Carbohydrate restriction and ketone bodies There are two things you can do to keep your ketones consistently high: 1) Fasting 2) Limit carbohydrates The physiological basis for these two to increase ketone body concentrations is It's all about not inducing blood sugar spikes. Why would suppressing blood sugar spikes lead to a constant increase in ketone body levels? For this you need to understand the hormone "insulin". Insulin secretion is induced by a blood sugar spike, causing a phenomenon called an insulin spike. When an insulin spike occurs, all the enzymes that synthesize ketone bodies are suppressed, and all the ketone body synthesis systems are shut out. normal diet (about60 % carbohydrates), ketone bodies are unlikely to increase. sugar if possible30-40% If you eat a diet that is suppressed to0.2~0.3 I think it goes up to about millimoles. Also, it is said that you can expect various effects of ketone bodies to some extent.

chocolate pudding recipe Ally of carbohydrate restriction Low sugar sweets chocolate pudding RECIPE * 1 can of coconut milk (400g) *A little less than 1g of powdered agar (around 0.8g) (For gelatin, 6 g → Soak in water and mix at the end.) * Sweetener 25g → Lakanto or coconut sugar (8 g for stevia) ＊Black cocoa 25g ***Add a little whiskey, rum, etc. for flavor. ~Precautions during cooking: Be sure to stay by your side so that it doesn't boil over~ ① Pour coconut milk into a small pan, sprinkle agar powder, Cook over medium-low heat, stirring occasionally. (Stay close so it doesn't squirt!) Add sweetener halfway through. ② When it boils, turn off the heat and strain the cocoa. (Miso strainer is convenient!) Let it rest for about 2 minutes on the lowest heat, stirring occasionally. ③ Turn off the heat and leave it for about 10 minutes. (To prevent burns...) → Transfer to a bowl while straining. How to make ① How to make ② ④ Divide into 5-6 cups before it cools down. ⑤ After it cools further, chill it in the refrigerator for about an hour. (Make a bamboo skewer between the cup and the pudding and then put it on the plate.) *** If you use 35 g of cocoa, it's more like a chocolate pudding. It will make a rich chocolate mousse. ＊＊＊＊ *** Substitute 13 g of matcha for a rich matcha mousse instead of cocoa. Topped with sweet red bean paste. . . ＊＊＊＊ Coconut milk is the source of MCT oil, Because it contains a large amount of medium-chain fatty acids, it can easily be used as an energy source, and can also be expected to increase ketone bodies. On top of that, as long as it contains minerals such as potassium and magnesium, as well as vitamin E and vitamin C! _cc781905-5cde-3194-bb 3b-136bad5cf58d_ just at once Please don't eat too much! ONE POINT Take a break! for the time of bittersweet

beyond science High Purity-PHB About (polyhydroxybutyric acid) The PHB provided by Beyond Science is the highest level in the world. PHB is now produced in many countries around the world. However, there are a limited number of companies and countries that can produce high-quality and highly safe PHB that can be used in pet food. PHB handled by Beyond Science , Produced in the world's top-level PHB laboratory. ～ History of high-purity PHB ~ Invention [Delivering ketone bodies to intestinal bacteria] ketobiotics is a rough definition of About six years ago, a Japanese researcher, Mr. S, who was researching ketone bodies, discovered it and named it as a new prebiotic. Mr. S said, ``This will surely be useful for mammals. ’ thought. Already then, ``it is only possible with very pure PHB. I was secretly aware of that. but, PHB is "safe enough for mammals to eat and has little off-taste" companies that deal with couldn't find it no matter how much I searched. At that time, the manufacturing technology/know-how itself There were several research institutes and companies that had Unfortunately, it was far from practical for practical use. First, high-purity PHB was too expensive. In addition, unfortunately, the place with equipment that can mass-produce enough to be released as a product domestically there wasn't one. However, Mr. S did not give up, and next Of overseas I kept looking, turning to the institutes and laboratories. and finally Researching high-purity PHB there is Institute with researchers I immediately contacted him and visited him without delay. When I met him, Mr. G was surprisingly a very friendly person despite being in a high position as a researcher. At the same time, however, Mr. S quickly discovered that he was very intelligent and an outstanding researcher. When I talked to Mr. G himself, the developer, "The hidden potential of high-purity PHB" for As expected I had already noticed. It didn't take long for the two to come to terms. the hidden potential talk about for a while They say they didn't run out. in this way Thanks to the miraculous exchanges between these researchers, it is now possible to release high-quality PHBs into the world. Research (world-class laboratories) the Research to realize "high-purity PHB" is Mr. G I went to study abroad in Europe and went there with my friends for more than 10 years. Laboratory after returning to Japan To Together with a group of bright young people, it has been studied for many more years and continues to this day. Manufacture (equipment with advanced technology) The PHB handled by Beyond Science is Specially manufactured in high-tech equipment commissioned by Mr. G's lab. Thorough hygiene control and high In equipment with technology, specially manufactured It is a thing. 《 Photo of highly purified PHB 》 Texture unimaginable with conventional PHB detail. Conventionally, the powder is coarser and has a lot of miscellaneous tastes, In terms of safety, There were various problems for mammals to eat. Only natural products can be refined to this extent thanks to advanced research and advanced technology. , and special equipment It is because of 《 ISO9001取得 》 国際標準化機構 (ISO) による品質マネジメントシステム に関する規格の認証を得た設備で製造しています。 シェア

安全性試験 ペットフード安全性検査　合格 PHB（ポリヒドロキシ酪酸） 安全性試験の結果 急性毒性・亜急性毒性検査　所見なし（合格） ポリヒドリキシ酪酸 2%混合ペレット飼料： ラットへの試食による 単回経口投与毒性試験【急性毒性試験】 試験結果 死亡はみられず、最小致死量は雌雄ともに5000 mg/kgを上回ると推定された。 雌雄ともにいずれ にも一般状態の異常はみられなかった。 雌雄ともに被験物質投与による体重への影響はみられなかった。 ※本試験は以 下のガイドラインに準拠して実施した。 • 「動物の愛護及び管理に関する法律」 • 「実験動物の飼養及び保管並びに苦痛の軽減に関する基準」 • 「動物実験の適正な実施に向けたガイドライン」 ※ 本試験は動物実験委員会（IACUC）の承認を受けて実施した。 ポリヒドリキシ酪酸 2%混合ペレット飼料： ラットへの試食による 4 週間混餌投与毒性試験【亜急性毒性試験】 試験結果 一般状態　　　　一般状態の異常はみられなかった。 体重　　　　　　体重への影響はみられなかった。 摂餌量　　　　　摂餌量への影響はみられなかった。 尿検査（摂水量測定含む）　被験物質投与による影響はみられなかった。 血液学検査 　　　　　　　被験物質投与による影響はみられなかった。 血液化学検査　　　　　　被験物質投与による影響はみられなかった。 器官重量 　　　　　　　被験物質投与による影響はみられなかった。 病理組織学検査　　　　被験物質投与に起因する変化はみられなかった。 小核試験 　　　　　被験物質投与群のPCE2000個中に占めるMNPCEの出現頻度は3 ± 2であった。こ の値は対照群の値に 統計学的に有意な増加を示さなかった。 本試験条件下では 被験物質の染色体異常誘発能は陰性と判定した。 PHB(ポリヒドロキシ酪酸) 　　安定性試験（加速試験） の結果

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 a ketone donor? To better understand ketone donors, let us first define the concept of "degree of polymerization (N)". "Degree of polymerization" refers to how many ketone bodies (or equivalents) are contained in the molecule, That's what it means. N=1 means ketone body (3R-hydroxybutyric acid) itself. Ketone bodies alone are strong acids (like acetic acid), so sodium salts of ketone bodies are used. It has too much of a peculiar flavor to eat. Therefore, free ketone bodies are rarely used, A compound obtained by neutralizing ketone bodies with sodium hydroxide may be used. Next is the ketone ester (N=2), which is an ester of a ketone body and an alcohol. The beauty of this is that it is hydrolyzed by mammalian digestive enzymes. In other words, when ketone esters are eaten, they are immediately hydrolyzed in the small intestine, and ketone bodies can be rapidly increased. It is used in certain places such as among athletes (mostly in the research stage), but it is characterized by a unique taste (flavor like glue). In contrast, PHB / polyhydroxybutyric acid (N > 1000) is not hydrolyzed by mammalian enzymes, but is hydrolyzed by intestinal bacterial enzymes. In this case, it is conceivable that a constant ketone body concentration will persist. Although it has not yet been approved for humans, it is expected to be used to maintain the health of pets and industrial animals. Classification of ketone donors The criteria for classifying ketone donors is how many ketone bodies are released. It is indicated by the value of the degree of polymerization N. Ketone bodies release 1 ketone body itself. →→ N=1 A ketone ester is one ketone body and one equivalent. →→ N=2 Oxidized in the body to ketone bodies. PHB is a polymer in which 1000 or more ketone bodies are ester-bonded. →→ N>1000 It is broken down by intestinal bacteria and gradually released into ketone bodies. It allows you to maintain a constant ketone body concentration. "Ketone Donor 1: Ketone Body Salt" Ketone bodies (chemical formula 1), also called 3-beta-hydroxybutyrate, are organic acids and one of the most important energy substrates. Since ketone bodies are weak acids as weak as acetic acid, they are usually used as sodium or arginine salts. These salts readily ionize in aqueous solutions. Ketone bodies mostly exist as ions in the weakly alkaline environment of the small intestine and are readily and rapidly absorbed into the body via specific monocarboxylic acid transporters. However, eating ketone bodies by themselves is not a good idea. A single ketone body is a strong acid, and it is impossible to eat several tens of grams of it as it is because of its strong stimulation. Ketone salts (eg, sodium salts) can be eaten up to tens of grams, but sodium loading becomes a problem. In general, ketone bodies are very hydrophilic and are very difficult to precipitate, requiring know-how to precipitate salts, and high-purity products are said to be expensive. "Ketone Body Absorption Mechanism" In order to increase blood ketone body concentration, ketone bodies themselves may be orally administered. In this case, since the ketone body itself is acidic, a sodium salt or the like of the ketone body is used. Ketone body salts become free acids in the acidic environment of the stomach and are transported into the body by a specific transporter (monocarboxylic acid transporter) in the epithelium of the small intestine. To increase. "Ketone Donor 2: Ketone Ester" The formal name of the ketone ester (chemical formula 2) is 3-hydroxybutyl-3-hydroxybutyrate, which is a synthetic compound in which the ketone body of an organic acid having a carboxylic acid and an alcohol are ester-bonded. Since this ester bond is rapidly decomposed by esterase in the small intestine, the ketone body ionizes and exists in the form of an anion in the small intestine, which is in a weakly alkaline environment. Like ketone bodies, it is readily absorbed by the body via specific monocarboxylic acid transporters. Also, the ester-bonded alcohol is oxidized to a carboxylic acid and converted to a ketone body. Since the sodium salt of ketone bodies poses a problem of sodium loading, arginine salts and the like have been devised, but there are problems such as further increase in cost. To solve this problem, ketone esters were devised. A ketone ester is a form of an ester bond between a ketone body and 1,3-butanediol. It is broken down by digestive enzymes in the small intestine to produce ketone bodies. Ketone bodies are absorbed by specific transporters in the small intestinal epithelium and exert various health functions. "Absorption Mechanism of Ketone Esters" Mammals also have enzymes that hydrolyze the ester bond of ketone esters, and they can rapidly (within minutes) produce ketone bodies in high concentrations. Ketone esters are broken down by digestive enzymes in the small intestine to produce ketone bodies. Ketone bodies are absorbed by a specific transporter (monocarboxylic acid transporter) in the small intestinal epithelium, rapidly increasing the concentration of ketone bodies. Like ketone body salts, ketone esters also have an immediate effect, increasing the blood ketone body concentration to several mM in several minutes. "Ketone donor 3:PHB" PHBs (Polyhydroxybutyrate) is a compound in which a ketone body is polymerized by an ester bond (average degree of polymerization: about 2000), and this ester bond cannot be hydrolyzed by mammalian esterases.PHBs can be hydrolyzed by only some intestinal bacteria, which makes it behave differently than other ketone donors. In addition, whereas ketone bodies and ketone esters are highly hydrophilic,PHBs One of the characteristics is that the hydrophilicity is extremely low. "PHB absorption mechanism" PHB is decomposed into ketone bodies by the lipase of intestinal bacteria in the large intestine, absorbed from the large intestine epithelium of animals, and has the effect of contributing to the maintenance of ketone body concentration. シェア

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

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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

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

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.

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.