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The ingredients of
are extremely complex. In breast milk related to human health, oligosaccharides are the most remarkable active ingredients and a treasure to be explored!
Recently, DSM, a world-renowned supplier of HMOs, announced that the safety application for six HMOs synthetic strains submitted to relevant Chinese departments has been approved, which means an important step for HMOs to strive for compliance status in China. Godert zijlstra, global business director of DSM HMOs, said: in the future, it needs to accept the national food safety risk assessment center (CFSA) Technical review, public consultation, approval of the National Health Commission (NHC) and other cumbersome and complex steps.
Nevertheless, it is gratifying that the safety of this strain has been approved. DSM expects that it will take at least four years for HMOs to be commercialized in China. Many enterprises have long favored this huge market and have planned their layout ahead of time. It is reported that cohenson, a well-known ingredient enterprise, also sent a message this year that the approval process of HMOs produced by it is in progress in China and will continue in the future Permission is expected within two years.
Overseas, HMOs has become the most popular functional ingredient. Relevant research results emerge one after another, and the formula added with HMOs appears to be on the market on a large scale. What is the charm of HMOs, so that capital is willing to increase its weight and consumers are willing to pay for it? In the face of the blue ocean market full of opportunities and vast territory, how can players in various countries show their skills, seize the highland and create their own HMOs Kingdom? The rudiment of the current market pattern has emerged. Where will the next opportunity point of HMOs be?
Powerful health effects give birth to broad business opportunities
Dietary guidelines for Chinese residents (2016) It is clear that breast milk is the most ideal food for infants. Exclusive breastfeeding can satisfy all the liquid, energy and nutrients required by infants within 6 months of age. Besides, breast milk is beneficial to the establishment of intestinal healthy microenvironment and the maturation of intestinal function, and to reduce the risk of infection and allergy. The powerful health effect of breast milk is incomparable to formula milk powder. Infinitely close to the standard of breast milk has become the ultimate goal of the continuous iterative upgrading of formula milk. With the continuous evolution of modern analytical technology, the mystery of breast milk has been lifted layer by layer, and a large number of active families with amazing benefits – breast milk oligosaccharides have emerged in front of the world.
As early as 1886, Escherich, an Australian pediatrician and microbiologist, discovered that there was a link between bacteria in infant intestines and digestive function. In 1900, Moro and Tissier confirmed that there were differences in the composition of bacteria in the feces of breastfed and artificially fed infants respectively. Scientists therefore came up with a bold hypothesis: whether there were bacteria in breast milk that caused the imbalance of infant intestines What about the same ingredients? This hypothesis was confirmed in 1926. Sch ö nfeld found that the whey of breast milk contained a promoting factor to promote the growth of bifidobacteria. Due to the limitations of technology at that time, people could not determine the true identity of this promoting factor. Later, French scientists polonowski and lespagnol detected components with carbohydrate characteristics from breast milk whey It was not until 1954 that Gy ö rgy confirmed that the promoting factor for the growth of bifidobacteria was a class of oligosaccharides. In the same year, polonowski and Montreuil separated oligosaccharides from milk oligosaccharides by two-dimensional paper chromatography.
In 1983, egge et al. Confirmed HMOs by rapid atomic bombardment mass spectrometry. After 2000, a series of studies on HMOs analysis and function have developed rapidly. The latest research shows that different genetics, regions and environments will have an impact on HMOs, and HMOs in breast milk of different countries and ethnic groups have significant differences. The publication of this result also lays a foundation for the localized development of HMOs market in various countries Foreshadowing.
HMOs research process Source: ymini
Nowadays, the world has made it clear that HMOs is a kind of compound oligosaccharide, which exists in breast milk in free form, with a content of about 5-15g / L, second only to lactose and fat, and is the third largest nutritional component in breast milk. Breast milk oligosaccharides are generally polymerized from 3-9 monosaccharides, including D-glucose (GLC), D-galactose (Gal), N-acetylglucosamine (GlcNAc), L-fucose (fuc) and sialic acid (SIA). At present, more than 250 HMOs have been confirmed in human milk. The main research objects are 2 ‘- fucosyllactose (2’ – FL), 3-fucosyllactose (3-fl), lactose-n-tetraose (LNT), 3 ‘- salivary lactose (3’ – SL) and 6 ‘- salivary lactose (6’ – SL).
Composition of breast milk and HMOs Source: Kyowa Hakko bio
A large number of studies have confirmed that HMOs have the main functions of maintaining intestinal microecological balance, regulating immunity, preventing necrotizing enterocolitis, promoting brain development and reducing infection. Over the years, the physiological efficacy, extraction and preparation and commercial product development of HMOs have become the hot spots pursued by experts, scholars, food giants and capital giants.
Physiological function of HMOs. Source: ymini
No matter how effective the ingredients are, if they cannot reach mass production, their value will be greatly reduced. In general, global HMOs research has always kept pace in the two directions of efficacy exploration and production technology. The production technology of HMOs can be divided into natural extraction, chemical synthesis and microbial synthesis. HMOs content is very small, the cost of natural extraction is very high, and it is difficult to industrialization. Due to low efficiency, complex process and potential food safety hazards, chemical synthesis has great market limitations and general development prospects. The microbial synthesis technology based on bioengineering bacteria such as Escherichia coli and yeast is the most active field in the commercial practice of HMOs because of its advantages of low production cost and low environmental pollution.
HMO production model based on synthetic biology. Source: sciphi.cn
According to the breast milk oligosaccharide market report released by MarketWatch, the global market scale of HMO in 2018 was US $78.82 million, which will maintain a compound annual growth rate of 15.3% in the future and reach US $238.8 million in 2026. Among them, North America, as the main market position of HMOs, accounts for 70% of the global share.
The United States and Europe are the regions where HMOs were first commercialized. The most abundant 2 ‘- fl (2’ – fucosyllactose) in breast milk has been licensed by the US and Europe market regulation in 2014. Abbott launched infant formula containing 2 ‘- FL in 2016, becoming the “first enterprise to eat crab” in HMOs market. Nestle (Wyeth) followed suit and launched similar products in 2017. The European and American markets are more blooming, and the Asia Pacific region is also eager to try. The multinational regulatory authorities have issued relevant opinions on 2′-FL security. Singapore, Malaysia, Vietnam, Australia, New Zealand, Hongkong, China and Taiwan China have passed the 2’-FL regulatory approval and are gradually being applied to infant food. According to incomplete statistics, HMOs containing products have been produced and sold in 45 countries (regions) around the world since 2016.
Source: public information
In Chinese mainland, as early as 2016, the State Health Planning Commission has announced to the public that 2′-FL will be consulted as a new food additive. On October 21 this year, the national food safety risk assessment center again issued a document to solicit opinions from the whole society, and plans to expand the scope of use of 2 ‘- fl (synthetic method) from infant formula food to children’s milk powder. In combination with the recent year, several enterprises have submitted evaluation applications related to HMOs applications to government agencies, which makes it more obvious that HMOs has ushered in the dawn of compliance in the mainland.
In addition to the favorable policies successively issued to create a good market environment for HMOs, the “fuel” of commercialization promoters in various countries makes this HMOs fever continue to heat up all over the world.
1. Overseas players join the game and strive to deploy HMOs market strategy first
Throughout the world, there are no more than 20 manufacturers of HMOs, all of which expand their market territory by optimizing production technology, expanding production scale and production base.
Major foreign HMOs manufacturers. Source: CB insights
Glycosyn LLC is a biotechnology based therapeutic, diagnostic and dietary supplement company. Glycosyn has developed a special E. coli that can efficiently synthesize high-purity 2 ‘- FL for commercial use. The company also has patented technology to treat inflammatory bowel disease and irritable bowel syndrome with HMO and use HMOs as prebiotics. At present, glycosyn has cultivated production strains and fermentation / purification processes that can synthesize 15 neutral and acidic HMOs, some of which have reached or approached commercial standards. In addition, glycosyn’s laboratory is regularly producing a sufficient number of rare HMOs to support preclinical research on related nutrition and diseases, and provide a stable supply of raw materials for scientific research institutions, experts and scholars.
Schematic diagram of 2 ‘- FL / 3-fl produced by E. coli engineering bacteria. Source: ACS
In May 2019, glycosyn signed a cooperation agreement with BASF, a global chemical giant, to promote the development and commercialization of HMOs in the fields of dietary supplements, functional nutrition and medical food. According to the agreement, BASF will obtain an exclusive patent license for glycosyn’s intestinal health product portfolio outside the field of infant nutrition products.
Glycom, a biotechnology company based in Denmark, is the only HMOs supplier with full chain capabilities of product development, preclinical and clinical development, supervision and mass production.
The founders of glycom are five world-famous carbohydrate scientists, injecting strong scientific research strength into the enterprise. In 2005, glycom began to crack the complicated code behind HMOs, produced a large number of HMOs monomers for scientific research for the first time by reorganizing HMOs crystals through chemical synthesis technology, and carried out a large-scale clinical experiment of synthesizing HMOs in 2007. With the continuous upgrading and optimization of synthesis technology, glycom began to shift its focus from organic chemical synthesis to microbial fermentation, invested in the relevant research and development of “monosaccharide based, fucosyltransferase catalyzed synthesis of HMOs”, and invested a lot of money to build a world-class HMOs microbial fermentation production base, which was put into operation in 2017. At present, glycom has nearly 100 patents. In addition to HMOs synthesis patents, it also distributes the pharmaceutical and health industry.
Glycom invested 50 million euros to build HMOs manufacturing base. Source: European Biotechnology
On February 24, 2020, glycom was acquired by Royal DSM group of the Netherlands at a price of 765 million euros. With the addition of glycom, DSM further consolidated its dominant position in the field of nutrition and dietary supplement in the early stage of life. DSM currently has the production capacity of 10 HMOs, of which 6 have been put on the market, which can be regarded as the biggest promoter of HMOs commercialization.
（3） Jennewein Biotechnologie
Jennevein biotechnologie, a German biotechnology company, is also one of the pioneers in the field of biosynthetic HMO. In addition to six commercial HMOs products, it also has a complete product line, global customer base and intellectual property portfolio – more than 200 patents in major global markets. In the research and development of HMOs production technology, jennevein implanted a specific glycosyltransferase gene in E. coli to enable the bacteria to express complex milk oligosaccharides and produce a large amount of activated sugars as the starting material of HMO structure.
In September 2020, cohenson, the global leader in probiotic industry, which aims to strengthen its own microbial and fermentation technology platform and implement the “2025 strategy”, announced the acquisition of jennevein biotechnologie. Mauricio Graber, CEO of cohenson, said: “jennewein is the leader in the HMOs industry, and their products will be with our LGG ® And Bb-12 ® This acquisition will undoubtedly accelerate cohenson’s entry into the HMOs industry and become a leading player.
His eyes turned to the East. Among Asian enterprises participating in HMOs commercialization competition, Kirin company of Japan has become an important member of HMOs industrial chain by establishing production plants.
In November 2020, kylin holding subsidiary Xiehe fermentation biology announced that it would open a new plant in Thailand for HMOs manufacturing and production (put into use in the summer of 2022), which would be the world’s first HMO production system meeting industrial standards. The new plant can produce three kinds of microbial fermentation HMOs, namely 2 ‘- fl (2’ – fucosyllactose), 3’SL (3 ‘- sialic acid lactose) and 6’sl (6’ – sialic acid lactose). The annual production capacity is expected to reach 300 tons. In addition to the development of Concorde fermentation and other products of Kirin, the HMOs produced are also planned to be supplied to companies and scientific research institutions in need all over the world.
HMOs was produced by Kirin microbial fermentation. Photo source: Kirin
In addition to the above enterprises, conagen and prozyme, biotechnology companies from the United States and inbiose, a Belgian biotechnology company, have become important members of the global HMOs market with advanced HMOs production technology.
2. Domestic rising stars catch up and plan ahead for a potential market of 10 billion yuan
Cnr.com predicts that the market scale of Homs in China will reach 30-60 billion yuan in the next few years. Domestic enterprises have identified the huge business opportunities of HMOs and have already started the technical layout. Among them, Yixi biology and Henglu biology are the representatives.
In 2020, Yixi biological announced that HMOs would be put into production test at the end of the year and put into large-scale production in 2021. This move not only fills the gap in the domestic HMO market, but also makes Yixi biology the leading enterprise in the domestic HMOs industry. In terms of production technology, Yixi biology abandoned the traditional synthetic process, successfully integrated synthetic biology and artificial intelligence algorithms through independent research and development of genetically modified strain platform GMM, and changed the metabolic pathways of dozens of genes based on the “evolution base” research and development path of data strain prediction verification established by GMM platform, The whole metabolic pathway is modularized and integrated by machine learning, which greatly improves the production yield of 2 ‘- FL and reduces the production cost.
GMM platform independently developed by Yixi biology source: 36 krypton
In October 2020, the biotechnology service provider “Henglu biology” won the pre-A round of financing of tens of millions of yuan from Huayao capital. Founded in March 2018, Henglu biology specializes in the R & D, production and sales of sugars, marine biopeptides, special medical food and biomedicine. At the end of 2017, Professor Fang Xu, the founder and chief scientist of the company, led the team to successfully synthesize two HMOs by using the “biological enzymatic method” and “biocatalysis” technologies with independent intellectual property rights, using sucrose, glucose and lactose as substrates. The purity of purified oligosaccharides and their derivatives was more than 90%.
Source: chinanews.com Shandong
This innovative technology indicates that domestic enterprises will get rid of their long-term dependence on European and American suppliers in the field of HMOs. In the field of enzymatic biosynthesis of HMOs, China has been at the forefront of the world.
The health tide promotes market upgrading,
Where is the future of HMOs?
From a commercial perspective, the greatest value of HMOs is that it finds an excellent breakthrough for the upgrading of functional foods, including formula foods and special medical foods. From the pursuit of all natural ingredients and high freshness, to scientific and accurate formulas, and then to the introduction of scientifically verified functional components, the focus of food innovation has become increasingly scientific and professional, reflecting the rapid upgrading of people’s demands for health. With the excavation and research of active ingredients from animal milk becoming more and more mature and lack of follow-up, breast milk HMOs, which are far more complex than animal milk and have a low level of cognition, has become a treasure house for finding new power for functional food.
1. HMO leads the next round of innovation boom of formula milk powder
At present, the innovation hot spot of formula milk powder has moved from the macro nutritional composition distribution ratio to breast milk (such as the balanced allocation of whey protein and casein, minerals and vitamins, DHA / EPA and other unsaturated fatty acids), and towards the reproduction of micro components. This includes the “supplement” of many trace active ingredients, such as lactoferrin, OPO structural lipid, milk fat globule membrane, etc. As HMOs are recognized in terms of industrial feasibility (stable, high-yield, low-cost synthesis or separation and extraction process) and safety, it will continue to add new vitality to the formula.
First of all, there are thousands of oligosaccharides in breast milk. At present, more than 200 kinds of oligosaccharides have been determined, but only a few are really commercialized. In view of the unique role of these trace components in promoting the development of brain, nerve and immune system of infants (including patients with special diseases), HMOs will become the most important source of functional differentiation of formula milk powder.
Secondly, the research on the ethnic and regional characteristics of Chinese breast milk has been carried out for several years, and dairy enterprises represented by Yili and Feihe have accumulated a large amount of statistical data. These data have become an important basis for the design of localized formula, and HMOs has become one of the carriers reflecting regional characteristics.
Photo source: www.mr-gut.cn
For example, in September 2021, quantum hi tech biological (QHT) researchers found that Chinese mothers were less likely to secrete 2 ‘- fl than people in North and South America. Adding labels from HMOs of various countries can also reflect this problem. For example, according to the composition of oligosaccharides in European breast milk, the EFSA expert committee stipulates that the addition concentration of 2 ‘- FL is not higher than 1.2g/l; The Australian and New Zealand Food Standards Authority (FSANZ) stipulates that the addition concentration of 2 ‘- fl shall not exceed 2.4g/l.
At present, the main commercial territory of HMOs is still focused on infant formula. HMO has become an important fulcrum for milk powder enterprises to reflect differentiation on high-end product lines.
For example, Abbott launched Similac Pro advance containing 2 ‘- fl as early as 2016 to improve infant immune support by activating immune cells to release protective proteins. Soon after, a liquid formula containing 2 ‘- fl was introduced. In November this year, Abbott launched Similac 360 total care containing five HMOs (2 ‘- FL, 3-fl, 3’ – SL, 6 ‘- SL and LNT), covering three categories: fucosylation, sialylation and acetylation. It is the latest formula to receive breast milk ingredients on the market.
Nan OPTIPRO supreme series milk powder containing two HMOs launched by Nestle in Germany in 2017; Wyeth illuma and Garbo have launched different forms of HMO formula supplemented by DHA, probiotics, OPO, phospholipids and other functional ingredients.
Wyeth UK brand SMA ® Advanced first infinite milk. Source: Wyeth official website
2. Assist in the research of adult functional food, and the commercial value of HMO continues to expand
From the perspective of biological evolution, HMO is mainly to help infants establish their own intestinal microecology, immune system and maintain normal brain development. However, with more studies on adults, the value of HMO in the development of adult functional food has become increasingly prominent.
The latest research in Finland shows that Streptococcus mutans, one of the important bacteria causing dental caries, cannot proliferate in the environment containing 2 ‘- FL, and HMOs has become one of the key factors for breast milk to prevent dental caries. It is reported that based on this result, DuPont is conducting an in-depth study on the potential of HMO for the prevention and control of dental caries.
BASF is committed to the correlation between HMO and the changes of intestinal microbiota involved in weight control. The results show that 2 ‘- fl can prevent weight gain, obesity and hyperphagia caused by intestinal brain axis dysfunction. In the future, HMOs is expected to play an eye-catching role in weight management and weight loss products.
In July 2020, standard process, an American nutrition company with a history of nearly 100 years, launched the first dietary supplement containing 2 ‘- fl. 2’ – FL, together with beetroot and okra, increased the abundance of bifidobacteria in the intestine and improved the health of adult digestive and immune system. The launch of this product marks the formal expansion of functional foods containing HMOs to the adult field.
Source: standard process of central Texas Facebook
Dr. Sara moukarcel of the school of Health Sciences at the University of California, San Diego, who has been committed to HMO research, believes that the human body’s resistance mechanism to pathogens and chronic diseases is similar in infancy and adulthood. The physiological effects of HMO in infant formula inspire us to find more examples in adults. HMO clinical research on adults is expected to reach definite conclusions and enter the stage of commercialization within 5 years. They can treat obesity, Crohn’s disease, cardiovascular disease, and even the outbreak of bacterial infections such as norovirus.
Pathogens are described as binding to HMOs rather than human receptors.
Source: nutrition insight
Of course, for adults, the intake form and dosage of HMO need to be accurately studied.
Throughout the world, the research on HMO has become a prairie fire in academia and industry. In the future, at the technical level, HMOs research will focus on: 1. More accurate and efficient molecular structure identification technology; 2. Higher yield microbial synthesis technology; 3. Safe purification technology of HMO monomer from mixture; 4. Study on the efficacy correlation of physiological demands of different populations.
At the commercial level, on the one hand, designing competitive packaged food and actively promoting the regulatory approval process will provide landing support for HMO to the public as soon as possible.
Over the past five years, with the continuous innovation of formula containing HMO, people have become more and more interested in this mysterious ingredient. Although only a few HMOs have been commercialized and the category forms are also concentrated on formula milk, foodaily firmly believes that HMO will eventually lead the next upsurge of functional food after witnessing the active investment of various enterprises and research institutions at home and abroad in HMO research!
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