When people begin to have a deeper understanding of intestinal health, probiotics become one of the most concerned raw materials in the market. Japan is the world’s most mature market for probiotics. Supermarkets and convenience stores are full of all kinds of probiotic products, from traditional dairy products to drinks, biscuits, jelly, candy and even instant noodles.
It is well known that probiotics, which are sensitive to high temperature and environment, have become sensitive to high temperature in vivo. How to maintain the viability and stability of the flora in the production process, and ultimately extend the shelf life of live bacteria products, has become an urgent problem for the industry. This also promoted the birth of the concept of inactivated probiotics, namely, postbiotics.
The question is, can inactive probiotics still have physiological effects? What is the attitude of industry and consumers towards it? Compared with active probiotics, what are its advantages? What challenges will be encountered in promoting the commercialization of epigenetics in China?
Seven years of hard work,
Epigenetics lead a new era of intestinal health
In 2013, Katerina tsilingiri, a Spaniard, formally put forward the concept of “postciotics”. In the following years, researchers from different countries have given various names to epigenetics: non viable probiotics, inactivated probiotics, non biotics, ghost probiotics, metaboitics, and parabiogenes. Up to now, there is no authoritative or official definition of epigenetic yuan. In 2019, Philippe Langella and Rebeca mart í n, two microbiologists from the University of Paris Thackeray in France, put forward a metabiotic definition that has been recognized by many academic colleagues: “bacterial body composition or microbial metabolites of microorganisms with biological activity”.
From the perspective of intestinal health, probiotics, prebiotics and epigenetics all play an important role in the human body. Metabiotics contain bioactive substances released by probiotics after lysis, such as phosphoparidic acid, peptidoglycan and its derived peptides, cell surface proteins, vitamins, short chain fatty acids, organic acids, cell-free supernatant and other nutrients. In view of this, the international academic community is increasingly interested in epigenetics. Since 2013, from in vitro experiments, animal experiments to clinical trials, the number of research projects involving epigenetics has increased rapidly.
Although compared with probiotics / prebiotics, both the starting time and the total number of papers, epigenetics are far behind, but they still show a huge charm that fascinates the academic and industrial circles.
Since 1970, the number of research papers on probiotics, prebiotics and epigenetics has been published worldwide. Source: int. J. mol. SCI. 2019, 20 (19), 4673
Due to the multiple components of epigenetics, the physiological mechanism is extremely complex. At present, the academic community tends to analyze the function of a single purified substance in epigenetics, such as surfactant protein. A large number of experiments have confirmed that it can be used as a biological agent to improve colitis for clinical treatment. Epigenetics have been found to play an important role in anti-inflammatory, intestinal barrier maintenance, obesity, immune regulation, hypertension, cardiovascular disease and cancer.
In terms of promoting the proliferation of probiotics, epigenetics also have excellent performance, without losing prebiotics. Taking “yijuzhi” developed by Jinqi biology as an example, four kinds of probiotics are better than breast milk oligosaccharides in terms of their proliferative effects.
“Yijuzhi” and milk oligosaccharides promote the growth of different probiotics. Photo source: Jinqi biology
In addition to physiological function studies, organic acids, cyclic dipeptides and bacteriocins have also been found to have potential applications in food preservation. Compared with synthetic products, these natural food preservatives have more advantages in safety. In addition, scientists have found that extracellular polymers in epigenetics can improve the flow characteristics of dairy products, such as viscosity and mellow feeling. Therefore, natural food additives based on epigenetics will greatly enrich the existing food ingredients system.
The physiological mechanism of epigenetics is illustrated. Source: microbialcell factories
Compared with active probiotics, what are the advantages of metabiotics? In general, epigenetics have clear chemical structure and safe dose parameters. Epigenetics have good absorption, metabolism and body distribution. Studies have shown that epigenetic components are easy to be absorbed by the intestinal tract, and metabolites released after cell wall breaking can directly contact with intestinal epithelial cells to enhance the utilization rate. In addition, epigenetics will not be interfered by antibiotics; extraction, transportation and storage are more convenient.
The use of metabiotics can not only obtain the similar probiotic effect of probiotics, but also avoid the problems of low bioavailability, unstable effect and easy transmission of drug-resistant genes. It is a new research direction in the field of probiotics in the future.
Photo source: Jinqi biology
Nowadays, the industry regards epigenetics as the fourth generation of intestinal microflora after probiotics, prebiotics and synbiotics, and “probiotics 4.0” has become a clarion call to encourage epigenetic research and industrialization.
Probiotics 1.0 to 4.0 era. Photo source: Jinqi biology
Different from the prosperity of academia, consumers show contradictory attitudes towards the new thing epigenetics. On the one hand, most people still believe that probiotics are the most important intestinal health factor, and 47% of Americans are more concerned about the number of live probiotics when they buy probiotic products. On the other hand, consumers are interested in the new concept of epigenetics. According to a survey conducted by Mintel in August 2019, the degree of global Internet users’ attention to probiotics, prebiotics and epigenetics through social media has increased compared with that in 2018. Among them, the attention to epigenetics has increased nearly twice.
In 2019, netizens’ attention to probiotics, prebiotics and epigenetics on social media has increased compared with that in 2018. Source: Mintel
The commercialization of overseas posterity a 6031
Supported by sufficient scientific research and clinical trials, epigenetics has been rapidly commercialized in recent years. Nutrition and health care products are the earliest experimental field developed by epigenetics in the field of food. From the invention patents related to epigenetics in the past three years, we can see that most epigenetics are used in pediatric nutrition, gastrointestinal disease treatment, lactose intolerance infant formula, weight loss functional food and other functional products except coffee.
The main form of epigenetic products is the drying and milling of mixed fermentation broth. At present, under the joint promotion of global food giants and life science research enterprises, a preliminary industrial chain has been formed.
The common production process of epigenetics. Photo source: Jinqi biology
(1) Driven by Cargill, ADM and DuPont, the US epigenetic food supplement market
Epigenetic products in the United States can be traced back to 1998 and developed by diamond V, the world’s largest manufacturer of microbial fermentation products. The company found that workers’ immune systems improved significantly due to frequent exposure to yeast fermentation on the production line. After repeated experiments, epigenetic preparation Epicor made from yeast fermentation broth was finally developed. The preparation contains dozens of compounds and metabolites and has been clinically proven to regulate intestinal flora and support the immune system. After ingestion of Epicor, it is absorbed into the intestine at a low dose of 500 mg per day in the human body without abdominal distension, a common side effect of prebiotic fiber intake.
Image source: embriah ealth
Epicor is stable to heat, extreme pH and pressure, and is now widely used in snack bars, chocolate, fudge and shot drinks. Although the raw material has a slight salty taste and brown appearance, these small defects can be well handled through clever formula design and processing technology.
Products with Epicor as the core functional component. Source: epicrimmum
After acquiring diamond V in 2017, Cargill continued to promote the commercialization of Epicor. In September 2019, Cargill set up the health technology department (CHT), focusing on epigenetic product development with Epicor as the core. In the three years since the acquisition, Epicor’s sales have grown at a compound annual rate of 67%. In February 2020, Cargill submitted a gras application to FDA, hoping to give Epicor an authoritative recognition of its safety, so that it can be marked as “(dry) yeast broth” or “yeast fermentation broth made from Saccharomyces cerevisiae” in the product ingredient list of adding Epicor.
Epicor has been developed for 20 years and has become a classic case of epigenetic commercialization in the United States. Encouraged by it, other food giants have also accelerated the pace of catching up in the field of epigenetics.
In 2019, ADM company developed Bifidobacterium lactis subsp. Lactis bpl-1, which is the world’s first epigenetic preparation for weight management. The strain is isolated from the feces of breast fed infants, which helps to reduce body fat, cholesterol content, antioxidation and inflammation. It can be used in food, beverage, dietary supplements and other products.
Application of bpl-1 epigenetic preparation in various products. Image source: ADM biopolis
In September this year, DuPont human microbiology venture capital and P & G jointly launched the NGPs project to jointly develop the next generation of probiotics for human health. It includes probiotics, prebiotics and epigenetics that explore great potential for probiotics. The probiotic products developed will focus on maternal and infant, intestinal, metabolic and brain health fields.
(2) Haoshi, Asahi and Riqing led the spread of Japanese epigenetic application to conventional food
As the most mature market for probiotics in the world, Japan also leads the world in the commercialization of epigenetics.
In 2018, the total market size of probiotic products in Japan reached 400 billion yen. Among them, about 75% are live bacteria products and 25% are dead bacteria (metabiotics) products. Due to the fierce competition in the market of live bacteria, more and more food and health products enterprises, especially the leading enterprises, have turned their attention to the epigenetic market with higher adaptability and low development level. In addition to the good food that has been deeply cultivated in the field of inactivated bacteria for many years, Senyong, Qilin, Guitian fruit making and other industry leaders have entered the Bureau, causing a boom in the development of epigenetics. The annual sales growth rate of several epigenetic raw materials suppliers has reached 10-30%. Even so, the demand for epigenetic raw materials is still in short supply.
Japan’s research on epigenetics can be traced back to the early 20th century. In 1914, Kotaro masakaki founded the Japanese Society of lactic acid bacteria. In 1940s, Zhengyuan Yiyi discovered the metabolites of lactic acid bacteria in his research. It was made from soybean or yoghurt, fermented by lactic acid bacteria and yeast, and then purified. This is the earliest prototype for the utilization of epigenetics.
Photo source: Koei- science.com
Up to now, the use of epigenetics in Japan has been very rich, including capsules, tablets, epigenetic liquid, health drinks and other forms, which can meet the daily needs of different groups of people.
In terms of epigenetic development and utilization, Japanese House food can be regarded as the pioneer of the industry. L-137 lactic acid bacteria is not only used in the production of traditional Lactobacillus drinks and yoghurt, but also used in curry, milkshakes and other products; there are not only products with added strains, but also powder suitable for normal temperature storage and can be directly served with water, so it has a wide range of applications.
Photo source: Haoshi official website
The research on l-137 Lactobacillus in Haoshi food began in the 1990s. At that time, Takeda food industry, the predecessor of Haoshi, found a unique lactic acid strain that could decompose starch, but other lactic acid strains did not. The researchers tried to add the strain to vegetable juice, sweet wine and pickled food, but none of them could improve the flavor of the products. At that time, Takeda food industry was developing food with immune function, so the physiological indexes of l-137 strain were compared with other lactic acid bacteria, and it was found that l-137 had a strong induction effect on the lymphokine interleukin-12 produced by immune cells. In the experiment, the researchers found that with the increase of the number of bacteria, the ability of the strain to induce the production of lymphokines will be weakened, so in order to ensure that the induction of the strain can be in the best state, the bacteria group was heat inactivated.
The results showed that the bacteria after heat treatment could not only adapt to normal temperature storage, but also less susceptible to the influence of digestive juice, and the enhancement effect of intestinal immunity did not decrease, but increased; the number of bacteria contained in 1g of inactivated lactic acid bacteria was also significantly higher than that of living bacteria, and all kinds of characteristics reflected that l-137 was a kind of lactic acid bacteria that could fully adapt to heat treatment.
Left: after heating, the effect of lactic acid bacteria on improving immunity is more significant. Right: compared with other lactic acid bacteria, l-137 is more effective in enhancing immunity. Photo source: Haoshi official website
After heat treatment, the effect of l-137 Lactobacillus in artificial intestinal fluid was better. Photo source: Haoshi official website
The health effects of l-137 were mainly reflected in the improvement of immune function, prevention of cold and improvement of periodontitis. It can also improve the feeding quality of livestock and aquatic products, and improve the disease resistance of animals. L-137 also has a promising application prospect in improving hyaluronic acid secretion of epidermal cells.
In addition to Haoshi, Japan’s other dairy giants have also joined the battle of epigenetic market. In April 2020, Asahi’s Calpis, the first functional product with epigenetic ingredients, was officially launched. The addition of 10-hoa, the metabolite of Lactobacillus amyloliquefaciens cp1563, which was developed exclusively, helps to reduce abdominal fat.
A lactobacillus beverage containing epigenetic component 10-hoa. Photo source: Yahoo! Japan
Compared with ordinary drinks, this lactobacillus beverage containing 10-hoa can significantly reduce abdominal fat area. Photo source: Calpis official website
Haoshi, Asahi and other companies mainly focus on the improvement of human health, while the latter developed by Riqing company has refreshing effect.
At the beginning of January 2019, Nissin launched the “ヒアルイスト発ヒアルイスト発発ヒアイスト発発ヒアルイスト発), which contains lactic acid strains. The amount of hyaluronic acid in a bottle of beverage is 5 times as much as that of the same kind of products. At the same time, with collagen, it is a representative new product of epigenetics in terms of beauty appeal. By July 2020, the product has won seven best beauty product awards, which can be called a black horse in the beauty beverage industry.
In addition, Guitian fruit processing has launched two kinds of epigenetics made of plant-derived lactic acid bacteria, which can inhibit skin dryness and improve immunity, and fight pollen allergy respectively; the epigenetics of IHM Co., Ltd. has the functions of anti-inflammatory, inhibiting tumor cell growth and preventing influenza; the metabiotics of BRM Co., Ltd. claims to be able to activate white blood cells, thus enhancing immunity.
Chinese epigenetic yuan,
A 6031 is born out of doubt and hindrance
Compared with probiotics and prebiotics, which have established a solid and healthy image, epigenetics is still too small and frontier in China. Among them, the misunderstanding of the efficacy of epigenetics and the lag of laws and regulations are the two obstacles that the epigenetics must face.
(1) Is it effective to live? Misunderstandings on metafunction cognition in China
Nowadays, people generally pursue “health” and “freshness”, and the concept of “activity” is particularly important for all kinds of products added with probiotics. With the continuous strengthening of advertising, the vast majority of consumers will think that “active probiotics are effective” and “living to the gut is the best”. Therefore, inactivated probiotics are incompatible with the mainstream concept.
Photo source: the skininginer
The advantages of metabiotics over probiotics have been described in detail. Here we will analyze the advantages of epigenetics from the perspective of quantity and security.
First of all, lactic acid bacteria cultured in suitable medium can be highly enriched after sterilization by heating. Generally, it is the technical limit to culture the living bacteria to 100 billion cells / g, while the inactivated lactic acid bacteria can reach 7 trillion cells / g. Obviously, adding a small amount of inactivated bacteria can absorb more bacteria.
Moreover, the effectiveness and safety has always been the focus of consumers.
Probiotics associated with intestinal tract are very sensitive to low temperature, high temperature, gastric acid, bile, dryness, oxygen and so on. They are easy to inactivate, and will continue to die during storage, transportation and shelf life. However, the probiotics remain inactivated. Compared with living bacteria, the storage life of inactivated bacteria can reach 2 years. Moreover, the inactivated bacteria no longer grow, and the pollution risk in the process of using is almost zero.
Adding epigenetics can avoid consumption disputes and lawsuits caused by unstable active ingredients and unreliable use effect of probiotics containing products, which is conducive to maintaining product image and corporate reputation.
Dr Mary Ellen Sanders, of Dairy & food culture technologies, said there was no difference in efficacy between inactivated and active probiotics in about 75% of the studies. About 40% of the comparison results showed that the effect of inactivated bacteria was better than that of placebo or live bacteria.
(2) The lag of laws and regulations and the backwardness of technology restrict the development
In 2001, China released the list of probiotics strains that can be used in health food and the list of fungal strains that can be used in health food. Since then, in 2010 and 2011, the list of probiotics that can be used in health food and the list of strains that can be used in infant and young children’s food were successively issued in 2010 and 2011. As of 2019, the edible species list contains 35 species or subspecies.
China’s current probiotic food management regulations and related technical specifications have been implemented for a long time, some provisions and requirements have been unable to adapt to the latest development of probiotics research, such as the application of inactivated bacteria and strain metabolites, there are no relevant provisions.
In terms of probiotic safety standards, due to the different provisions of probiotics in different countries, there is still a lack of unified probiotic safety evaluation methods and management requirements at the international level. In the world probiotics safety evaluation method, the author sorted out the safety evaluation methods of probiotics in vivo and in vitro in various countries. Although most probiotics are safe, there are still some deficiencies in the test of probiotics used in vivo and in special populations. In addition, the safety standard of probiotics is also lagging behind, which limits the commercial development of epigenetics.
At present, due to the limitation of technical level, most researches only focus on active substances such as proteins and polysaccharides, and fail to identify effectors with higher resolution. The key point of probiotics identification in the future is whether the probiotics can be separated and metabolized.
(3) Jinqi biology: a model of commercialization of epigenetics in China
Jinqi biological group is the largest R & D and production enterprise of epigenetic products in China. On November 2, at the 2020 China special food conference, with years of experience in probiotics technology reserve and development, Jinqi biology released the “totipro extract application program”, which triggered heated discussion in the industry.
Totipro extract strictly selects probiotics which have been proved to be effective by clinical human experiments, simulates human intestinal fermentation environment in vitro, optimizes culture conditions, and stimulates the secretion of bioactive factors. In addition, with Taiwan Food Industry Development Research Institute, it innovates and develops heat locking technology and multi-layer composite resistance micro profit technology to metabolize metabolizing metabiotics at specific growth time points of functional bacteria Since its launch in 2017, it has been applied to various functional foods, including instant brewing products, candy, flavor drinks, etc., to realize the daily life of nutrition products, and show the development strength of diversified products. It has been awarded the innovation category for 2 consecutive years The award was affirmed, and it was known as “a landmark product towards the era of probiotics 4.0”.
Totipro extract has been used in beverage, soup, candy, functional food and so on. Photo source: Jinqi biology
Totipro yicui has applied for 9 international patent applications, and its exclusive thermal latch technology won the 16th Taiwan Innovation Award.
In 2018, a well-known academic journal “trends in Food Science & Technology” published an article, which predicted that epigenetics / synbiotics would be the future stars of functional food.
On August 20 this year, the Chinese society of food science and technology released the “ten hot spots of probiotics scientific research” and “probiotics and metabiotics / analogs” ranked seventh.
Since the formal concept was put forward, the posterity yuan has just reached the age of seven. Although it does not have a unified definition and standard, but its extraordinary temperament makes the food industry see broad business opportunities. Epigenetics brings not only better and safer probiotic function solutions, but also a series of basic and applied sciences such as microbiology, nutrition, food processing technology, flavor texture adjustment technology, preservation technology and so on. Therefore, the dimension of food innovation will be greatly enriched.
No matter whether the public cognition can be updated or not, and whether food enterprises pay attention to it or not, the era of epigenetic has come quietly. What can we take to meet the new era?
Reference: editorial: next generation microbiology: from commercial bacterium to new drugs and food supplies. Front. Microbiol., 27 August, 2019
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