JP7138391B1 - Propionic acid-releasing agents, acetic acid-releasing agents, and antiflatulent agents - Google Patents

Abstract

(1) Propionic acid liberating agent containing PHB powder having a weight average molecular weight of 10,000 or more, (2) Acetic acid liberating agent containing PHB powder having a weight average molecular weight of 10,000 or more, (3) Propionic acid or acetic acid for porcine intestinal bacteria To provide a swine growth promoter containing PHB powder having a weight average molecular weight of 10,000 or more, which liberates

Description

TECHNICAL FIELD The present invention relates to a feed additive that contributes to growth promotion and intestinal regulation of pigs and cows. It also relates to a pet food that is involved in intestinal regulation and chronic kidney disease (CKD) control in dogs and cats.

Along with growing worldwide interest in global environmental problems, there is growing interest in biodegradable plastics that are completely decomposed in the natural world. A large amount of poly(R)-3-hydroxybutyric acid (hereinafter referred to as "PHB") used as biodegradable plastic accumulates in bacteria as PHB granules, and a method of refining this as PHB powder has been established. Furthermore, it has been revealed that PHB powder induces various physiological actions, and its practical use as a pet supplement is awaited (see Patent Documents 1 and 2).

PHB powder has different physiological functions for fish and shrimp. PHB powder has remarkable effects such as 1) restoring healthy intestinal flora, 2) imparting resistance to infectious diseases, and 3) promoting growth. It is expected as a feed additive to replace "antibacterial growth promoters (antibiotics)" (Non-Patent Documents 1 to 3).

PHB powder had a significant growth-promoting effect in small mammals such as rats. On the other hand, in large mammals such as pigs, PHB powder was significantly effective in reducing foul odors and suppressing loose stools, but was not significantly effective in promoting growth (Patent Document 1). Moreover, the intestinal regulation effect and CKD inhibitory effect caused by chronic inflammation of the urinary system of cats and dogs were not clear.

International publication number WO2005/021013 International publication number WO2019/035486

Qiao G, Xu C, Sun Q, Xu DH, Zhang M, Chen P, Li Q. Effects of dietary poly-β-hydroxybutyrate supplementation on the growth, immune response and intestinal microbiota of soiny mullet (Liza haematocheila). Fish Shellfish Immunol 2019 Aug;91:251-263. Franke A, Roth O, Schryver P, Bayer T, Garcia-Gonzalez L, Kunzel S, Bossier P, Miest JJ, Clemmesen C. Poly-β-hydroxybutyrate administration during early life: effects on performance, immunity and microbial community of European sea bass yolk-sac larvae. Sci Rep. 2017 Nov 8;7(1):15022. Situmorang ML, De Schryver P, Dierckens K, Bossier P. Effect of poly-β-hydroxybutyrate on growth and disease resistance of Nile tilapia Oreochromis niloticus juveniles. Vet Microbiol. 2016;182:44-9.

Therefore, development of PHB powder as a propionic acid or acetic acid liberating agent is desired. Specifically, we have established a technology that allows PHB powder to exhibit a growth-promoting effect in pigs, and have developed growth promoters and intestinal regulators for pigs and cattle, or intestinal regulators and CKD inhibitors for dogs and cats, using PHB powder as an active ingredient. is required. PHB powder exhibits various physiological effects in the digestive system of large mammals such as pigs. In the prior art, no significant growth promotion was observed in pigs fed with PHB (5%) for one month during the early fattening period (up to 90 days after birth) (Patent Document 1). Although the growth-promoting action was significant in small mammals such as rats, the growth-promoting action was not significant in large mammals such as pigs and cattle (Patent Document 1). In the prior art, the purity (30% or less) is too low, the weight-average molecular weight (800,000 or more) is too high, and the hydrolysis of PHB is likely to be insufficient.

The inventor of the present invention found that a PHB powder having a purity (70% or more) and a weight-average molecular weight (700,000 or less) functions as a swine intestinal regulating agent. An object of the present invention is, as an example, to provide pig farmers with a swine intestinal regulator containing PHB powder as an active ingredient (Table 1). Another object is to provide an inhibitor of CKD, which is said to affect 30% of elderly cats (10 years old or older).

The present invention is as follows.
(1) Propionic acid release agent containing poly(R)-3-hydroxybutyric acid powder (PHB powder) having a weight average molecular weight of 10,000 or more (2) Poly(R)-3-hydroxybutyric acid powder having a weight average molecular weight of 10,000 or more (3) a swine growth promoter containing poly(R)-3-hydroxybutyric acid powder with a weight average molecular weight of 10,000 or more that releases propionic acid or acetic acid to swine intestinal bacteria (4) of swine A porcine intestinal regulating agent containing poly(R)-3-hydroxybutyric acid powder having a weight average molecular weight of 10,000 or more, which releases propionic acid or acetic acid in intestinal bacteria (5) Releases propionic acid or acetic acid in intestinal bacteria of cattle, Bovine intestinal regulating agent containing poly(R)-3-hydroxybutyric acid powder with a weight average molecular weight of 10,000 or more (6) Poly(R)-3 with a weight average molecular weight of 10,000 or more that liberates propionic acid or acetic acid in bovine intestinal bacteria - Cattle ruminal environment improving agent containing hydroxybutyric acid powder (7) Feline intestinal regulating agent containing poly(R)-3-hydroxybutyric acid powder having a weight average molecular weight of 10,000 or more, which releases cat intestinal bacteria propionic acid or acetic acid (8) Canine intestinal regulating agent containing poly(R)-3-hydroxybutyric acid powder with a weight average molecular weight of 10,000 or more that releases canine intestinal bacteria propionic acid or acetic acid (9) Cat intestinal bacteria propionic acid or acetic acid Feline Chronic Kidney Disease (CKD) suppressant (10) containing poly(R)-3-hydroxybutyric acid powder with a weight average molecular weight of 10,000 or more to liberate propionic acid or acetic acid from the intestinal tract of dogs, weight average molecular weight Canine CKD inhibitor containing 10,000 or more poly(R)-3-hydroxybutyric acid powders (11) Poly(R)-3- with a weight average molecular weight of 10,000 or more, which liberates canine intestinal bacteria propionic acid or acetic acid Canine CKD inhibitor containing hydroxybutyric acid powder (12) Suppression of canine ulcerative colitis containing poly(R)-3-hydroxybutyric acid powder with a weight average molecular weight of 10,000 or more that releases canine intestinal bacteria propionic acid or acetic acid Agent (13) A feline ulcerative colitis inhibitor containing poly(R)-3-hydroxybutyric acid powder having a weight average molecular weight of 10,000 or more, which releases feline intestinal bacteria propionic acid or acetic acid

The PHB powder according to the present invention can promote liberation of propionic acid and acetic acid by intestinal bacteria living in the large intestine of animals. As a result, for example, in pigs or cattle, the development of a pig growth promoter or intestinal regulator containing PHB powder as an active ingredient has brought about a significant cost reduction in livestock such as pig farming, and the sound development of the Japanese pig farming industry. be able to contribute to

Also, feeding 2% PHB (wt% of PHB powder in feed) to pigs resulted in significant increases in acetic acid, propionic acid and butyric acid, but not in lactic acid. Therefore, the PHB according to the present invention induces a weakly acidic intestinal environment through an increase in propionic acid and acetic acid, and functions as an intestinal regulator and also as an agent for improving the rumen environment of cattle (Fig. 1). In addition, the PHB powder of the present invention can be used as an active ingredient to develop an intestinal regulator, CKD inhibitor, or ulcerative colitis inhibitor for dogs or cats, thereby contributing to maintaining the health of pets.

Physiological effects of PHB powder mediated by propionic acid or acetic acid are shown. PHB powder activates intestinal bacteria and promotes the release of acetic acid and propionic acid from the intestinal bacteria, and these fatty acids induce intestinal regulation in pigs and CKD inhibitory action in cats. Physiological effects resulting from the activation of intestinal bacteria by PHB powder are shown. Ketobiotics with PHB powder are shown. The mechanism by which PHB powder activates intestinal bacteria is shown. Ketone donor type II for PHB powder is shown. It shows promotion of bone formation by weakly acidic intestinal environment. The increase in digestive capacity due to the weakly acidic intestinal environment is shown. Activation of the brain-gut interaction by the weakly acidic intestinal environment is shown. The mechanism by which PHB powder, which works in the large intestine but not in the small intestine (ketone donor type II) activates intestinal bacteria, is shown. It shows that PHB powder increased acetic acid, propionic acid and butyric acid in the large intestine of pigs. It shows that PHB powder induces a weakly acidic intestinal environment in the large intestine of pigs. Figure 2 shows that PHB powder suppressed nitrogen (BUN) in cats with CKD.

The composition and effects of the poly(R)-3-hydroxybutyric acid powder of the present invention are described below. The poly(R)-3-hydroxybutyric acid powder of the present invention is characterized by having a weight average molecular weight of 10,000 or more. This feature produces the following effects.

Effective during the pre-fattening period: pigs are breast-fed until about 21 days of age, after which they are fed progressively with chow. During this period from 21 days after birth to 60 days after birth, changes in the intestinal microflora occur and then stabilize. Generally, pigs are put on the market at about 180 days after birth, and the period up to 90 days after birth is called the early fattening period, and the period after 90 days after birth is called the late fattening period. Giving growth promoters between 21 and 60 days of age is believed to have a positive effect on the growth of pigs. Monk fruit extract and Bacillus padeius (a kind of bacteria) showed significant growth promotion in pigs (Japanese Patent Application No. 2008-253190 and WO01/028551). However, the old PHB powder (purity of 30% or less and weight average molecular weight of 800,000 or more) did not show significant growth promotion (Patent Document 1).

Effective during the late fattening period: The present invention had the effect of increasing short-chain fatty acids even when started at 90 days after birth (late fattening period) when the intestinal flora was stable. This fact is important. This is because the effect of promoting growth can be expected even in the later fattening period of pigs. In addition, the remarkable increase in short-chain fatty acids even after the intestinal flora was stabilized is even more pronounced when given from 21 days to 60 days of age, when the intestinal flora is stabilized. An increase in short-chain fatty acids can be expected, and the growth-promoting action starting from this is also considered significant. That is, the growth promoter for pigs containing new PHB powder (purity of 70% or more and weight average molecular weight of 700,000 or less) as an active ingredient is effective for the early fattening period (up to 90 days after birth) as well as the late fattening period (90 days after birth). It is thought that there is also a significant growth-promoting effect on the growth after day-old).

Lower triglycerides: The peculiarity of the growth-promoting action of PHB powder is that it has physiological characteristics that are clearly different from "obesity". It is a decrease in neutral fat in the blood. Physiological characteristics of obesity include 1) increased subcutaneous fat, 2) increased visceral fat, and 3) increased triglyceride in the blood. New PHB works to reduce these indicators of obesity in order to sustainably increase blood ketone body levels. This is because it binds to a membrane protein called GPR43, one of the receptors for ketone bodies, and reduces neutral fat and visceral fat (Miyamoto J, et al. Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions. Proc Natl Acad Sci USA. 2019 Nov 19;116(47):23813-23821).

This is a physiological feature that is clearly different from "antibacterial growth promoters (antibiotics)" (Otsubo and Kitazawa, Development of Alternative Antibacterial Growth Promoting Agents for Pigs Based on Porcine Intestinal Microbiome Research, Tohoku Livestock Society Bulletin 68 Volume No. 1). "Antibacterial growth promoters" increase feed efficiency and induce significant growth promotion in pigs, but since they increase triglycerides in the blood, they cannot be said to induce healthy growth promotion. Since PHB induces growth promotion and lowers neutral fat in the blood, it can be seen that PHB induces healthy growth promotion.

Overall description of FIG. 2: The PHB powder of the present invention is hydrolyzed in intestinal bacteria to produce ketone bodies in the intestinal bacteria and activate metabolism (A). Due to this activation of intestinal bacteria (A), PHB powder induces pathways via ketone bodies (B), acetate and propionate (C), and butyrate (D). Furthermore, the PHB powder of the present invention functions as a porcine growth promoter through activation of pathway groups (B), (C) and (D) via an increase in these short chain fatty acid groups. The entirety of pathways (A), (B), (C) and (D) by PHB powder, which originate from the activation of intestinal bacteria by PHB, is called “ketobiotics”.

The "ketobiotics" of the present invention are quite different from the prior art "ketogenics". This is because "ketogenic" originates from ketone bodies produced in the liver of mammals (eukaryotes), while "ketobiotics" originates from ketone bodies produced in intestinal bacteria. .

An outline of each route will be described below.
Route (B): PHB powder activates mitochondria by increasing the concentration of ketone bodies in the blood, activates tissue energy metabolism, and promotes pig growth.
Route (C): PHB powder increases the production of acetic acid and propionic acid, maintains a weakly acidic intestinal environment, enhances digestive and absorptive functions, and promotes pig growth.
Pathway (D): PHB powder increases colonic butyrate (chemically strictly n-butyrate) concentration, activates macrophages in Peyer's patches, activates regulatory T cells, and chronic inflammation of the gut. control and promote pig growth. Other organic acids and lower fatty acids include succinic acid, lactic acid, formic acid, iso-butyric acid, iso-valeric acid and n-valeric acid.

Route of FIG. 2(A) (detailed in FIG. 3): Chemically, PHB powder is a ketonic polyester. If this ester bond is hydrolyzed by the lipase of intestinal bacteria, ketone bodies are released in the intestinal bacteria, and the intestinal bacteria can be activated. These ketone bodies primarily become energy substrates for intestinal bacteria. In other words, the metabolism of intestinal bacteria is activated, and the intestinal bacteria come to release a large amount of short-chain fatty acids. Pathway (A) is involved in porcine growth promotion by promoting pathways (B), (C) and (D) through the increase of these short chain fatty acids.

Route shown in Fig. 2(B): PHB powder is decomposed into ketone bodies by the lipase of intestinal bacteria in the large intestine, released into the colon lumen, absorbed from the colon epithelium, and induces an increase in blood ketone body concentration. . Since the process in which PHB powder is degraded by intestinal bacteria in the large intestine to produce ketone bodies progresses slowly, the blood ketone body concentration is maintained at a high level. Ketone bodies activate membrane receptors (GPR43 and HCAR2) to activate energy metabolism (Boccella S, et al. Ketones and pain: unexplored role of hydroxyl carboxylic acid receptor type 2 in the pathophysiology of neuropathic pain FASEB J. 2019 Jan;33(1):1062-1073). Ketone bodies also function as direct energy substrates. That is, ketone bodies are not metabolized in the cytoplasm but are directly consumed by mitochondrial oxidative phosphorylation, and are said to have an ATP production efficiency of at least several tens of percent higher than that of glucose.

In general, mitochondrial oxidative phosphorylation is much more energy efficient than cytosolic glycolysis for ATP production. Therefore, if ketone bodies are continuously supplied, cells will inevitably use mitochondria to efficiently produce ATP. As a result, an increase in blood ketone body concentration promotes the production of ATP, which is an energy substrate in tissues (Williamson DH. Ketone body metabolism during development. Fed Proc. 1985 Apr;44(7):2342-6). ). As a result, tissue energy production is maintained at a high level, promoting pig growth.

Pathway (C) (intestinal regulation) (detailed in Figures 1 and 4): Short-chain fatty acids produced in the large intestine are mainly produced by intestinal bacteria from indigestible carbohydrates. It is said that acetic acid and propionic acid occupy 90% to 90% (Sakata and Ichikawa, Physiological activities of short-chain fatty acids, Journal of the Japan Oil Chemistry Society, Vol. 46, No. 10). PHB powder activates intestinal bacteria and causes them to release acetic acid and propionic acid, inducing a weakly acidic intestinal environment. The weakly acidic intestinal environment induces the effects as described below in paragraphs 0032-0038, allowing the PHB powder to function as a porcine growth promoter or flatulence agent.

Compounds that have the effect of adjusting the intestinal environment are bovine ruminal environment improving agents (Baaske L, Gabel G, Dengler F. Ruminal epithelium: a checkpoint for cattle health. J Dairy Res. 2020 Aug;87(3 ):322-329) as an ulcerative colitis inhibitor in dogs and cats (Valcheva R, Koleva P, Martinez I, Walter J, Ganzle MG, Dieleman LA. short-chain fatty acids levels. Gut Microbes. 2019;10(3):334-357). It has been shown that the intestinal flora of mammals resemble each other ((Ericsson AC. The use of non-rodent model species in microbiota studies. Lab Anim. 2019 Jun;53(3):259-270.)). Therefore, PHB powder can function as an intestinal regulator in dogs and cats as well.

Since propionic acid is also an activator of HCAR2, a ketone body receptor, it may exert anticancer and anti-inflammatory effects of ketone bodies (Sivaprakasam S, Prasad PD, Singh N. Benefits of short-chain fatty acid acids and their receptors in inflammation and carcinogenesis. Pharmacol Ther. 2016 Aug;164:144-51.). Propionic acid activates Tregs in the intestinal tract and can exert anti-CKD, anti-inflammatory, anti-allergic and anti-ulcerative colitis effects (Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J , deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, Rudensky AY. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013 Dec 19;504(7480):451-5.) It has been reported.

Pathway (C) (contribution to CKD inhibitory action) (Fig. 1): Certain dietary fibers (such as resistant starch) and certain sugars are not degraded in the small intestine and reach intestinal bacteria. has been reported (Zaman SA, Sarbini SR. The potential of resistant starch as a prebiotic. Crit Rev Biotechnol. 2016;36(3):578-84.). Such ingredients are known to activate intestinal bacteria. In addition, foods such as certain types of dietary fiber release short-chain fatty acids (SCFA) such as butyric acid through the activation of intestinal bacteria (Huang W, Zhou L, Guo H, Xu Y, Xu Y. The role of short-chain fatty acids in kidney injury induced by gut-derived inflammatory response. Metabolism. 2017 Mar;68:20-30.).

Increased SCFA is known to suppress chronic inflammatory diseases such as CKD and ulcerative colitis. There are several reports on such pathways for dietary fibers such as resistant starch. In addition, among SCFAs, it has been suggested that an increase in propionic acid, in particular, is essential for the suppression of chronic inflammation such as CKD and ulcerative colon (Al-Asmakh M, Sohail MU, Al-Jamal O, Shoair BM, Al -Baniali AY, Bouabidi S, Nasr S, Bawadi H. The Effects of Gum Acacia on the Composition of the Gut Microbiome and Plasma Levels of Short-Chain Fatty Acids in a Rat Model of Chronic Kidney Disease. Front Pharmacol. 2020 Dec 22; 11:569402.).

In the prior art, it is mentioned that when 2% PHB (PHB powder in food is 2%) is given to rats, the concentration of ketone bodies in the blood increases and the number of butyric acid bacteria increases, but the concentration of butyric acid is mentioned. (PCT/JP/2020/023042). On the other hand, the PHB according to the present invention is expected to be effective for renal fibrosis, acute kidney injury, chronic renal diseases such as CKD, diabetic nephropathy, diabetic nephrosclerosis, and the like.

Moreover, as shown in the test results in FIG. 8, it was also confirmed that the PHB powder shown in FIG. 1 liberates propionic acid and acetic acid apart from certain types of dietary fiber. This is an extension of the propionic acid release means.

Enhancement of absorption of minerals (detailed in FIG. 4): When the intestinal environment is inclined to the acidic side of calcium, potassium, iron, etc., ionization is promoted, and the solubility in solutions is greatly increased. As a result, the weakly acidic intestinal environment promotes the absorption of minerals that greatly affect bone growth and bone formation. This will promote pig growth (Ramakrishna BS. Role of the gut microbiota in human nutrition and metabolism. J Gastroenterol Hepatol. 2013 Dec;28 Suppl 4:9-17).

Gastrointestinal motility promotion (detailed in FIG. 5): Gastrointestinal motility is mediated by the movement of gastrointestinal smooth muscle immediately below the gastrointestinal epithelium. Smooth muscle is innervated by cholinergic neurons, whose firing has been found to be stimulated by increased proton concentrations. A mildly acidic intestinal environment stimulates cholinergic neurons, promotes the release of acetylcholine, and enhances smooth muscle motility. Therefore, a weakly acidic intestinal environment enhances digestive and absorptive capacity and promotes pig growth (Greenwood-Van Meerveld B, et al. Gastrointestinal Physiology and Function. Handb Exp Pharmacol. 2017;239:1- 16).

Promotion of secretion of digestive juice (mucus) (detailed in FIG. 5): Secretion of digestive juice (mucus) is carried out by gastrointestinal epithelial cells. Secretion is governed by cholinergic stimuli. It has been found that this neuronal firing is enhanced by increasing the concentration of protons. A weakly acidic intestinal environment stimulates cholinergic neurons and increases the secretion of digestive juices (mucus). Therefore, a slightly acidic intestinal environment enhances digestive capacity and promotes pig growth (Greenwood-Van Meerveld B, et al. Gastrointestinal Physiology and Function. Handb Exp Pharmacol. 2017;239:1-16).

Promoting the growth of beneficial bacteria: Eubacterium, Roseburia, Coprococcus, Faecalibacterium, Ruminococcus, Lachnospira, Clostridium Bacterial groups belonging to groups IV, XIVa and XVIII of the Clostridium cluster, such as the genus Clostridium, produce short chain fatty acids.

A group of bacteria capable of releasing into the colonic lumen (butyric acid bacteria) and Lactobacillus, Enterococcus, Lactococcus, Pediococcus, Leuconostoc (Leuconostoc), a group of bacteria (lactic acid bacteria) such as Streptococcus (genus Streptococcus) are weakly acidic and grow quickly. Bad bacteria are neutral and grow quickly. Therefore, in a weakly acidic intestinal environment, the proliferation of these beneficial bacteria is promoted and the proliferation of bad bacteria is suppressed. As a result, the intestinal flora becomes an environment dominated by butyric acid bacteria, and the secretion of acetic acid, propionic acid, and butyric acid is further enhanced, further activating the pathway of C in Fig. 1, and promoting the growth of pigs. Sakata and Ichikawa, Physiological activities of short-chain fatty acids, Journal of the Japan Oil Chemistry Society, Vol. 46, No. 10). Intestinal bacteria that proliferate further promote tryptophan hydroxylation and induce a healthy brain-gut relationship.

Healthy brain-gut relationship (detailed in FIG. 6): Higher animals such as large mammals become emotionally unstable under a stressful environment, and promotion of growth cannot be expected. Serotonin is called "happiness hormone" in humans and is a neurotransmitter essential for emotional stability. Serotonin is also a hormone absolutely necessary for healthy growth with little stress. In the intestinal tract, serotonin regulates intestinal motility and secretion of digestive juice (mucus). It regulates the activity of gut motility through indirect action via cholinergic neurons, rather than direct action on effector organs such as smooth muscle, as cholinergic neurons do.

It is known that serotonin is synthesized in the brain and intestinal tract, starting from the hydroxylation of tryptophan, an amino acid, to produce 5-hydroxytryptophan, but much of this hydroxylation depends on intestinal bacteria. is doing. For example, it has been reported that transplantation of butyric acid-dominant intestinal bacteria into depression model mice significantly alleviates symptoms of depression. This is believed to be because the transplanted intestinal bacteria promoted the hydroxylation of tryptophan, allowing serotonin to function in the brain. The significance of these studies is that the healthy functions of the intestinal tract and brain are highly dependent on intestinal bacteria, and that improving intestinal bacteria can normalize brain function. This became known as the “brain-gut connection”. If the intestinal flora is healthy with PHB powder, the possibility of maintaining healthy brain and intestinal function is increased (Wang HX and Wang YP. Gut Microbiota-brain Axis. Chin Med J (Engl). 2016 Oct 5;129(19):2373-80).

It has been shown in experiments using indigestible starch that the intestinal environment is caused by a weakly acidic intestinal environment in pigs. When poorly soluble starch is fed to pigs, the intestinal microbiota is altered to produce acetic acid and propionic acid, inducing a weakly acidic intestinal environment. It has been shown that this intestinal environment promotes digestion and absorption, thereby inducing growth promotion (Regassa A, Nyachoti CM. Application of resistant starch in swine and poultry diets with particular reference to gut health and function. 2018 Sep;4(3):305-310.).

Route (D): PHB powder improves intestinal flora. That is, increasing a group of bacteria capable of producing butyric acid belonging to Clostridium clusters IV, XIVa and XVIII of the Clostridium cluster such as Eubacterium, Roseburia, Coprococcus, Faecalibacterium, Ruminococcus, Lachnospira, and Clostridium, Increases production of butyrate in the large intestine (Narushima S, et al. Characterization of the 17 strains of regulatory T cell-inducing human-derived Clostridia. Gut Microbes. 2014 May-Jun;5(3):333-9).

An increase in butyric acid concentration can be induced by the proliferation of these intestinal bacteria groups with a high ability to produce butyric acid. Butyric acid produced by enteric bacteria of the colonic flora activates macrophages residing in Peyer's patches in the large intestine. Activated macrophages activate naive T cells to differentiate into regulatory T (Treg) cells. Tregs are highly effective in preventing inflammatory diseases of the digestive system with symptoms such as diarrhea and loose stools, which are common in pigs. In pigs, the maintenance of healthy digestive and absorptive functions in the gastrointestinal tract is a prerequisite for healthy growth, so the butyric acid pathway (D) contributes to the growth promotion of pigs.

In addition, since PHB induces the activation of Treg cells, it has been shown to be effective in treating typical domestic animal diseases such as foot-and-mouth disease, anthrax, brucellosis, tuberculosis, Johne's disease, bovine spongiform encephalopathy (BSE), bluetongue, akabane disease, and chuzan. disease, bovine viral diarrhea/mucosal disease (BVD/MD), infectious bovine rhinotracheitis (IBR), bovine leukemia, ainovirus infection, Ibaraki disease, bovine epidemic fever, emphysema, salmonellosis, bovine adenovirus disease, bovine coronavirus disease, bovine respiratory syncytial virus disease, bovine rotavirus disease, bovine pasteurella disease, bovine piroplasmosis, bovine lungworm disease, coccidiosis, papillary strongyloidiasis, cryptosporidiosis, neosporosis, nitrate poisoning, Cerebral necrosis, swine fever, Owensky's disease, porcine reproductive and respiratory syndrome (PRRS), porcine epidemic diarrhea (PED), infectious gastrointestinal (TGE), porcine erysipelas, toxoplasmosis, porcine pleurisy, porcine colibacillosis , exudative epidermatitis (soot disease), equine infectious anemia, equine influenza, equine rhinopneumonia, equine infectious metritis, equine paratyphoid, equine heartworm, Newcastle disease, low pathogenic Newcastle disease, highly pathogenic avian influenza (HPAI), low pathogenic avian influenza (LPAI), avian influenza, poultry salmonella infection, avian mycoplasmosis, foul rot, and red tick disease.

Ketone donors (detailed in Figure 7): Molecules that release ketone bodies in the gastrointestinal tract are called "ketone donors" (Figure 6). There are ketone donor type 1 that releases ketone bodies in the small intestine and ketone donor type II that releases ketone bodies in the large intestine. Type I ketone supplements are characterized by a spike in ketone bodies in the blood within a few minutes after ingestion and a drop to the original level within a few hours, including ketone bodies and ketone esters. Since activation of intestinal bacteria (A) does not occur with ketone donor type I, there is no effect of inducing (B), (C), and (D) that occur from (A) as a starting point (Fig. 1 ). On the other hand, ketone donor type II induces (A) activation of intestinal bacteria and (B), (C) and (D) as a starting point (Fig. 1). The feature of ketone donor type II (PHB powder) is that the concentration of ketone bodies in the blood gradually increases over several hours after ingestion, and the ketone body concentration increases continuously for 10 hours or longer. A sustained increase in ketone body concentration is required for porcine growth promotion, and PHB powder, which is a ketone donor type II, should be used.

Form of swine growth promoter: The effective amount of PHB powder is in the range of 10 to 2000 mg/kg body weight (preferably 100 to 1000 mg/kg body weight) per pig, divided into dosage units once or several times a day. can be administered as These doses or intakes can be expressed by calculation, if necessary, as PHB intakes or doses per day for a pig with a body weight of 60 kg, assuming that the body weight of the pig is 60 kg.

Production of PHB powder: Among ketone donors, ketone bodies and ketone esters can rapidly increase blood ketone body levels, while PHB powder can increase blood ketone body levels. It takes about 5 hours. On the other hand, PHB powder is suitable for continuous use (pig growth promoter) because it can continuously increase blood ketone body concentration. Since PHB powder is tasteless and odorless, it can be easily used as a growth promoter for pigs.

If the weight average molecular weight of the PHB powder is less than 10,000, the blood ketone body concentration cannot be increased sustainably. On the other hand, when the weight-average molecular weight of the PHB powder exceeds 700,000, hydrolysis by intestinal bacteria takes time, so it is thought that it takes too long to increase the blood ketone body concentration. Therefore, it is preferable that the weight average molecular weight of the PHB powder is, for example, 10,000 or more and 700,000 or less. The purity and weight average molecular weight of the PHB powder are believed to affect the time required for blood ketone levels to rise. The purity of PHB powder is, for example, 50% or higher. PHB powder with a purity of 50% or more is relatively easy to mass-produce, and can bring about a sustained increase in blood ketone body concentration. In order to enhance the blood ketone body concentration-raising effect of the PHB powder, the PHB powder may have a purity of 70% or more. In order to further enhance the effect of the PHB powder on increasing the blood ketone body concentration, the PHB powder may have a purity of 90% or more. PHB powder having a purity (70% or more) and a weight average molecular weight (600,000 or less) is preferable.

Production of PHB powder: PHB is a polymer of (R)-3-hydroxybutyric acid (ketone form) with an ester bond. PHB powder can be synthesized by a fermentation method or a chemical synthesis method. When chemical synthesis is used, expensive (R)-3-hydroxybutyric acid is used as a starting material, resulting in high synthesis costs. On the other hand, in the fermentation method using microorganisms, inexpensive raw materials containing carbohydrates are used for efficient biosynthesis, so large amounts can be easily prepared. PHB powder is synthesized, for example, using bacteria. Although it is possible to chemically synthesize PHB powder by increasing the degree of polymerization of ketone bodies using an asymmetric catalyst, it is impossible to synthesize PHB powder having a molecular weight exceeding 10,000. Therefore, it is necessary to use bacteria to synthesize PHB powder having a weight average molecular weight of 10,000 or more.

Production of PHB powder: PHB granules are produced in Halomonas by fermentation using bacteria. Subsequently, after adding a surfactant to the culture medium containing the cells, the mixture is autoclaved several times. At this time, PHB powder having a weight average molecular weight of about 700,000 can be obtained by using PHB derived from the genus Halomonas, adding less than 1% of a surfactant, and subjecting the mixture to autoclaving several times. In addition, PHB powder having a weight average molecular weight of about 590,000 can be obtained by using PHB derived from the genus Halomonas, adding 1% to 2% of a surfactant, and autoclaving several times. In this step, the bacterial cell components other than PHB are solubilized in the aqueous solution, and the PHB powder precipitates as an insoluble component. Thus, the weight average molecular weight can be changed by the concentration of the surfactant.

Preparation of PHB powder: Next, PHB granules are sedimented by centrifuging the insoluble components containing PHB at 10000 rpm for 10 minutes. In addition, instead of centrifuging to remove precipitates of PHB granules, a vacuum Leonida method is performed in which the solution is heated, and after heating, the pressure in the container containing the solution is reduced to reduce the volume of the solution and concentrate the cells. good too. Insoluble components including PHB granules may be removed using a filter press method in which the pressurized solution is filtered by a pressurizing device after performing the vacuum Leonida method.

Preparation of PHB powder: PHB granules taken out as sediment are washed with water. By this washing, it is possible to remove bacterial components other than the PHB granules by dissolving them in water. By repeating washing with water, the purity of the PHB powder can be increased to 90% or higher. The collected residue is dried, and the dried residue is ground in a blender to synthesize PHB powder. By autoclaving or heat drying, the cell membrane of the bacterium was destroyed, and PHB granules in the bacterium formed a higher-order structure due to weak intermolecular forces and hydrogen bonds (number average degree of polymerization of 10,000 or more). can be made into PHB powder with an average degree of polymerization of several thousand. PHB powder is in a state in which linear chains of PHB are present without association, unlike PHB granules in cells in which linear chains of PHB are associated by weak intermolecular forces or hydrogen bonds to form a higher-order structure.
The required degree of bonding can be achieved by repeating the above heat treatments, which may be used.

<Test Example 1>
The effect of the high-purity new PHB powder on the blood cell count in the microminipig blood was confirmed. Once a day, 2g (equivalent to 2% of weight) of PHB powder (purity 98%) per 100g of feed was orally administered to the microminipigs for 40 consecutive days. Body weight measurement, blood collection and stool collection were performed over time. On the 0th, 10th, 20th, 30th and 40th days from the start of the test, no abnormal values were observed in body weight and general blood test (Table 1). The PHB used in this test had a purity of 98% (by weight of PHB powder), a number average molecular weight of 2500 and a weight average molecular weight of 650,000.

<Test Example 2 (Fig. 8) (Fig. 9)>
[Method]
PHB powder (PHB purity 94%) in the feed was 2% by weight. Specifically, the PHB powder used in this test had a PHB purity of 94%, a number average molecular weight of 2200, and a weight average molecular weight of 580,000. Short-chain fatty acids (acetic acid, propionic acid, butyric acid and lactic acid) were quantified using high performance liquid chromatography (HPLC) using feces collected from pigs on days 0, 20 and 40 after the donation. The following were used for HPLC analysis.
HPLC: Prominence; Shimadzu, Kyoto, Japan
Detector: CDD-10A; Shimadzu
Duplex column (Shim-pack SCR-102H, 300 × 8 mm ID; Shimadzu) and guard column n (Shim-pack SCR-102H, 50 × 6 mm ID; Shimadzu)

Samples were suspended in Milli-Q and heated at 80°C for 15 minutes. Add zirconia beads, vortex, centrifuge at 14,200 g for 10 minutes, filter the supernatant through a 0.45 micron aperture membrane filter, and add 5 mM p-toluenesulfonic acid, 100 micromol EDTA, 20 mM Bis-Tris solution. reacted. The flow rate was 0.8 ml/min and the flow was performed at 45°C.

[result]
Pigs are weaned at about 21 days of age and increase until 60 days of age, but are said to be constant after 60 days of age. Therefore, 90-day-old microminipigs were used to observe the effect of PHB powder (94% purity) on short-chain fatty acids. Concentrations of short-chain fatty acids acetic acid, propionic acid, butyric acid and lactic acid in feces were measured in the above directions. Taking 90 days of age as day 0 and using this as a control, the concentrations of short-chain fatty acids in feces were measured on days 20 and 40, and the percentage change from the control is shown in the graph.

Changes in the concentration of short-chain fatty acids in the feces of 90-day-old microminipigs fed with PHB powder (purity 94%) for 40 days: Acetic acid and propionic acid increased significantly, about 3-5 times. Increased. There was also a significant increase in butyric acid, but no significant increase in lactic acid was observed (Fig. 8).

Based on the above results, there was a theory that dietary fiber is degraded by intestinal bacteria and releases propionic acid, etc., but unlike this theory, PHB is decomposed by intestinal bacteria and releases propionic acid, etc. Tests made it clear. In addition, administration of PHB significantly decreased fecal pH (from 8.2 to 7.5) (Fig. 9). It can be evaluated that a weakly acidic intestinal environment was induced.

<Test Example 3 (Fig. 10)>
[Method]
Blood was collected from 10 cats aged 10 years or older, urea nitrogen (BUN) and creatinine (CRE) were measured, and 2 cats with CKD advanced to stage 2 or higher (cat 1 and cat 2) were selected. These two cats were fed 2% PHB (2% weight ratio of PHB powder to feed), bled weekly, and BUN and creatinine were measured over 3 weeks. The PHB powder used in this test had a PHB purity of 90%, a number average molecular weight of 2000, and a weight average molecular weight of 550,000.

[Results] BUN decreased in both cat 1 and cat 2 after 3 weeks. Therefore, it was clarified that feeding 2% PHB (2% weight ratio of PHB powder to feed) suppresses feline CKD.

Possibility of industrial application

Pig farming industry not dependent on 'antimicrobial growth promoters': The feed additives most needed by pig farmers in the field are growth promoters for pigs. A growth promoter is a formulation that allows a marketable weight to be reached as quickly as possible. The most widely used growth promoters today are those called "antimicrobial growth promoters". Most of these are "antibiotics" used in the medical field, and the large-scale use of antibiotics in livestock is said to be a hotbed for the emergence and spread of resistant bacteria, and does not depend on "antibacterial growth promoters". Establishment of pig farming industry is required. It is also highly likely that growth promotion by antibiotics is producing "obese pigs," so-called "obese pigs," which fatten greatly on minimal feed.

"Short-chain fatty acids" and "intestinal bacteria": In the "Guidelines for Antibacterial Agent-Independent Livestock Farming" (2003, Institute of Livestock Science and Safety), various " Taking up the possibility of "probiotics", which are direct additions of "organic acids" (short-chain fatty acids) and bacteria to the feed, tests were conducted in chickens and pigs in the field and in laboratory buildings. Both “organic acids” and “probiotics” had significant growth-promoting effects in chickens, but in pigs, the use of “organic acids” or “probiotics” alone and the “combination of organic acids and probiotics” were significant. There was also no significant growth promotion in "combination". A possible reason for the lack of significant growth enhancement in pigs is that only one type of organic acid (short-chain fatty acid) (fumaric acid or formic acid) was used.

A new “pig growth promoter”: PHB powder, which boosts up all of the acetic acid, propionic acid, and butyric acid normally present in the large intestine and makes the intestinal environment weakly acidic, can induce growth promotion in pigs as well. Probability is high. That is, PHB powder, which activates intestinal bacteria and increases organic acids (short-chain fatty acids) such as acetic acid and propionic acid, has the potential to become a new "pig growth promoter" for pigs. Therefore, by developing a pig growth promoter containing PHB powder as an active ingredient, it is possible to bring about a significant cost reduction in the pig farming industry and contribute to the sound development of the Japanese pig farming industry. Furthermore, there is a high possibility that they can make a great contribution not only to Japan but also to the pig farming industry all over the world.

A new "flat regulator": PHB powder pushes up all of the acetic acid, propionic acid, and butyric acid that normally exist in the large intestine, making the intestinal environment weakly acidic. and can be expected as an antiflatulent agent.

A new "CKD inhibitor": PHB powder, which boosts up all of the acetic acid, propionic acid, and butyric acid normally present in the large intestine and changes the intestinal environment to a weak acidity, normalizes the immune response in cats with frequent CKD. and can be expected as a CKD inhibitor.

Mammals have many common intestinal bacteria, such as butyric acid bacteria, which are significant in humans and pigs, and are commonly found in rats, dogs, and cats (Ericsson AC. The use of non-rodent model species in microbiota studies. Lab Anim. 2019 Jun;53(3):259-270.). In particular, dogs and cats have much in common because they are both carnivorous (Grzeskowiak L, Endo A, Beasley S, Salminen S. Microbiota and probiotics in canine and feline welfare. Anaerobe. 2015 Aug;34:14-23. ) From these facts, the intestinal regulation action of PHB in pigs should also occur in cats and dogs.

Similarly, PHB inhibition of CKD in cats should also occur in dogs (Zhang J, Rodriguez F, Navas MJ, Costa-Hurtado M, Almagro V, Bosch-Camos L, Lopez E, Cuadrado R, Accensi F, Pina-Pedrero S, Martinez J, Correa-Fiz F. Fecal microbiota transplantation from warthog to pig confirms the influence of the gut microbiota on African swine fever susceptibility. Sci Rep. 2020 Oct 19;10(1):17605.) .

[Form of formulation]
The "releasing agent", "improving agent", "antiflatulent agent" and "inhibitor" of the present invention take the form of "oral preparation". The oral preparation according to this embodiment can be produced by mixing PHB powder as an active ingredient with physiologically acceptable carriers, excipients, binders, diluents and the like. Oral preparations are manufactured in a form that can be taken orally (WO2020/25098017, PCT/JP2020/023042). , capsules, syrups, emulsions or suspensions.

Oral formulations can be formulated with pharmaceutically acceptable excipients. Examples of pharmaceutically acceptable additives include excipients, carriers, disintegrants, binders, lubricants, buffers, coating agents, thickeners, colorants, stabilizers, emulsifiers, dispersants, Suspending agents, preservatives, perfumes and the like are included. Excipients include, for example, lactose, sucrose, starch, mannitol and the like. Examples of carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tolaganth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, cocoa butter, and the like. is mentioned. Examples of disintegrants include calcium carbonate, hydroxymethylcellulose calcium, and the like. Binders include, for example, pregelatinized starch, gum arabic, hydroxymethyl cellulose, polyvinyl picolidone, hydroxipyl cellulose and the like. Lubricants include talc, magnesium stearate, polyethylene glycol 6000 and the like. Buffers include phosphates, citrates and the like. Coating agents are added, for example, for the purpose of masking mucus, or for the purpose of ensuring enteric or long-lasting properties. Coating agents include, for example, ethyl cellulose, hydroxymethyl cellulose, polyoxyethylene glycol, cellulose acetate phthalate, hydroxipyl methyl cellulose phthalate and Eudragit (methacrylic acid-acrylic acid copolymer).

In order to produce an oral preparation, first, for example, excipients, disintegrants, binders or lubricants (talc, magnesium stearate, polyethylene glycol 600, etc.) are added to PHB powder, and the mixture is compression-molded. Subsequently, if necessary, the compacted PHB powder is coated with a coating agent.

[Adjustment of oral preparations]
Oral preparations containing PHB powder can be blended into health foods for humans and animals or therapeutic diets for pets (WO2020/25098018, PCT/JP2020/023042). Various proteins, saccharides, fats, trace elements, vitamins, etc. may be added to health foods and the like together with the PHB powder. Health foods and the like may be liquid, semi-liquid, solid, or pasty. Health foods and the like may be in the form of ordinary foods or nutritional supplements such as supplements.

The packaging of health foods, etc. may indicate the function of treating, preventing, or improving diseases or conditions that can be treated, prevented, or improved by increasing the concentration of ketone bodies. Alternatively, it may be labeled with anti-inflammatory ability. Health foods and the like may be beverages, and sugars, flavors, fruit juices, food additives, and the like that are used in the production of ordinary beverages can be added as appropriate. The food according to the present invention can take various forms, and the food according to the present invention may be manufactured according to known pharmaceutical manufacturing techniques. In that case, it can be produced using the additives described above.

When administering or ingesting an oral drug or food containing PHB powder, the dosage or intake of PHB powder depends on the age and weight of the treatment subject, symptoms, administration time, dosage form, administration method, combination of drugs, etc. can be determined by For example, when the PHB powder according to the present invention is administered as a health food, the effective amount of the PHB powder is in the range of 10-2000 mg/kg body weight (preferably 100-100 mg/kg body weight) per adult once a day or several times. It can be administered in divided doses into single dosage units. These dosages or intakes can be expressed by calculating, if necessary, as the intake or dosage of PHB per day for an adult with a body weight of 60 kg, assuming that an adult weighs 60 kg. .

PHB powder as a propionic acid or acetic acid liberating agent can be expected to be effective for the following diseases. Multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, acute hemorrhagic leukoencephalomyelitis, Hurst's disease, encephalomyelitis, optic neuritis, spinal cord lesions, acute necrotizing myelitis, cross section myelitis, chronic progressive myelopathy, progressive multifocal leukoencephalopathy, radiation myelopathy, HTLV-1-associated myelopathy, monolayer independent demyelination, central pontine myelination, leukodystrophy, inflammatory demyelinating multiple lesions neuropathy, acute Guillain-Barré syndrome, polyneuritis, myasthenia gravis, Eaton-Lambert syndrome, encephalomyelitis, inflammatory bowel disease, Crohn's disease, lupus, systemic lupus erythematosus, asthma, Leber's disease, Devick's disease, Fried Reich's ataxia, mitochondrial central nervous system disease, scleroderma, uveitis, antiphospholipid antibody syndrome, polyarthritis, polyarticular juvenile idiopathic arthritis, sickle cell disease, ankylosing spondylitis, myositis, Atherosclerosis, diabetic peripheral neuropathy, head injury, stroke, HIV-dementia, myocardial infarction, angina pectoris, heart failure, psoriasis, psoriatic arthritis, Sjögren's syndrome, diabetes, blistering skin disease, sarcoidosis, Osteoarthritis, ulcerative colitis, vasculitis, pulmonary fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, renal fibrosis, acute kidney injury, chronic kidney disease, diabetic nephrosclerosis, graft versus host reaction, Hashimoto's thyroiditis, Graves' disease, pernicious anemia, hepatitis, neurodermatitis, retinitis pigmentosa, mitochondrial encephalomyopathy, osteochondritis syphilis (Wegener's disease), marbled skin (Libedo's vasculitis), Behcet's disease, Panarteritis, osteoarthritis, gout, arteriosclerosis, Reiter's disease, pulmonary granulomatosis, encephalitis, endotoxin shock, sepsis, pneumonia, anorexia, Rennert's T-lymphomatosis, mesangial nephritis, Postangioplasty restenosis, reperfusion syndrome, cytomegalovirus retinopathy, adenoviral disease, AIDS, postherpetic neuralgia, postherpetic neuralgia, polyneuropathy, cystic fibrosis, Bechtereff's disease, Barrett's esophagus, Epstein - Barr virus infection, cardiac remodeling, interstitial cystitis, human tumor radiosensitization, multi-resistance of malignant cells to chemotherapeutic agents, granuloma annulare, cancer, chronic obstructive pulmonary disease, PDGF induction of bronchial smooth muscle cells thymidine uptake, bronchial smooth muscle cell proliferation, adrenoleukodystrophy, alcoholism, Alpers disease, ataxia-telangiectasia, Batten's disease, bovine spongiform encephalopathy, cerebral palsy, Cockayne's syndrome, corticobasal degeneration, Creutzf Veert-Jakob disease, familial fatal insomnia, frontotemporal lobar degeneration, Kennedy disease, Lewy body dementia, neuroborreliosis, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple system atrophy, Narcolepsy, Niemann-Pick disease, Pick disease, primary lateral sclerosis, prion disease, progressive supranuclear palsy, Refsum disease, Sandhoff disease, Schilder disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, spinal cord Cerebellar ataxia, spinal muscular atrophy, Steele-Richardson-Olsewski disease, myeloplasia, toxic encephalopathy, MELAS (mitochondrial encephalomyopathy; lactic acidosis; stroke), MERRF (myoclonic epileptic red ragged fibers), PEO (progressive) Leigh syndrome, MNGIE (myopathy and external ophthalmoplegia; neuropathy; gastrointestinal; encephalopathy), Kearns-Thayer syndrome, NARP, hereditary spastic paraplegia, mitochondrial myelopathy, optic neuritis, progressive polyps Focal leukoencephalopathy, pyoderma gangrenosum, erosive pustular dermatosis of the scalp, Sweet syndrome, bowel-related dermatopathy-arthritic syndrome, pustular psoriasis, acute generalized exanthematous pustulosis, pyorrheic keratoderma , Sneddon-Wilkinson disease, sterile pustulosis of skin folds, acropustulosis of the infantile, transient neonatal pustulosis, neutrophilic eccrinhidritis, rheumatoid neutrophilic dermatitis, neutrophilic urticaria, Stille disease, erythema vulgaris, unclassified intermittent fever syndrome/autoinflammatory syndrome, bullous systemic lupus erythematosus, neutrophilic dermatosis on the back of the hand (pustular vasculitis), hypersensitivity, allergic rhinitis, allergic asthma , lung cancer, severe asphyxia episodes of asthma, acute lung injury, acute respiratory distress syndrome, ischemia-reperfusion injury, sepsis with multiple organ dysfunction, unclassifiable colitis, sickle cell crisis, acute chest syndrome, scleroderma pulmonary disease, chronic asthma, radiation-induced fibrotic sarcoidosis, pulmonary hypertension, bronchopulmonary dysplasia (BPD), lung transplant rejection, pulmonary GVHD complications, interstitial pneumonitis syndrome (IPS) in transplant recipients ), COPD, silicosis, asbestosis, primary sclerosing cholangitis (PSC), alcohol-induced liver fibrosis, autoimmune hepatitis, chronic viral hepatitis (HepB, C), primary biliary cirrhosis (PBC) ), nonalcoholic steatohepatitis (NASH), liver transplant rejection, hepatic complications of GVHD, venous occlusion in transplant recipients, focal segmental glomerulosclerosis (FSGS), diabetic nephropathy, IgA Nephropathy, renal complications of GVHD (organ dysfunction after AKI organ transplantation), after CABG acute kidney injury (AKI after CABG), lupus nephritis, hypertension-induced renal fibrosis, HIV-associated nephropathy, peritoneal dialysis-induced peritoneal fibrosis, retroperitoneal fibrosis, idiopathic glomerulosclerosis, renal transplantation Alport syndrome, restenosis, subarachnoid hemorrhage (SAH), heart transplant rejection, cosmetic surgery, chronic wounds, burns, surgical adhesions, keloids, donor graft re-epithelialization, myelofibrosis, corneal transplantation, LASIX, trabeculectomy, systemic sclerosis, radiation-induced fibrosis, peripatellar fibrosis, Dupuytren's contracture, Dykin's lymphoma, non-Hodgkin's lymphoma, lymphosarcoma, lymphoblastic leukemia, acute lymphoblastic leukemia, Acute myelocytic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, hemangioma, hemangioendothelioma, hemangiopericytoma, angiosarcoma, Kaposi's sarcoma, osteosarcoma, fibrosarcoma, esophageal squamous cell carcinoma, pancreatic cancer, gastrointestinal tumor, colon cancer, rectal cancer, gastric cancer, lymphangioma, brain tumor, neuroblastoma, Schwannoma, chromocytoma, lung cancer, head and neck squamous cell carcinoma, melanoma, non-melanoma skin cancer, leiomyoma, Leiomyosarcoma, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, cervical cancer, renal cancer, and prostate cancer.

Although the present invention has been described above using the embodiments, the technical scope of the present invention is not limited to the scope described in the above embodiments, and various modifications and changes are possible within the scope of the gist thereof. be. For example, all or part of the device can be functionally or physically distributed and integrated in arbitrary units. In addition, new embodiments resulting from arbitrary combinations of multiple embodiments are also included in the embodiments of the present invention. The effect of the new embodiment caused by the combination has the effect of the original embodiment.

Claims (10)

A large intestine propionic acid releasing agent containing poly(R)-3-hydroxybutyric acid powder having a weight average molecular weight of 10,000 or more. A large intestine acetic acid release agent containing poly(R)-3-hydroxybutyric acid powder having a weight average molecular weight of 10,000 or more. A large intestine butyric acid releasing agent containing poly(R)-3-hydroxybutyric acid powder having a weight average molecular weight of 10,000 or more. A pH-lowering agent in the large intestine containing poly(R)-3-hydroxybutyric acid powder having a weight average molecular weight of 10,000 or more. A swine large intestine regulating agent containing poly(R)-3-hydroxybutyric acid powder having a weight-average molecular weight of 10,000 or more, which releases propionic acid, acetic acid or butyric acid to intestinal bacteria in the large intestine of pigs. A bovine rumen environment-improving agent containing poly(R)-3-hydroxybutyric acid powder having a weight-average molecular weight of 10,000 or more, which releases propionic acid, acetic acid or butyric acid to intestinal bacteria in the bovine rumen. A feline intestinal regulating agent containing poly(R)-3-hydroxybutyric acid powder having a weight-average molecular weight of 10,000 or more, which releases propionic acid, acetic acid or butyric acid to intestinal bacteria in the cat 's large intestine. A regulating agent for the large intestine of dogs, containing poly(R)-3-hydroxybutyric acid powder having a weight-average molecular weight of 10,000 or more, which releases propionic acid, acetic acid or butyric acid to intestinal bacteria in the large intestine of dogs. A feline chronic kidney disease (CKD) inhibitor containing poly(R)-3-hydroxybutyric acid powder having a weight average molecular weight of 10,000 or more, which liberates propionic acid or acetic acid in the intestines of cats. A canine chronic kidney disease (CKD) inhibitor containing poly(R)-3-hydroxybutyric acid powder having a weight average molecular weight of 10,000 or more, which releases propionic acid or acetic acid in the intestines of dogs.

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