​Ketone bodies and receptors ​Reevaluation of ketone bodies Ketone bodies have been discovered as substances for more than 100 years, but it is only in the last 20 years that we have begun to understand their physiological effects. During that time, countless papers have been published among researchers, and the various effects of ketone bodies have been highly evaluated. Two of them are particularly interesting here. First, unlike other organic acids, ketone bodies have specific receptors on the cell membrane. The two main proposed receptors for ketone bodies are: HCR2 (H car two) With the discovery of HCAR2, ketone bodies have come to be recognized as molecules with special physiological effects that differ from other organic acids. HCAR2 can be activated by organic acids with hydroxyl groups, but it is particularly strongly activated by ketone bodies, and is involved in many physiological activities such as anti-inflammatory action and lipolysis. ​ ​​GPR43 (GP 43) The most prominent physiological effect caused by an increase in ketone bodies is the decomposition of fat. Many researchers thought that there might be a special receptor for this, but last year (September 2019) it was discovered that it was a protein called GPR43. When carbohydrates are restricted, the concentration of ketone bodies increases and GPR43 is activated, so fat is preferentially broken down. (* References 1​ ) Graff EC, Fang H, Wanders D, Judd RL. Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2. Metabolism. 2016 Feb;65(2):102-13. doi: 10.1016/j.metabol.2015.10.001. Epub 2015 Nov 13. PMID: 26773933. ​ (* References 2 ​ ) Miyamoto J, Ohue-Kitano R, Mukouyama H, Nishida A, Watanabe K, Igarashi M, Irie J, Tsujimoto G, Satoh-Asahara N, Itoh H, Kimura I. Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions. Proc Natl Acad Sci U S A. 2019 Nov 19;116(47):23813-23821. doi: 10.1073/pnas.1912573116. Epub 2019 Nov 4. PMID: 31685604; When ketone bodies bind to receptor proteins such as HCAR2 in immune cells and GPR43 in adipocytes, they amplify signals within immune cells and adipocytes. ​The paper suggests that by amplifying intracellular signals, it suppresses inflammatory responses and inhibits fat synthesis.

​Ketobiotics Philosophy PHB は大腸に届く We would like to contribute to maintaining the health of the intestinal flora through a new methodology called "Ketobiotics". poly-hydroxybutyrate /PHBs Most importantly, it is not degraded by mammalian digestive enzymes. Only the enzymes of intestinal bacteria can hydrolyze. ​ In order to be hydrolyzed by the enzymes of intestinal bacteria, ketone bodies are first produced in the intestinal bacteria. In other words, intestinal bacteria are the first target. ケトン体の原核細胞への働き Since research on ketone bodies has focused on their effects on mammals (eukaryotic cells),PHBs The function of ketone bodies is the relationship with intestinal bacteria, so it can be said that it is the unknown half of ketone bodies that "acts on prokaryotic cells". It opens up new horizons for ketone body research and creates a new research field. ケトン体は消化管でも産生される Ketone bodies hydrolyzed by the intestinal flora contribute to maintaining an ideal intestinal flora. Therefore, it can be said that "ketobiotics" are a new type of prebiotics. We want to protect the health of pets and industrial animals by working on good bacteria, especially butyric acid bacteria, in the intestinal flora and helping to maintain the health of the large intestine. That's what ketobiotics are. Contributes to maintaining an ideal intestinal flora そんな貴重なケトン体を外から腸内細菌叢に補充すること で健康維持に役立てようという、新しいタイプのプレバイオティクス。 それこそが「ケトバイオティクス 」です。 腸内細菌たちが元気でいることによって期待できること エネルギーが十分で腸内細菌たちが元気でいてくれれば、 ・ 好ましい割合の善玉菌を維持して腸内細菌叢の理想的な状態を保ち、 良好な便通を保つことが可能になる。 ・ 制御性T細胞／Treg細胞の適切な働きを維持できるため、 免疫力を好ましいレベルで保つことが可能になる。 ・ 脳腸相関により 健康的な脳の状態を維持することが可能になる。 ・ 腸腎相関により 健康的な腎臓の状態を維持することが可能になる。 「 ケトバイオティクス 」がそのために役立つようにとの強い思いで、私たちは今も研究を続けています。 （＊​１） PHBは一部の腸内細菌が膜表面上に持つPHBデポリメラーゼでゆっくりと加水分解されて、ケトン体 （3-ヒドロキシ酪酸）をゆっくりと放出します。 ケトン体は酪酸菌などの3-ヒドロキシ酪酸デヒドロゲナーゼという酵素を持つ細菌群のエネルギー基質となって消費されます。 これにより酪酸菌のエネルギー代謝が活性化され、酪酸の放出量が増加します。酪酸は制御性T細胞の適切な働きをサポートすることが知られています。 文献： Satoh T. New prebiotics by ketone donation. Trends Endocrinol Metab. 2023 Jul;34(7):414-425. doi: 10.1016/j.tem.2023.05.001. Epub 2023 Jun 2. PMID: 37271711. （＊​2）参考文献 Zou K, Hu Y, Li M, Wang H, Zhang Y, Huang L, Xie Y, Li S, Dai X, Xu W, Ke Z, Gong S, Wang Y. Potential Role of HMGCS2 in Tumor Angiogenesis in Colorectal Cancer and Its Potential Use as a Diagnostic Marker. Can J Gastroenterol Hepatol. 2019 Jul 1;2019:8348967. doi: 10.1155/2019/8348967. PMID: 31355161; PMCID: PMC6634068. Kim JT, Li C, Weiss HL, Zhou Y, Liu C, Wang Q, Evers BM. Regulation of Ketogenic Enzyme HMGCS2 by Wnt/β-catenin/PPARγ Pathway in Intestinal Cells. Cells. 2019 Sep 19;8(9):1106. doi: 10.3390/cells8091106. PMID: 31546785; PMCID: PMC6770209. Camarero N, Mascaró C, Mayordomo C, Vilardell F, Haro D, Marrero PF. Ketogenic HMGCS2 Is a c-Myc target gene expressed in differentiated cells of human colonic epithelium and down-regulated in colon cancer. Mol Cancer Res. 2006 Sep;4(9):645-53. doi: 10.1158/1541-7786.MCR-05-0267. Epub 2006 Aug 28. PMID: 16940161. （＊​3） 参考文献 Cheng CW, Biton M, Haber AL, Gunduz N, Eng G, Gaynor LT, Tripathi S, Calibasi-Kocal G, Rickelt S, Butty VL, Moreno-Serrano M, Iqbal AM, Bauer-Rowe KE, Imada S, Ulutas MS, Mylonas C, Whary MT, Levine SS, Basbinar Y, Hynes RO, Mino-Kenudson M, Deshpande V, Boyer LA, Fox JG, Terranova C, Rai K, Piwnica-Worms H, Mihaylova MM, Regev A, Yilmaz ÖH. Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet. Cell. 2019 Aug 22;178(5):1115-1131.e15. doi: 10.1016/j.cell.2019.07.048. PMID: 31442404; PMCID: PMC6732196. ケトバイオティクス理念ページ シェア

About P HB for pet therapy food This is a kind of “New-Prebiotics”. We call it "Ketobiotics". Our commitment is to be “Beyond Science”. Polyhydroxybutyrate (PHB) made from a bacteria which originally live in the sea and salt lake.From a chemical point of view, PHB is a simple compound, a polymer of ketone bodies.PHB is known as an energy substrate for hunger saved in the bacteria and has been regarded as a candidate of biodegradable plastic. However, because it is too fragile to be used as a substrate of tissue engineering, it has not been realized as a bioplastic up to the present time. use of this compound in another biological field. Since this is hydrolyzed and primarily used as an energy substrate in the enterobacteria, it may affect and modulate the composition of intestinal microbial flora. This is a kind of “New-Prebiotics”. We call it "Ketobiotics". Beyond Science Ltd. has been aiming at the industrialization of this compound as an effector of prebiotics. This is the straightforward way for realization of “Eatable Ketone body” according to social demand for pet health. And we believe that this method is a useful tool to practice easy keto diet and ketogenic life for dogs, cats and so on. PHBs metabolized by enterobacteria PHB is a beta-hydroxybutyrate (ketone body)-polymerized compound, in which ketone body connects with each other by an ester bond(1-2). small intestine and reaches large intestine. Just enterobacteria can digest this compound by their own enzymes(2-3). As a result, enterobacteria produce ketone body in their bodies and metabolize it through a chain of chemical reactions for energy production. Thus, PHB can significantly improve microbiological environment of large intestine and this is the physiological basis of health benefits of PHB . PHB and the improvement of the environment of large intestine can induce various health benefits and we call these mechanisms as “New-Prebiotics”, which is a novel mode of “Prebiotics”. body can be diffused into the space of large intestine as well as consumption inside bacterial body. ​References Obruca S, Sedlacek P, Krzyzanek V, et al. Accumulation of Poly(3-hydroxybutyrate) Helps Bacterial Cells to Survive Freezing. PLoS One. 2016;11(6):e0157778. Published 2016 Jun 17. doi:10.1371/journal. pone.0157778 Gowda USV, Shivakumar S. Poly(-β-hydroxybutyrate) (PHB) depolymerase PHAZ Pen from Penicillium expansum: purification, characterization and kinetic studies. 3 Biotech. 2015;5(6):901–909. doi:10.1007/s13205- 015-0287-4 Tseng CL, Chen HJ, Shaw GC. Identification and characterization of the Bacillus thuringiensis phaZ gene, encoding new intracellular poly-3-hydroxybutyrate depolymerase. J Bacteriol. 2006;188(21):7592–7599. doi:10.1128/JB.00729 -06 Various bacteria can save polyhydroxybutyrate (PHB) into granule-like shaped body inside the bacteria for energy substate(4). This is supposed to be a sort of bacterial insurance against their food crisis. Beyond Science Ltd. makes use of a peculiar strain, in which PHB often occupies over 80% of all space of the bacterial body. In this bacterial culture, PHB can be refined as pure powder by a simple method (Patent: WO2019/035486) (5-6). Since PHB is almost tasteless and odorless, this is one of the best ingredients of pet food for dogs and cats. ​References 4. Wang X, Jiang XR, Wu F, Ma Y, Che X, Chen X, Liu P, Zhang W, Ma X, Chen GQ.Microbial Poly-3-Hydroxybutyrate (PHB) as a Feed Additive for Fishes and Piglets. Biotechnol J. 2019 Dec;14(12):e1900132. doi: 10.1002/biot.201900132. Epub 2019 Jun 27. 5. Yu LP, Yan X, Zhang X, Chen XB, Wu Q, Jiang XR, Chen GQ.Biosynthesis of functional polyhydroxyalkanoates by engineered Halomonas bluephagenesis. Metab Eng. 2020 May;59:119-130. doi: 10.1016/j.ymben.2020.02.005. Epub 2020 Feb 29. 6. Yokaryo H, Teruya M, Hanashiro R, Goda M, Tokiwa Y.Direct Production of (R)-3-Hydroxybutyric Acid of High Optical Purity by Halomonas sp. OITC1261 Under Aerobic conditions. Biotechnol J. 2018 Feb;13(2). doi: 10.1002/biot.201700343. Epub 2017 Oct 30. Activation of regulatory T cells (7) ​ PHB makes enterobacteria produce ketone body inside bacterial body and activates the growth of various enterobacteria through energy production due to increase in ketone body. Good enterobacteria are supposed to activate regulatory T cells and suppress unnecessary immunological reactions(8-9). increase in good enterobacteria, regulatory T cells are activated through macrophages of Payer board of the large intestine. Regulatory T cells can suppress excess symptoms of various inflammations such as allergy and autoimmunity and return to the basal line of the reaction. ​References 7. Sakaguchi S, Mikami N, Wing JB, Tanaka A, Ichiyama K, Ohkura N.Regulatory T Cells and Human Diseases. 2020 Feb 4. doi: 10.1146/annurev-immunol-042718-041717. 8. Ladinsky MS, Araujo LP, Zhang X, Veltri J, Galan-Diez M, Soualhi S, Lee C, Irie K, Pinker EY, Narushima S, Bandyopadhyay S, Nagayama M, Elhenawy W, Coombes BK, Ferraris RP, Honda K, Iliev ID, Gao N, Bjorkman PJ, Ivanov II.Endocytosis of commensal antigens by intestinal epithelial cells regulates mucosal T cell homeostasis. Science. 2019 Mar 8;363(6431). pii: eaat4042. doi: 10.1126/science.aat4042. 9. Narushima S, Sugiura Y, Oshima K, Atarashi K, Hattori M, Suematsu M, Honda K.Characterization of the 17 strains of regulatory T cell-inducing human-derived Clostridia. Gut Microbes. 2014 May-Jun;5(3):333-9. doi: 10.4161/gmic.28572. Epub 2014 Mar 18. Sustained increase in ketone body by PHB (10) PHB can induce the sustained increase the concentrations of blood ketone body, which is in a sharp contrast to that of ketone ester, another type of ketone donor. 5 hours(11-12). In contrast, PHB needs 5 hours to begin the increase, but induces the sustained increase at least over 10 hours. This may be due to digestion just by enterobacteria, but not to digestive enzymes of small intestine. Further, this sustained increase in ketone body is the biological key to the preventive effects against various lifestyle-related diseases. References 10. Patent number: WO2019/035486 11. Abdul Kadir A, Clarke K, Evans RD.Cardiac ketone body metabolism. Biochim Biophys Acta Mol Basis Dis. 2020 Jun 1;1866(6):165739. doi: 10.1016/j.bbadis.2020.165739. Epub 2020 Feb 19 12. Newman JC, Verdin E. Ketone bodies as signaling metabolites. Trends Endocrinol Metab. 2014;25(1):42–52. doi:10.1016/j.tem.2013.09.002 A novel type of prebiotics The first biological target of PHB may be enterobacteria, already suggested by a prior art (patent: WO2005/021013). Pigs, kept for 5 days or 4 weeks and fed with PHB5%, increased the amount of excrement and defecation frequency(13) These results suggest that the number of enterobacteria is increased. In addition, PHB significantly decreased the amount of odor ingredients. Previous reports suggested that PHB can be digested by enzymes of enterobacteria. Thus, PHB can increase the ketone body and activate the growth of the bacteria. References 13. Patent number: WO2005/021013 Ketone body as a promising molecule of anti-aging Ketone body, which produces energy within mitochondria of the cells, is a simple C4 organic acid composed of carboxylic acid and hydroxyl group and thus two ketone bodies can form a connection through an ester bond. When great number of ketone bodies exist, they can form Ketone body is no longer regarded as a metabolic intermediate, as it regulates a broad range of physiological events at cellular and systemic levels. Importantly, ketone body functions as a stress response to maintain redox homeostasis in response to environmental and metabolic challenges(14-15). References 14. Veech RL, Bradshaw PC, Clarke K, Curtis W, Pawlosky R, King MT.Ketone bodies mimic the life span extending properties of caloric restriction. IUBMB Life. 2017 May;69(5):305-314. doi: 10.1002 /iub.1627. Epub 2017 Apr 3. 15. Roberts MN, Wallace MA, Tomilov AA, Zhou Z, Marcotte GR, Tran D, Perez G, Gutierrez-Casado E, Koike S, Knotts TA, Imai DM, Griffey SM, Kim K, Hagopian K, McMackin MZ, Haj FG, Baar K, Cortopassi GA, Ramsey JJ, Lopez-Dominguez JA.A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice. Cell Metab. 2017 Sep 5;26(3):539-546.e5. doi: 10.1016/j.cmet.2017.08.005.2018 May 1;27(5):1156 . References 16. Patent number: WO2015/072456 17.Patent number: WO2008/120778 Three types of ketone donors ketone donor is defined as substance which produces ketone body by enzymes of the small and large intestine. The most prominent feature is the production of ketone body under no influence of insulin. types of ketone donors. One is ketone body salt, for example, sodium salt of ketone body(16-17). The second is ketone ester, which ketone body is connected to alcohol through an ester bond(11-12). is PHB, which is a polymer of ketone body(10). I have focused on PHB as a mammals' supplement for these three years. Ketone body and ketone ester is hydrolyzed by enzymes of the small intestine and PHB is hydrolyzed by those of the This difference makes a big difference of physiological effects by them in the point that just PHB can induce a sustained increase in ketone body concentration. ​Beyond Science Ltd. A new ketogenic diet for pet therapy food beyondscience( A T. )polyhydroxyphb.com _cc781905-5cde-3194-bb 3b-136bad5cf58d_ _cc781905-5cde-3194 -bb3b-136bad5cf58d_ _cc7 81905-5cde-3194-bb3b-136bad5cf58d_ _cc781905 -5cde-3194-bb3b-136bad5cf58d_ Toky o / JAPAN BACK シェア

About serotonin シェア Serotonin that controls happiness Serotonin is a “force” Serotonin is a tiny, tiny molecule that you can't see, but scientists call it the happy substance. Do you know the that appears in the movie "Star Wars"? You could say it's something like that. The Force is what gives the universe justice and order, while serotonin is what gives happiness and peace. If you fill your brain with serotonin, it may be possible to free your brain from the grip of stress and carve out your own future. And the biggest key to filling the brain with force is "food". ​ By the way, it is known that when the gene for the enzyme that synthesizes serotonin is knocked out to prevent the brain from producing serotonin, two things will happen. Bone density decreases. decreased appetite; Conversely, if you fill serotonin, you can expect two things to happen. Increases bone density. Appetite increases. ​ This gives important suggestions in aiming for anti-aging. In other words, "a happy life", "preferable diet" and "athletic ability" are strongly linked by the molecule serotonin, and exist as if they were a single phenomenon. The role played by serotonin for healthy longevity is infinitely large. Brain-Gut Interaction and Serotonin It is known that there is a close relationship (brain-gut correlation) between the gut (intestinal bacteria) and the brain (mental activity). In other words, a good gut flora increases your chances of a happy life, and a poor gut flora decreases your chances of a happy life. Synthesis of serotonin starts from tryptophan, but tryptophan is mostly produced by enzymatically decomposing animal proteins, after which tryptophan is hydroxylated by intestinal bacteria and changed to hydroxylated tryptophan. ​ In this way, about 90% of hydroxylated tryptophan is produced by intestinal bacteria, so it can be said that most of it is dependent on intestinal bacteria. Hydroxyl tryptophan is absorbed from the intestinal epithelium, enters the bloodstream, and is sent to the blood-brain barrier. You can freely pass through that narrow gate. and can reach the brain. Furthermore, it is a mechanism that changes to serotonin by an enzyme in the brain and works as a happy substance. Furthermore, it changes into melatonin in nerve cells and functions as a sleep substance. Serotonin is known to be higher during the day and melatonin is higher at night. ​ These two hormones create a rhythm of being active during the day and resting at night. It seems that keeping the circadian rhythm of serotonin (happiness substance) and melatonin (sleep substance) is the basis for living happily. stress and cortisone The biological definition of stress can be described as the body's response to external stimuli, and cortisone plays a central role in the body's response to stress. Cortisone has a strong anti-inflammatory effect, but it is also known to have strong side effects. Cortisone is also thought to be one of the causes of depression, and it is highly possible that cortisone suppresses the action of serotonin. Cortisone has a wonderful effect only temporarily, but if it continues to act for a long time (stress persists), depression-like symptoms tend to become stronger. I also think that cancer is more likely to appear as a result of sustained cortisone release disrupting the brain-gut connection. This is because cortisone strongly suppresses the three physiological functions necessary for the establishment of the brain-gut interaction. ​ Digestive function in the intestinal tract immune function in blood Neural function in the brain Creating an environment in which these functions are persistently suppressed increases the likelihood of cancer. Cancer immunity by NK cells is particularly strongly affected by persistent stress. NK cells are one of the innate immunity and the most basic defense mechanisms against cancer. Since it is known that this NK cell-mediated cancer immunity is strongly suppressed by cortisone, there is a high possibility that persistent stress leads to cancer. Many researchers have also reported that the anti-cancer effects of NK cells are influenced by emotions. Life is full of waves of emotions, but if you live with a sense of happiness, NK cells maintain a highly active state and create a state that makes it difficult for you to develop cancer. On the other hand, negative emotions such as anger inhibit the cancer prevention mechanism by NK cells. In order to enjoy the effects of serotonin through the brain-gut interaction, it is essential to appropriately control external stimuli that cause negative biological reactions and to build a stress-free living environment. happy brain Currently, the leading theory for the cause of depression is the so-called “serotonin theory”. According to the serotonin theory, the basic thing for feeling "happiness" in the brain is that "serotonin" works normally. On the other end of the spectrum, "depression" is thought to be caused by serotonin not working properly or lacking serotonin. Common antidepressants are compounds called specific serotonin reuptake inhibitors (SSRIs), which inhibit the breakdown of serotonin. The "serotonin theory" is also very informative for all of us. This is because the necessary condition for the brain to feel happy is that serotonin, the happiness hormone, works normally. I think this will bring the gospel to many people. In order to be happy, all you have to do is give the brain conditions to be happy. All you have to do is create an environment in your brain where serotonin works normally. In order to "activate serotonin with food", it is necessary to prepare the following three conditions for serotonin to work normally in the brain. ​ Eat "tryptophan" which is a material of serotonin (eat fish and meat) Adjust the "intestinal bacteria" necessary for the synthesis of serotonin (eating vegetables and seaweed) Avoid excess sugar intake (eat good fats) Activation of serotonin by food ​ State the three conditions one by one. Eating a diet rich in tryptophan, the raw material for serotonin. Tryptophan is abundant in animal proteins and low in plant proteins. It means that humans need to eat fish and meat in order for their large brains to function properly (but be careful not to overeat). This is more than eating high-energy foods, it normalizes brain function. ​ You need normal gut bacteria. Tryptophan must be hydroxylated by intestinal bacteria. This hydroxylated tryptophan is free to move into the brain and become serotonin. Brain health (happiness) is mostly brought about by “food”. So eating fermented foods, seaweed and vegetables is a great way to keep your gut bacteria healthy. ​ You need to avoid excess sugar. Excess carbohydrates can lead to the release of insulin and lower blood sugar levels than normal. Among the nerve cells, there are remarkably large nerve cells. When viewed under a microscope, these neurons clearly differ in morphology from other neurons, are large, and receive input from many neurons. They act like hubs in neural networks and require large amounts of energy. Nerve cells that work with serotonin are such large-sized nerve cells, and in order to effectively transmit this energy substrate, refrain from excessive sugar intake and consider taking in good-quality fat accordingly. should Serotonin and heart The brain is the tissue that consumes the most energy, and it is the brain that is most affected by mitochondrial function in the body. The 24-hour rhythm of living organisms is called the circadian cycle, and normally the body secretes more serotonin in the morning and more melatonin in the evening along the time axis from morning to night. Melatonin is a sleep substance and serotonin is a happiness substance. The balance of its secretion controls the mechanism of sleep and wakefulness. How the brain and body work according to this circadian cycle is determined by how well the mitochondria in the brain work. If serotonin is secreted properly and the brain works normally, it is normal to be filled with happiness and work well from 2:00 to 3:00 in the afternoon. The serotonin pathway is an excitatory synapse, so it consumes a lot of energy. To do this, your mitochondria need adequate nutrition. The brain can be compared to a hybrid engine in a car. The fuel efficiency of a hybrid engine car is higher than that of a gasoline car because it uses both gasoline and electricity. The brain is also in the most efficient state when it is a hybrid engine of glucose and ketone bodies. Driven by this hybrid of glucose and ketone bodies, the serotonin pathway works best and gives us a sense of well-being. When you think that your brain is not working well, it is better to eat fruits (preferably in season) containing organic acids that "activate mitochondria" rather than "eating sweets". シェア

What is poly-hydroxybutyrate /PHB? Produced by bacteria ➡➡➡➡ ​➡➡➡➡Fine powder History as a biodegradable plastic PHB is a simple polymer made up of thousands of ketone bodies made from fungi (a type of organism/bacteria) that live in seas and lakes. For several decades, it has been known that it accumulates in the body of bacteria in the form of granules, and its potential as a raw material for biodegradable plastics has been pointed out. However, due to its extremely fragile structure, its practical use as a plastic is limited. However, in recent years, it is expected to be applied in other fields. ​ ​ Potential as a prebiotic It is possible that this substance may have a positive effect on the intestinal flora because it is degraded by bacteria, ie as a "prebiotic". We are aiming for this "prebiotics with ketone bodies". ​ Patented ​ PHBs (Polyhydroxybutyric acid) is patented. patent 7138391 Patent 6571298 ケトバイオティクス粉末ページ ​ *PHB is planned to be sold as pet food, pet supplement, pet therapeutic food, or feed additive. Human approval is not currently available.

​PR Office A new methodology called "Ketobiotics", a new prebiotic We aim to go beyond ketogenic for our pets. Protect your pets' health A new methodology called "Ketobiotics", new prebiotics for maintaining the health of dogs and cats. As a pet supplement and pet food. ペットたちの健康を守りたい。 ペットたちに、ずっと健康でいてほしい。 PHB が、 お役に立てるかも知れません。 シェア

​Ketone bodies as energy substrates chemical formula of ketone bodies Carboxylic acid at the α (alpha) position A hydroxyl group at the β (beta) position The carbon at the β (beta) position is an asymmetric carbon and produces stereoisomers, and organisms produce only the D form. A derivative of butyric acid and a kind of organic acid. Energy substrate for mitochondria. Ketone bodies (formal name / β-hydroxybutyric acid) are also included in food ingredients, It is also produced by the liver using neutral fat as a raw material. Normally, the human body breaks down the sugars ingested in the diet and uses them as an energy source. When it runs out, it breaks down fat in the body and produces ketone bodies. ​ Ketone bodies belong to the group of organic acids and are characterized by having a hydroxyl group at the β position. The presence of this hydroxyl group increases the water solubility. In other words, it can circulate in the body while being dissolved in the blood at a high concentration. Its physiological role is called "energy substrate", which is synthesized from fat in the liver, enters the blood circulation, is completely oxidized in skeletal muscle, etc., and becomes the intracellular energy currency adenosine 3-phosphate (ATP). It is transformed and consumed in various physiological processes.

Message for pets being ketogenic We advocate maintaining high ketone body levels sustainably as one of the easiest ways to live a long and healthy life. It can also be said to be "to make a ketogenic constitution". Ketone bodies act as energy substrates in the same way as other organic acids such as pyruvate, but only ketone bodies for which specific receptors such as HCAR2 and GPR43 are present have much lower Physiological effects can be induced by concentration. Therefore, it is not necessary to greatly increase ketone body concentration by unreasonable dietary restrictions, and maintaining a slightly higher state for a long time is one of the basic standards for maintaining good health. So what if, for example, we had a new technology to add ketone bodies exogenously? It can be said that it is a "ketone donor". Being a prebiotic One of the most noteworthy is the new prebiotics based on polyhydroxybutyric acid (PHB). It is called "ketobiotics" because it provides ketone bodies to intestinal bacteria. We provide therapeutic diets, supplements, and healthy pet foods for pets and industrial animals. We are now aiming to put this “ketobiotics” into practical use. We believe that it should be applied effectively to contribute to the health maintenance of mammals, including pets. Aiming beyond the ketogenic and making a new history in biology. This project (Beyond Science) is the result of this researcher's strong aspirations. シェア

Ketobiotics A new concept for pet health Beyond ketone bodies お知らせ 2024/06 Amazon.co.jp さんでの販売が始まりました。長らくお待ち頂いた方がいらっしゃれば、誠に申し訳ございませんでした。 アマゾンさんで ビヨンドサイエンス と入れていただき、検索してください。 何卒よろしくお願いいたします。 トップ お知らせ 2023/11 ​ポリヒドロキシ酪酸のペットサプリメントでの ​クラウドファンディングの募集期間が終了致しました。 ​おかげ様で希望額を上回るご支援を賜りました。 ​本当にありがとうございました。 お知らせ 2023/11 武内製薬さんのホームページにインタビュー記事を掲載して頂きました。 https://takeuchi-md.jp/?p=1414&preview=1&_ppp=5e5a99d2fe トップ ​What we offer Beyond Science proposes a scientifically cutting-edge health method that utilizes polyhydroxybutyrate. Poly-hydroxybutyrate is hydrolyzed by the enzymes of intestinal bacteria to produce ketone bodies in the intestinal bacteria, and the ketone bodies contribute to maintaining the health of the intestinal flora. This is a new concept called "Ketobiotics" that we aim to popularize. We hope it will be useful for your precious pets. Poly-hydroxybutyrate (PHB) is hydrolyzed by enzymes of enterobacteria to produce ketone bodies and activate enterobacteria. This is a totally novel tool of prebiotics and new ketogenic diet for pets. ONE GIANT LEAP for mammals. Presented by Beyond Science Ltd. ​What is poly-hydroxybutyrate? Poly-hydroxybutyrate ( P HB) is a polymer of ketone bodies, so the ketone bodies are long chains1000 more than one are connected. Therefore, it is not degraded in the stomach and small intestine of mammals, and is hydrolyzed only by intestinal bacteria in the large intestine. Enzymes in intestinal bacteria use the ketone bodies that are decomposed one by one, and short-chain fatty acids such as butyric acid, acetic acid, and propionic acid increase in the intestinal flora, resulting in an optimal state of the large intestine. helps to maintain It is a completely new type of prebiotic that is possible only because it is a natural compound consisting of ketone bodies linked together like a chain. In addition, excess ketone bodies are absorbed into the body and contribute to maintaining immunity by supporting health maintenance. ポリヒドロキシ酪酸についてもっと知りたい方はこちら 【 PHBの詳細説明 】 PHB（ポリヒドロキシ酪酸）​ の ​ ～ 安全性試験結果 ​～ ～安定性試験結果～ ​About high-purity PHB provided by Beyond Science read Produced in the world's top-level PHB laboratory. And it is manufactured by equipment with thorough hygiene control and high technology that produces raw materials for medical materials to be implanted in the human body. ミトコンドリアのはたらき 読む ケトン体は、直接ミトコンドリアを活性化することができ、​このことが神経細胞の保護やセロトニンの分泌に役立ちます。 as an energy substrate ​ketone bodies read Ketone bodies belong to the group of organic acids and are characterized by having a hydroxyl group at the β-position. ​About serotonin read If you fill your brain with serotonin, it may be possible to free your brain from the grip of stress and carve out your own future. And the biggest key to filling the brain with force is in ketone bodies. ​ Column ketone donor read The criteria for classifying ketone donors is determined by how many ketone bodies are released. Carbohydrate restriction and ketone bodies read If possible, if you eat a diet with carbohydrates reduced to 30-40%, the ketone body concentration will rise to about 0.2-0.3 millimolar. ～MESSAGE～ ケトジェニックであること 読む 特異的な受容体が存在するケトン体だけが、他の有機酸よりもはるかに低い濃度で生理作用を誘導します。 アンカー 1 Beyond Science Ltd. シェア

​ Mitochondria and anti-aging Mitochondria are small organelles inside cells that have DNA because they were originally bacteria. Therefore, it can divide and multiply autonomously. That is why it has a decisive role in controlling the life and death of cells in the human body. Impaired mitochondrial energy metabolism releases factors that induce cell death. If the mitochondria are actively working, the cells are also lively and anti-aging effects can be expected. Cells make energy in two places: the cytoplasm and the mitochondria. The energy metabolism pathway in the cytoplasm is called "glycolysis", which mainly decomposes glucose and converts it into an energy source that is easy to use in the body. However, this route cannot be said to have good metabolic efficiency because part of the glucose changes to lactic acid during decomposition and is not completely oxidized. Mitochondrial energy metabolism is very efficient. This is because the compounds called ketone bodies and pyruvate reach directly and are completely oxidized and everything becomes energy. Therefore, the key to healthy longevity is how to use these highly energy-efficient mitochondria. The reason that carbohydrate restriction is good for the body is that lowering carbohydrates suppresses insulin spikes and increases the concentration of ketone bodies, which become an energy source in mitochondria and improve metabolic efficiency. This is because mitochondria are activated. シェア

Detailed description of poly-hydroxybutyrate (PHB) PHBとは、ケトン体が鎖状に繋がった天然の化合物 poly-hydroxybutyrate(PHB) is accumulated as an energy substrate material in the cells of bacteria that live in seas and lakes. It seems that bacteria are like insurance when they run out of energy. of the volume of bacteria 80 %More than PHBs can be purified by a relatively simple operation. History as a biodegradable plastic PHBs teeth For a long time, its potential as a raw material for biodegradable plastics has been pointed out. However, the structure is very fragile, and the practical application as a plastic is still limited. Potential as a prebiotic However, in recent years, it is expected to be applied in other fields. It is possible that this substance may have a positive effect on the intestinal flora because it is degraded by bacteria, ie as a "prebiotic". We are aiming for this "prebiotics with ketone bodies". ​ Because it is almost tasteless and odorless (it tastes slightly like milk) and has fine particles, it is thought to be suitable as a pet food material that satisfies the palatability of dogs and cats. 腸内細菌に届く poly-hydroxybutyrate ( PHB ) is a polymerized compound of ketone bodies. mammals are PHBs Because it cannot be decomposed, it passes through the small intestine and reaches the large intestine, where it is taken up by intestinal bacteria living in the mucous membrane that covers the large intestine epithelium and is hydrolyzed by the enzymes inside. Ketone bodies are released in the intestinal flora, and short-chain fatty acids such as butyric acid, acetic acid, and propionic acid increase in the intestinal flora, thereby helping to maintain optimal colon health. In addition, ketone bodies that are not utilized by intestinal bacteria diffuse into the colon lumen and enter the blood circulation of mammals through colon epithelial cells, contributing to health maintenance. アンカー 1 ケトバイオティクスとして働く １、腸内細菌叢の酪酸・酢酸・プロピオン酸といった短鎖脂肪酸を維持して、腸内細菌たちのための理想的な環境をキープするお手伝いが可能です。 （生後90日齢のマイクロミニブタに2%のPHBを40日間混餌で与えたデータ） ケトン供与体として働く ２、さらにケトン供与体として、腸内細菌叢でのケトン体（エネルギー基質）が充足した状態を保つお手伝いが可能なため、哺乳類の免疫力の維持にも貢献できます。 毒性試験に合格 ★急性毒性試験 ★亜急性毒性試験 において合格（問題なし）でした。 ​ 安全性試験の結果 はこちら 非常に安定した物質 まず酸化還元されることがほぼ無いため、 腐敗などの心配が少ないとされる物質です。 ​実際、安定性試験（加速試験）においては、 4 年に値する期間を経過しても、分子量の変化がほとんど見られませんでした。 分子量10000以上の割合（％） サンプル0 スタ ート時 99.4 サンプル3 3ヵ月40℃保存後 99.0 サンプル6 6ヵ月40℃保存後 99.1 サンプル8 8ヵ月40℃保存後 99.2 （加速条件(40℃)における試験において、 少なくとも常温で48か月の安定性が推定された。） Patented ​ PHBs (Polyhydroxybutyric acid) is patented. patent 7138391 Patent 6571298 ​Paper presentation In recent years,PHBs Researchers around the world are paying attention to its role as a prebiotic. Here are some of the papers published as the result of their research. Literature: Fernández J, Saettone P, Franchini MC, Villar CJ, Lombó F. Antitumor bioactivity and gut microbiota modulation of polyhydroxybutyrate (PHB) in a rat animal model for colorectal cancer. Int J Biol Macromol. 2022 Apr 1;203:638- 649. doi: 10.1016/j.ijbiomac.2022.01.112. Epub 2022 Jan 25. PMID: 35090944. Reference: Ma, N., Guo, P., Chen, J. et al. Poly-β-hydroxybutyrate alleviated diarrhea and colitis via Lactobacillus johnsonii biofilm-mediated maturation of sulfomucin. Sci. China Life Sci. (2022). //doi.org/10.1007/s11427-022-2213-6 Literature: Suzuki R, Mishima M, Nagane M, Mizugaki H, Suzuki T, Komuro M, Shimizu T, Fukuyama T, Takeda S, Ogata M, Miyamoto T, Aihara N, Kamiie J, Kamisuki S, Yokaryo H, Yamashita T, Satoh T. The novel sustained 3-hydroxybutyrate donor poly-D-3-hydroxybutyric acid prevents inflammatory bowel disease through upregulation of regulatory T-cells. FASEB J. 2023 Jan;37(1):e22708. Literature: Satoh T. New prebiotics by ketone donation. Trends Endocrinol Metab. 2023 Jul;34(7):414-425. doi: 10.1016/j.tem.2023.05.001. Epub 2023 Jun 2. PMID: 37271711. Trends in Endocrinology and Metabolism 2023 in press の 表紙に採用されたポリヒドロキシ酪酸と酪酸菌のイメージ図 【酪酸菌を活性化する次世代プレバイオティクスの論文発表 ジャーナル表紙に採用】として一部のニュースサイトで掲載されています ​★ミニ情報 １★ PHBが腸内細菌たちに届くと。。。 腸内細菌でエネルギー基質であるケトン体が放出され、腸内細菌叢で利用されます。 ​★ミニ情報 ２★ エネルギーが十分で腸内細菌たちが元気でいてくれれば。。。 ★ 好ましい割合の善玉菌を維持して腸内細菌叢の理想的な状態を保ち、良好な便通を保つことが可能になります 。 ★ 腸内細菌叢で短鎖脂肪酸や制御性T細胞の理想的な量を維持できるため、免疫力を保つことが可能になります。 ★ 脳腸相関により健康的な脳の状態を維持することが可能になります。 ★ 腸腎相関により健康的な腎臓の状態を維持することが可能になります。 ​ *PHB is planned to be sold as pet food, pet supplement, pet therapeutic food, or feed additive. Human approval is not currently available. シェア

Ketone bodies ​ and dementia brain and stress Nerve cells in the hippocampus of the brain are vulnerable to stress and are the first to degenerate under strong stress. This is why older people often develop dementia rapidly after traumatic events. Compounds that protect hippocampal neurons from oxidative stress have been extensively explored, as they are particularly vulnerable to reactive oxygen species. brain and drugs The following three conditions are necessary for the development of drugs targeting dementia. 1. to protect nerve cells. 2. transfer to the brain in sufficient quantity 3. No side effects. From the current level of science, condition 1 can be easily cleared. But 2 is a problem. It is said that most compounds have near zero penetration into the brain, and there is a clear physiological basis for this. This is because there are great challenges in getting drugs from outside the body into the brain. Even if it does pass, it is very small (a few percent at most). No matter what kind of excellent drug is developed, there remains the problem of how to send the drug to the brain at an effective concentration. However, ketone bodies are synthesized in the liver and can freely cross the blood-brain barrier. Therefore, it is far preferable to convert your body to the ketone body system and extend your healthy lifespan on your own. If the necessary amount of several mM (read as "millimol": unit of concentration) in the body can be easily achieved by restricting carbohydrates, it is better for (prevention of) dementia. increase. Ketone bodies and synapses Ketone bodies are not only energy substrates for nerve cells, but they also protect the nerves, promote synaptic regeneration in the brain, and maintain overall brain function. The action of ketone bodies is most effective at the "synapse" between nerve cells. Synapses play a similar role to semiconductors in computers. Just as the performance of semiconductors determines the performance of computers, the performance of synapses determines the performance of the brain. Ketone bodies can act directly on this synapse. When there is a certain level of electrical signal at the synapse, the electrical signal is transmitted across the synapse to the next nerve cell. The difference from semiconductors is that nerve cells are electrically insulated from each other. The transmission of information during this time is mediated by chemical substances called neurotransmitters, not by electrical energy. Because this substance is interposed, it is necessary to convert energy from electrical energy to chemical energy and from chemical energy to electrical energy. A large amount of energy is required for this energy conversion, and mitochondria are accumulated in synapses to cover that large amount of energy. Since mitochondria are the energy production factories of all cells, their concentration also means that there is a particularly high demand for energy in that location. Therefore, when nerve cells run out of energy, the synaptic function is the first to greatly decline. Synaptic transmission is not possible due to lack of energy. This is what is happening in neurons in the early stages of dementia. In the early stages of dementia, there are many neurons that are unable to perform synaptic transmission due to lack of energy, so ketone bodies are very useful for such neurons. If we can increase ketone bodies, we may be able to eliminate the energy shortage in nerve cells and alleviate the symptoms of dementia. Again, the great thing about ketone bodies is that they act directly on mitochondria, which are massively accumulated at synapses, to become energy substrates. In other words, it may be possible to solve the deterioration of synaptic function at once. Ketone bodies freely pass through the blood-brain barrier, pass through the cell membrane of nerve cells, reach the mitochondria of nerve cells, and become energy substrates. For the prevention of dementia, It seems that the liver should be in a state where it can synthesize ketone bodies in the body. Happiness substance serotonin and memory substance glutamate There are two neurotransmitters that play important roles in the brain. Serotonin and glutamate. Serotonin is called a “happiness substance” and is a neurotransmitter that is absolutely necessary for people to live life with a sense of happiness. If you don't have enough serotonin, you won't feel happy no matter what you do, and you tend to be negative about things. In other words, the possibility of becoming “depressed” increases. On the other hand, glutamate is called a "memory substance" and is a neurotransmitter that is absolutely necessary for remembering both the past and the present. If glutamate doesn't work properly, you can't remember what happened just a few seconds ago, or you'll go out and forget where you were and where you were going. Eventually you forget who you are. In other words, "dementia" ... Older Japanese now fear "dementia," while many younger Japanese suffer from "depression." These two brain diseases have something in common at the synaptic level. In other words, synaptic transmission fails due to lack of energy. It is said that neuronal cell death does not occur in the early stages of both depression and dementia. At the synapse, the energy produced by the mitochondria is in short supply. Since ketone bodies act directly on these mitochondria as energy substrates, it is thought that these two early pathological conditions can be greatly improved. In other words, if ketone bodies are continuously increased, the actions of serotonin and glutamic acid can continue to function normally, and it may be possible to greatly extend the healthy lifespan of the brain. Action on nerve cells I have seen that ketone bodies have the ability to solve the energy shortage of neuronal synapses at once, but why is that? This is because ketone bodies are better energy substrates than glucose. Compared to glucose, it has an overwhelmingly high energy efficiency, so to speak, it is a "super fuel". Glucose first enters the cytoplasm but is not completely oxidized, whereas ketone bodies enter the mitochondria directly and are completely oxidized. Therefore, the energy efficiency of ketone bodies is overwhelmingly high. In an experiment, when you add ketone bodies to nerve cells and observe the action of beta-hydroxybutyric acid, a compound of ketone bodies, on nerve cells, you will be amazed at the dramatic effects. Ketone bodies at 1 mM almost completely inhibited neuronal cell death caused by reactive oxygen species. This concentration of 1 mM is also a concentration that can be reached with daily carbohydrate restriction. “Restricting carbohydrates and increasing ketone bodies to 1 mM or more may prevent dementia.” ​. Finally, I will introduce the thesis. This is this year's (2020) paper on ketone bodies. ​ Experiments show that A beta (the causative substance of dementia) decreases when ketone bodies are applied to nerve cells. β-Hydroxybutyrate Ameliorates Aβ-Induced Downregulation of TrkA Expression by Inhibiting HDAC1/3 in SH-SY5Y Cells. 2020 Jan-Dec;35:1533317519883496. doi: 10.1177/1533317519883496. Epub 2019 Oct 24.PMID: 31648544 Free article. Tyrosine kinase receptor A (TrkA) plays an important role in the protection of cholinergic neurons in Alzheimer's disease (AD). This study was designed to investigate whether β-hydroxybutyrate (BHB), an endogenous histone deacetylase (HDAC) inhibitor, … The following paper is a famous paper that ketone bodies suppress HDAC and protect against oxidative stress. Suppression of Oxidative Stress by β-Hydroxybutyrate, an Endogenous Histone Deacetylase Inhibitor. Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, Newgard CB, Farese RV Jr, de Cabo R, Ulrich S, Akassoglou K, Verdin E . Science. 2013 Jan 11;339:211-214. In this study, we report that the ketone body β-hydroxybutyrate (βOHB) is an endogenous inhibitor of class I histone deacetylases (HDACs). Administering βOHB to mice or increasing endogenous βOHB by fasting or calorie restriction resulted in a global increase in histone acetylation in renal tissue. In addition, HDAC inhibition by βOHB increased the transcription of genes encoding oxidative stress resistance (FOXO3A, MT2, etc.). Addition of βOHB to HEK293 cells increased histone acetylation of the Foxo3a and Mt2 promoters, both of which gene expression was activated by selective deletion of HDAC1 and HDAC2. βOHB-treated mice showed resistance to oxidative stress (protein carbonylation by paraquat, etc.) along with increased FOXO3A and MT2 activity. [Conclusion] βOHB is an endogenous HDAC inhibitor, and when its concentration is increased by mM due to fasting or caloric restriction, it induces epigenetic changes (increase in histone acetylation) in tissues, resulting in the expression of oxidative stress resistance genes (Foxo3a, etc.). It has been clarified that increasing the oxidative stress resistance of living organisms is brought about. It has long been known that ketone body production by a low-carbohydrate diet confers resistance to neuronal oxidative stress damage (neuroprotective effect). The results of this study suggest that the effects of ketogenic diets and caloric restriction may be mediated by βOHB's HDAC-inhibiting effect.