfonylmethane (MSM), boron, boric acid, phytoestrogens, phytoandrogens, genistein, daidzein, L-carnitine, chromium picolinate, chromium tripicolinate, chromium nicotinate, acid / base modifiers, potassium citrate, potassium chloride, calcium carbonate, calcium chloride, sodium bisulfate; eucalyptus, lavender, peppermint, plasticizers, colorants, flavorings, sweeteners, buffers, lubricants, carriers, pH adjusters, natural ingredients, stabilizers, biological additives such as enzymes (including proteases and lipases), chemical additives, coolants, and chlorine. Examples of such agents include denaturants, pharmacoagulants, astringents, emulsifiers, topical analgesics, aromatic compounds, humectants, opacifying agents (such as zinc oxide and titanium dioxide), defoaming agents (such as silicones), preservatives (butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA), propyl gallate, benzalkonium chloride, EDTA, benzyl alcohol, potassium sorbate, parabens, and mixtures thereof), reducing agents, solvents, hydrotropes, solubilizers, suspending agents (non-surfactants), solvents, viscosity enhancers (aqueous and non-aqueous), scavengers, and / or keratolytic agents.

[0061] The probiotic component may include any suitable bacteria, yeasts, microorganisms, and / or any mixture thereof. Various probiotic microorganisms are well known in the art. In certain embodiments, the probiotic component may include bacteria of the order Lactobacillales, bacteria of the genera Bacillus, Bacteroides, and / or Bifidobacterium, yeasts of the order Saccharomyces, including the tribes Saccharomyces and Candida, and / or any mixture thereof. The probiotic may or may not form spores.

[0062] In certain embodiments, the pet food composition may contain polyphenols. In some embodiments, the polyphenol source includes phenolic compounds selected from ellagic acid, gallic acid, protocatechuic acid, p-hydroxybenzoic acid, catechins, and combinations of two or more of these. In some embodiments, the polyphenol source includes pecan shells or any other components of pecan nuts. Further examples of polyphenol sources may include tea extract, rosemary extract, rosmarinic acid, coffee extract, pecan shells, caffeic acid, turmeric extract, blueberry extract, grape extract, grape seed extract, and / or soybean extract.

[0063] The pet food composition preferably contains an effective amount of fiber-bound polyphenol components. The amount of fiber-bound polyphenols in the pet food composition may be about 0.1% to about 60% by weight, depending on the case. For example, in various embodiments, the pet food composition may be about 0.1% to about 60% by weight, about 0.1% to about 50% by weight, about 0.1% to about 40% by weight, about 0.1% to about 30% by weight, about 0.1% to about 25% by weight, about 0.1% to about 20% by weight, about 0.1% to about 17% by weight, about 0.1% to about 14% by weight, about 0.1% to about 11% by weight, about 0.1% to about 9% by weight, about 0.1% to about 7% by weight, about 0.1% to about 5% by weight, and about 0.1% by weight, based on the total weight of the pet food composition. Amount% to about 3% by weight, about 1% to about 60% by weight, about 1% to about 50% by weight, about 1% to about 40% by weight, about 1% to about 30% by weight, about 1% to about 25% by weight, about 1% to about 20% by weight, about 1% to about 17% by weight, about 1% to about 14% by weight, About 1% to about 11% by weight, about 1% to about 9% by weight, about 1% to about 7% by weight, about 1% to about 5% by weight, about 1% to about 3% by weight, about 5% to about 60% by weight, about 5% to about 50% by weight, about 5% to about 40% by weight, about 5% to about 30% by weight, About 5% to about 25% by weight, about 5% to about 20% by weight, about 5% to about 17% by weight, about 5% to about 14% by weight, about 5% to about 11% by weight, about 5% to about 9% by weight, about 5% to about 7% by weight, about 10% to about 60% by weight, about 10% to about 50% by weight Weight%, about 10% to about 40% by weight, about 10% to about 30% by weight, about 10% to about 25% by weight, about 10% to about 20% by weight, about 10% to about 17% by weight, about 10% to about 14% by weight, about 15% to about 60% by weight, about 15% to about 50% by weight The fiber-bound polyphenol component may be included in amounts of %, approximately 15% to 40% by weight, approximately 15% to 30% by weight, approximately 15% to 25% by weight, approximately 15% to 20% by weight, approximately 20% to 60% by weight, approximately 20% to 50% by weight, approximately 20% to 40% by weight, approximately 20% to 30% by weight, approximately 20% to 25% by weight, approximately 30% to 60% by weight, approximately 30% to 50% by weight, approximately 30% to 40% by weight, approximately 40% to 60% by weight, or approximately 40% to 50% by weight.

[0064] Pet food composition may be determined by any of the various methods for feed analysis that are well known to those skilled in the art. Feed analysis may be performed to measure any of the nutrient contents listed herein, including moisture, protein, fiber, carbohydrates, energy, vitamins, minerals, fat, and ash content.

[0065] Protein content may be measured and reported by any of the various methods well known to those skilled in the art. Protein may be reported as crude protein (CP) to measure both true protein content and non-protein nitrogen. Crude protein content may be further differentiated between degradable intake protein (DIP), undegradable intake protein (UIP), and metabolizable protein (MP). In certain embodiments, protein content may be differentiated to include heat-damaged or insoluble crude protein (ICP), adjusted crude protein (ACP), and digestible protein (DP).

[0066] Fiber content may be measured and reported by any of the various methods well known to those skilled in the art. Fiber content may be reported as total dietary fiber (TDF, a combination of soluble and insoluble fiber), crude fiber (CF), neutral detergent fiber (NDF), acid detergent fiber (ADF), and / or acid detergent lignin (ADL). Crude fiber is generally known to estimate the indigestible portion of plant material found in pet food compositions. ADF measures cellulose and lignin, which are components of plant cell walls. NDF measures the total material found in plant cell walls and includes hemicellulose in addition to the fiber content measured as ADF. ADL measures only the lignin portion of plant cell walls.

[0067] Energy content may be measured and reported by any of the various methods well known to those skilled in the art. Energy content may be reported as digestible energy (DE), metabolizable energy (ME), net energy (NE), total digestible nutrients (TDN), ether extract (EE), relative feed value (RFV), and relative feed quality (RFQ).

[0068] Herein, embodiments of the present invention will be further described by the following non-limiting examples. [Examples]

[0069] A retrospective study was conducted on serum and urine samples from 44 cats. Of the 44 cats, 6 received a clinical diagnosis of feline lower urinary tract disease (FIC), 3 received a clinical diagnosis of feline lower urinary tract disease (FLUTD), 13 received a clinical diagnosis of cystitis (UB), and 23 were used as healthy controls.

[0070] Cytokine analysis was performed on serum and urine samples measuring 19 cytokines (sFas, TNFα, IL-12p40, SCF, PDGF-BB, IL-13, IL-18, IL-6, IL-4, IL-2, GM-CSF, KC, RANTES, SDF-1, FLT-3L, IL-1β, IFNγ, MCP-1, and IL-8). Cytokine analysis demonstrated a significant decrease in urinary cytokine Flt3-L in FIC cats compared to healthy cats (Table 1 below). Shaded cells indicate clinically significant differences between groups (p<0.05). [Table 1]

[0071] Univariate analyses were performed to identify that urinary Flt3-L and cytokine SCF had a predictive value of 76% and 72%, respectively, for diagnosis (Table 2 below). Shaded cells indicate clinically significant differences between groups (p ≤ 0.5). [Table 2]

[0072] Following the analysis, two cats clinically diagnosed with FIC were fed either Feline Metabolic AOX upgrade dry or Feline k / d Chick Canned cat food for 28 days. Urine samples were collected on day 28 (at the end of the experiment) and several years after diagnosis. Cytokine analysis demonstrated that the urinary Flt3-L levels in the FIC group were close to the mean levels of urinary Flt3-L levels in healthy cats.

[0073] The present invention is described with reference to several embodiments described in considerable detail for the purpose of providing a complete disclosure of the invention, but such embodiments are merely illustrative and are not intended to limit or represent an exhaustive enumeration of all aspects of the invention. The scope of the invention should be determined by the claims appended herein. Furthermore, it will be apparent to those skilled in the art that numerous modifications can be made in these details without departing from the spirit and principles of the invention.

Claims

1. A method for increasing the level of Fms-like tyrosine kinase 3 (Flt3-L), a urinary cytokine, in a companion animal, comprising providing the companion animal with a pet food composition containing an effective amount of fiber-bound polyphenol component, wherein the companion animal is a feline that has developed feline interstitial cystitis (FIC).

2. The method according to claim 1, wherein the fiber-bound polyphenol component comprises a material selected from oat fiber, psyllium husk, tomato pomace, flaxseed, beet pulp, carrot powder, brewed rice, and two or more combinations thereof.

3. The method according to claim 1 or claim 2, wherein the fiber-bound polyphenol component comprises a material selected from brewed rice, oat fiber, plantain husk, and two or more combinations thereof.

4. The method according to any one of claims 1 to 3, wherein the fiber-bound polyphenol component comprises a material selected from tomato pomace, flaxseed, beet pulp, carrot powder, and two or more combinations thereof.

5. The method according to any one of claims 1 to 4, which increases the level of Fms-like tyrosine kinase 3 (Flt3-L) after about 14 days.

6. The method according to any one of claims 1 to 5, which increases the level of Fms-like tyrosine kinase 3 (Flt3-L) after about 28 days.

7. The method according to any one of claims 1 to 6, which increases the level of Fms-like tyrosine kinase 3 (Flt3-L) after about 21 days.

8. The method according to any one of claims 1 to 7, further increasing the levels of urinary cytokines selected from stem cell factor (SCF) and IL-12p40.

9. The method according to any one of claims 1 to 8, wherein the pet food composition is in the form of kibble.

10. The method according to any one of claims 1 to 9, wherein the fiber-bound polyphenol component is present in the pet food composition in an amount of about 0.1% to about 60% by weight.

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