Probiotics are not old, postbiotics have already arrived.

The postbiotic era is quietly approaching. With the advancement of the commercialization process, how much transformation and business opportunities will it bring to the food industry?Postbiotics商业化进程的推进，它将给食品产业带来多少变革与商机？

Written by: Lucy, Elva, Clara

Source: Foodaily Daily Food (ID: foodaily)

 

As people begin to have a deeper understanding of gut health, probiotics have become one of the most关注的原料 in the market. Japan is the most mature market for probiotics globally, with supermarkets and convenience stores filled with various probiotic-containing products, ranging from traditional dairy products to beverages, biscuits, jellies, candies, and even instant noodles.

 

It is well known that probiotics are sensitive to and tolerant of high temperatures, gastric acid, bile, and other internal environments, which has become an obstacle to expanding their applications.How to maintain the survival ability and stability of the microbial community during the production process, ultimately extending the shelf life of live bacterial products, has become a pressing issue for the industry.This has also led to the birth of the concept of inactivated probiotics, namely postbiotics.

 

The question arises: can inactive probiotics still exert physiological effects? What is the attitude of the industry and consumers towards it? What advantages does it have compared to active probiotics? What challenges will the domestic commercialization of postbiotics encounter?

 

 01. Seven years of honing, postbiotics lead a new era of gut health.

2013In 2013, Spanish researcher Katerina Tsilingiri officially proposed the concept of 'postbiotics'. In the following years, researchers from different countries have given postbiotics a variety of names: non-viable probiotics, inactivated probiotics, non-biotics, ghost probiotics, metabiotics, and parabiotics, among others. To this day, postbiotics have not yet received an authoritative or official definition. In 2019, two microbiologists from Paris-Saclay University in France, Philippe Langella and Rebeca Martín, proposed a definition of postbiotics that many in the academic community agree with: 'the bacterial components or microbial metabolites of microorganisms that have biological activity.'.

 

From the perspective of gut health, probiotics, prebiotics, and postbiotics all play important roles in the human body. Postbiotics contain bioactive substances released from probiotics after lysis, such as: peptidoglycan, derived peptides, cell surface proteins, vitamins, short-chain fatty acids, organic acids, and acellular supernatants. In light of this, international academia's interest in postbiotics is increasing day by day. Since 2013, the number of research projects involving postbiotics has shown rapid growth, from in vitro experiments to animal experiments and clinical trials.

 

Although postbiotics are far behind probiotics/prebiotics in terms of both starting time and total number of papers, they still exhibit enormous charm that captivates both academia and industry.

 

Since 1970, the global number of research papers published on probiotics, prebiotics, and postbiotics has been counted.Image source: Int. J. Mol. Sci. 2019, 20(19), 4673

 

Due to the multiple components contained in postbiotics, the physiological mechanisms are exceptionally complex. Currently, academia tends to conduct functional analyses on single purified substances within postbiotics, such as surfactant proteins, with numerous experiments confirming that they can serve as biological agents to improve colitis for clinical treatment. It has been found thatpostbiotics have effects on anti-inflammation, maintaining gut barrier, obesity, immune regulation, hypertension, cardiovascular diseases, and cancer..

 

In promoting the proliferation of probiotics, postbiotics also perform excellently, rivaling prebiotics. For example, the 'Yicui Quality' developed by Jinqi Biotechnology shows that for the proliferation of five different probiotic strains, four of them significantly outperform human milk oligosaccharides.

 

'Yicui Quality' compared to human milk oligosaccharides in promoting the growth of different probiotic strains.Image source: Jinqi Biotechnology

 

In addition to physiological function research,compounds such as organic acids, cyclic dipeptides, and bacteriocin-like substances have also been found to have potential applications in food preservation.Compared to synthetic substances, these naturally sourced food preservatives have advantages in safety. In addition, scientists have found thatthe extracellular polymers in postbiotics can improve the flow properties of dairy products,such as viscosity and mouthfeel. Therefore, natural food additives based on postbiotics will greatly enrich the existing food ingredient system.

Illustration of the physiological action mechanism of postbiotics. Image source: Microbial Cell Factories

 

What advantages do postbiotics have compared to active probiotics? Overall, postbiotics have clear chemical structures and safe dosage parameters. Postbiotics exhibit good absorption, metabolism, and distribution in the body. Research shows that postbiotic components are easily absorbed by the intestines, and the metabolites released after the bacterial cell wall is broken can directly contact the intestinal epithelial cells, enhancing utilization. For populations susceptible to live bacterial infections, there is no risk of the microbial community migrating from the intestinal cavity to the bloodstream; in addition, postbiotics are not affected by antibiotics; extraction, transportation, and storage are also more convenient.

 

Using postbiotics can achieve probiotic-like benefits while avoiding issues such as low bioavailability, unstable effects, and easy transmission of antibiotic resistance genes associated with live bacteria, marking a new direction for future research in the field of probiotics.

Image source: Jinqi Biotechnology

 

Today, the industry views postbiotics as the fourth generation of gut microbiota following probiotics, prebiotics, and synbiotics, with 'Probiotics 4.0' becoming a resounding call to action for postbiotic research and commercialization.

 

The era of probiotics from 1.0 to 4.0. Image source: Jinqi Biotechnology

 

Unlike the flourishing scene in academia, consumers show a contradictory attitude towards postbiotics, a new concept. On one hand, most people still believe that probiotics are the most important factor for gut health, with 47% of Americans being more concerned about the number of live bacteria when purchasing probiotic products. On the other hand, consumers are sufficiently interested in the new concept of postbiotics. According to a survey conducted by Mintel in August 2019, the level of attention global internet users pay to probiotics, prebiotics, and postbiotics on social media has increased compared to 2018, with the attention to postbiotics nearly doubling.

2019In the year, internet users' attention to probiotics, prebiotics, and postbiotics on social media has increased compared to 2018. Image source: Mintel

 

 02. The commercialization path of postbiotics overseas

Supported by sufficient scientific research and clinical trials, postbiotics have rapidly moved towards commercialization in recent years. Nutritional supplements are the earliest testing ground for postbiotics in the food sector. From the past three years of invention patents related to postbiotics, we can see that, apart from coffee, postbiotics are mostly used in functional products such as pediatric nutrition, gastrointestinal disease treatment, lactose-intolerant infant formula, and weight loss functional foods.

 

The main form of postbiotic products is generally a mixed fermentation liquid that is dried and powdered. Currently, with the joint promotion of global food giants and life science research companies, an initial industrial chain has taken shape.

Common production processes for postbiotics. Image source: Jinqi Bio

 

(1) Under the promotion of Cargill, ADM, and DuPont, the U.S. postbiotic market is making strides in dietary supplements.

 

The earliest postbiotic products in the U.S. can be traced back to 1998, developed by DiamondV, the world's largest manufacturer of microbial fermentation products. The company found that workers' immune systems significantly improved due to frequent contact with yeast fermentation products on the production line. After repeated experiments, they finally developed the postbiotic preparation EpiCor made from yeast fermentation liquid. The preparation contains dozens of compounds and metabolites, clinically proven to regulate gut microbiota and support the immune system. After ingestion, EpiCor is absorbed in the gut at a low dose of 500 mg per day, without causing the common side effect of bloating associated with the intake of prebiotic fibers.

Image source: embriahealth

 

EpiCorIt is stable to heat, extreme pH environments, and pressure, and is now widely used in snack bars, chocolate, gummies, and shot-type beverages. Although this ingredient has a slight salty taste and a brown appearance, these minor flaws can be well managed through clever formulation design and processing technology.

Products with EpiCor as the core functional ingredient. Material source: epicorimmune

 

2017After Cargill acquired Diamond V, it continued to promote the commercialization process of EpiCor. In September 2019, Cargill established the Health Technology Department (CHT), focusing on the development of postbiotic products centered around EpiCor. In the three years since the acquisition, EpiCor's sales performance has achieved a compound annual growth rate of 67%. In February 2020, Cargill submitted a GRAS application to the FDA, hoping to gain authoritative recognition of EpiCor's safety, allowing it to be listed as "(dry) yeast fermentation liquid" or "yeast fermentation liquid made from brewing yeast" in product ingredient lists.

 

EpiCorAfter 20 years of development, it has become a classic case of postbiotic commercialization in the U.S. Inspired by it, other food giants have also accelerated their pace in the field of postbiotics.

 

2019In the year, ADM developed the Lactobacillus bifidum subspecies BPL-1, the world's first postbiotic preparation aimed at weight management. This strain was isolated from the feces of breastfed infants and helps reduce body fat, lower cholesterol levels, provide antioxidant effects, and reduce inflammation. It can be used in various product forms, including food, beverages, and dietary supplements.

BPL-1The application of postbiotic preparations in various products. Image source: ADM Biopolis

 

In September of this year, DuPont's Human Microbiome Venture and Procter & Gamble jointly launched the NGPs project to develop the next generation of probiotics for human health, including exploring probiotics, prebiotics, and postbiotics with huge potential. The developed probiotic products will focus on maternal and infant health, gut health, metabolic health, and brain health.

 

(2) House Foods, Asahi, and Nissin lead the way, as Japan's postbiotic applications spread to conventional foods.

 

As the most mature market for probiotic development globally, Japan also leads the way in postbiotic commercialization.

 

2018In the year, 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 (postbiotics) products. Due to fierce competition in the live bacteria market, in recent years, more food and health product companies, especially leading enterprises, have turned their attention to the postbiotic market, which has higher adaptability and is still in the early stages of development. In addition to House Foods, which has long been engaged in the field of inactivated bacteria, industry leaders such as Morinaga, Kirin, and Kameda Seika have also entered the market, triggering a postbiotic development boom. Several postbiotic raw material suppliers have seen annual sales growth rates of 10-30%, yet postbiotic raw materials remain in short supply.

 

Japan's research on postbiotics can be traced back to the early 20th century. In 1914, Taro Masakaki founded the Japanese Society of Lactic Acid Bacteria. In the 1940s, Kazuyoshi Masakaki discovered lactic acid bacterial metabolites in his research, which were made from soybeans or yogurt through co-fermentation with lactic acid bacteria and yeast, and then purified, representing the earliest form of postbiotic utilization.

Image source: koei-science.com

 

To this day, the forms of postbiotic utilization in Japan have become very diverse, including capsules, tablets, postbiotic concentrates, health drinks, and various other forms, meeting the daily needs of different populations.

 

In the development and utilization of postbiotics, House Foods can be considered a pioneer in the industry. The core strain L-137 lactic acid bacteria is not only used in traditional lactic acid bacteria drinks and yogurt production but also applied in various products such as curry and milkshakes; there are not only products with added strains but also powders suitable for room temperature storage that can be taken directly with water, making the application range very broad.

Image source: House Foods official website

 

The research on L-137 lactic acid bacteria by House Foods began in the 1990s. At that time, the predecessor of House Foods, Takeda Food Industry, discovered a unique strain of lactic acid bacteria that could break down starch, a characteristic not found in other strains. Researchers attempted to add this strain to vegetable juices, sweet sake, and pickled foods, but it did not improve the flavor of the products as expected. At that time, Takeda Food Industry was developing immune-boosting foods, so in experiments, they compared the physiological indicators of the L-137 strain with other lactic acid bacteria and ultimately found that it had a strong inducing effect on the lymphocyte factor—interleukin-12 produced by immune cells. During the experiments, researchers found that as the number of bacteria increased, the strain's ability to induce lymphocyte production weakened. Therefore, to ensure that the strain's induction ability remained optimal, the bacterial population was heat-inactivated.

 

Experiments showed that the heat-treated bacterial population not only adapted to storage at room temperature but was also less affected by digestive juices, resulting in an enhanced effect on small intestine immunity; the number of bacterial cells in 1g of inactivated lactic acid bacteria was also significantly higher than that of live bacteria, reflecting that L-137 is a strain of lactic acid bacteria that can fully adapt to heat treatment.

Left image: The immune-boosting effect of lactic acid bacteria after heating is more significant. Right image: The immune-boosting effect of the L-137 strain is stronger compared to other lactic acid bacteria. Image source: House Foods official website.

 

After heat treatment, L-137 lactic acid bacteria showed better immune-boosting effects in artificial intestinal fluid. Image source: House Foods official website.

 

L-137The health benefits of the strain are mainly reflected in the increase of immune function, prevention of colds, and improvement of periodontal inflammation. It can also improve the breeding quality of livestock and aquatic products and enhance animals' disease resistance. L-137 also has promising application prospects in improving the secretion of hyaluronic acid by epidermal cells.

 

In addition to House Foods, other Japanese dairy giants have also joined the competition in the postbiotics market. In April 2020, Asahi's Calpis launched its first functional product using postbiotic ingredients, "Karada Calpis." The product includes the metabolic product 10-HOA from the exclusive strain Lactobacillus plantarum CP1563, which helps reduce abdominal fat.

The "Karada Calpis" lactic acid bacteria drink containing the postbiotic ingredient 10-HOA. Image source: Yahoo Japan.

 

Compared to ordinary drinks, this lactic acid bacteria drink containing 10-HOA can significantly reduce abdominal fat area. Image source: Calpis official website.

 

House Foods, Asahi, and other companies' postbiotics mainly target improvements in human health, while Nissin's postbiotics have refreshing effects.

 

2019In early January, Nissin launched "Hyalmoist Fermented Liquid," which contains a strain of lactic acid bacteria that can promote the human body to produce hyaluronic acid, making it the only lactic acid bacteria strain in the world claiming this function. A bottle of the drink contains five times the amount of hyaluronic acid compared to similar products, and combined with collagen, it represents a new product in postbiotics for beauty purposes. As of July 2020, this product has won seven best beauty product awards, making it a dark horse in the beauty drink industry.

Image source: www.hyalmoist.j

 

In addition, Kameda Seika launched two postbiotics made from plant-based lactic acid bacteria, which inhibit skin dryness and enhance immunity to combat pollen allergies; IHM Corporation's postbiotics have anti-inflammatory effects, inhibit tumor cell growth, and prevent influenza; BRM Corporation's postbiotics claim to activate white blood cells, thereby enhancing immunity.

 

 03 Postbiotics in China are emerging amidst skepticism and obstacles.

Compared to probiotics and prebiotics, which have established a strong health image, postbiotics are still relatively niche and cutting-edge in China. Among them, people's misconceptions about the effects of postbiotics and the lag in regulations are two obstacles that postbiotics must face in their emergence.

 

(1) Is being alive effective? Misconceptions about the efficacy of postbiotics in China.

 

In today's society, where people generally pursue "health" and "freshness," the concept of "activity" in various products containing probiotics is particularly important. With the continuous reinforcement of advertising, the vast majority of consumers believe that "active probiotics are effective" and "being alive in the intestines is the best." Therefore, inactivated probiotics seem to be at odds with mainstream views.

Image source: theskinengineer.

 

The advantages of postbiotics over probiotics have been detailed earlier. Here, we will analyze the benefits of postbiotics from the perspectives of quantity and safety.

 

First, lactic acid bacteria cultivated in suitable media can be highly concentrated after heat sterilization. Generally, cultivating live bacteria to 100 billion/g is already a technical limit, while inactivated lactic acid bacteria can reach 70 trillion/g. Clearly, adding a small amount of inactivated bacteria can provide a greater intake of bacterial cells.

 

Moreover, effectiveness and safety have always been the focus of consumer attention.

 

Probiotics that coexist with the intestines are very sensitive to low temperatures, high temperatures, gastric acid, bile, dryness, and oxygen, making them easily inactivated, leading to continuous cell death during storage, transportation, and shelf life. However, inactivated probiotics can maintain their efficacy. Compared to live bacteria, the shelf life of inactivated bacteria can reach 2 years. Additionally, inactivated bacteria do not grow, and the risk of contamination during use is almost zero.

 

Adding postbiotics can avoid consumer disputes and lawsuits caused by the instability of effective ingredients in probiotic-containing products and unreliable effects, which is beneficial for maintaining product image and corporate reputation.

 

Dairy & Food Culture Technologies.Dr. MaryEllen Sanders stated that in about 75% of studies, there is no difference in efficacy between inactivated bacteria and active probiotics. About 40% of comparative results show that inactivated bacteria are more effective than placebos or live bacteria.

 

(2) Lagging regulations and outdated technology create development constraints.

 

In 2001, China released the "List of Probiotic Strains Available for Health Food" and the "List of Fungal Strains Available for Health Food." Subsequently, in 2010 and 2011, the "List of Strains Available for Food" and the "List of Strains Available for Infant Food" were released. As of 2019, the list of edible strains includes 35 species or subspecies.

 

The current regulations and related technical specifications for probiotic foods in our country have been implemented for a long time, and some provisions and requirements can no longer adapt to the latest developments in probiotic research, such as the application of inactivated bacteria and bacterial metabolic products, for which there are no relevant regulations.

 

In terms of probiotic safety standards, due to different regulations in various countries, there is still a lack of unified probiotic safety evaluation methods and management requirements at the international level. In the 'World Probiotic Safety Evaluation Method', the author has organized the safety evaluation methods for probiotics in vivo and in vitro from various countries. Although most probiotics are safe, there is still a lack of testing for the use of probiotics in vivo and for special populations. In addition, the safety standards for probiotics are somewhat lagging, which limits the commercialization of postbiotics.

 

Currently, due to technological limitations, most research focuses only on active substances such as proteins and polysaccharides, and has not been able to conduct higher resolution identification of effect substances. In the future, the separation, identification, and functional evaluation of probiotic metabolic products will be key to the marketization of postbiotics.

 

 04 Summary

2018In the year, the renowned academic journal 'Trends in Food Science & Technology' published an article predicting that postbiotics/prebiotics will be the stars of functional foods in the future.

 

On August 20 this year, the Chinese Institute of Food Science and Technology released the 'Top Ten Hot Topics in Probiotic Scientific Research', with 'Probiotics and Postbiotics/Prebiotics' ranking seventh.

 

Since the formal concept was proposed, postbiotics have just turned 8 years old. Although it does not yet have a unified definition and standard, its extraordinary qualities have opened up vast business opportunities for the food industry. Postbiotics bring not only better and saferprobiotic functional solutions, but will also promote leapfrog development in a series of basic and applied sciences such as microbiomics, nutrition, food processing technology, flavor and texture adjustment technology, and preservation technology. The dimensions of food innovation will also be greatly enriched as a result.

 

Regardless of whether public perception can be updated or whether food companies are paying attention, the era of postbiotics has quietly arrived. What do we have to welcome the new era?

 

References:Editorial: Next-Generation Probiotics: From Commensal Bacteria to Novel Drugs and Food Supplements. Front. Microbiol., 27 August 2019

Foodaily Daily Food (Public Account ID: foodaily),has obtained reprint authorization

Original title:Probiotics are not old yet, postbiotics have already arrived. How many business opportunities are hidden in the changes of food technology?