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Danone: The gut microbiome and – 100 years of shared history

AUTHOR Patrick Veiga, Silvia Miret and Liliana Jiménez Research, R.D. 128, 91767, Palaiseau,

anone was founded 100 years ago on a Dbreakthrough concept of the time: that fermented foods and the bacteria they contained (not yet referred to as probiotics) could target the gut and its microbiome to bring health to all. One century later, Danone continues to place the gut and its microbiome at the core of its health strategy to deliver the company’s mission “bringing health through food to as many people as possible”. Today, the portfolio of the Danone Essential Dairy & Plant-Based division encompasses the traditional range of fermented dairy Figure 1. Danone yogurt was packaged and sold in ceramic pots in the early twentieth century. Source: Danone. products and probiotics. The portfolio was recently broadened are two examples of headlines that the lactate produced Building on Louis Pasteur’s to include plant-based products, that were written over the past during fermentation inhibited legacy, in 1899 Henri Tessier, expanding the possibility to couple of years, but they could the growth of pathogens and a paediatrician from the develop dairy and non-dairy have been written one hundred avoided food spoilage3. The Institut Pasteur, discovered ranges of healthy products years ago. By the end of the idea that not all bacteria were bifidum in that will contribute to nourish, nineteenth century, the field of prejudicial was a breakthrough faecal samples of breast-fed enrich and protect the gut and microbiology started to fulfil at the time. The scientific world infants and reported that the its microbiome. Here we present its first promises. Louis Pasteur was shaken by the promise of bacteria could be used to help the history of microbiology and discovered fermentation by modern microbiology, which prevent babies from developing Danone and reveal our research lactic acid bacteria, which he saw the rise of vaccines, the diarrhoea. The Russian-born priorities for the coming years. described as beneficial bacteria isolation of beneficial bacteria biologist Élie Metchnikoff, to protect foods from spoilage. and, later in the century, with the recipient of the Nobel prize in DANONE WAS BORN Despite the traditional use discovery in 1928 of penicillin physiology or medicine in 1908 DURING THE MICROBIOLOGY of fermentation in foods and by Alexander Fleming, the for his work on phagocytosis, REVOLUTION beverages to improve storage development of antibiotics. hypothesized that “there is a link “The secret to longevity may lie time, safety, functionality, Microbiology was seen by many between the gut flora and the in the microbiome and the gut”1. organoleptic quality and as uncharted scientific territory senile degeneration”4. The gut “Why the gut microbiome is nutritional properties, it was holding promises to improve microbiome and its metabolites crucial for your health”2. These Pasteur who demonstrated people’s lives. were linked to intestinal processes

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beyond food digestion and the hand-delivered as a health food were Escherichia coli Nissle gastrointestinal discomfort in absorption of nutrients. At the to pharmacies across the city. (1917), Lactobacillus acidophilus healthy adults10,11 and a decrease time, it was a breakthrough In 1924, the production site was LB (1907) and Lactobacillus casei in the severity of symptoms in concept: the bacteria in our visited by the College of Doctors Shirota (1935). In 1974, Richard people with IBS-C12 . guts could dictate our fate. of Barcelona who complimented B. Parker proposed a definition Metchnikoff also observed the product5 . of probiotics as “organisms and THE SECOND that food could be used to From pharmacies, yogurt substances which contribute to MICROBIOLOGY beneficially modulate the gut made it through to other intestinal microbial balance”9. REVOLUTION FED DANONE’S fora, in particular the bacteria channels accessible to a range An official definition was GUT HEALTH RESEARCH contained in fermented foods4. of consumers and became issued in 2001 by the Food Scientific discoveries often His hypothesis was that if the a mainstream product. One and Agricultural Organization rely on the development of lactate produced by bacteria decade later, Daniel joined the of the United Nations and the new technologies. The birth during fermentation can inhibit family business and successfully World Health Organization as of modern microbiology at the growth of harmful bacteria, expanded Danone across France. constituting “live microorganisms the end of the nineteenth and then the same process could In the late 1930s, with Europe that, when administered in beginning of the twentieth occur in the gut. Consequently, once again on the brink of war, adequate amounts, confer a century makes no exception. lactic acid bacteria could inhibit he decided to move to the United health benefit on the host”. The first microbiology revolution the ‘putrefaction’ and production States. In the years following Different types of bacteria was possible because of the of toxins in the gut. He worked the first world war and, later, (for example Lactobacillus, development of new technological to isolate pure cultures from a the second world war, yogurt Bifidobacterium, Streptococcus, tools, such as the microscope. sample of Bulgarian fermented was consumed as a way of Bacillus) and yeast or mould The advancements in genomics, milk, among them Lactobacillus providing healthy nutrients. The (for example Saccharomyces, proteomics and epigenomics bulgaricus and Streptococcus fermentation process means that Aspergillus, Candida) are qualified have propelled the field into a thermophilus, the two species yogurt contains higher quantities as probiotics. second revolution that will allow used today to produce yogurt. of vitamins B2, B6 and B12, and The first foodstuff to contain researchers to understand the The history of Danone begins the nutrients calcium, potassium, probiotics was probably precise mechanisms of action in 1916, when Greek businessman zinc and magnesium than other fermented milk, but today many of the bacteria in the gut. The Isaac Carasso took his wife dairy products such as milk6. other matrices can contain metagenomics sequencing tools and three children to Spain, his Yogurt promotes adherence probiotics. Danone started the available today represent similar ancestral home. Much of Europe to dietary guidelines for many production of two - technological advancements was experiencing the turmoil of nutrients, particularly those of containing fermented milks with because they allow scientists to the first world war and although concern, such as calcium. During Bifidobacterium lactis CNCM rapidly capture the complexity of Spain remained neutral, famine, fermentation, the breakdown of I-2494 (BFMP) and L. casei microbiomes and study invisible malnutrition and poor living lactose by enzymes present in CNCM I-1518 (LFMP) in 1987 microorganisms without the need standards were present in many L. bulgaricus and S. thermophilus and 1994, respectively named to isolate them. layers of society. Carasso was reduces lactose levels and Activia® and ®. With the At the forefront of this deeply affected by the levels of facilitates the consumption of ambition to build and substantiate second revolution were the malnutrition and disease that he dairy products by individuals the health benefits of probiotics, European and United States saw in Spanish children. who might be sensitive to a vast programme of studies was consortia of laboratories, Carasso was open and curious lactose levels found in milk7. launched in the 1990s, resulting MetaHIT (Metagenomics of about scientific developments Recent population studies have in more than 40 peer-reviewed the Human intestinal Tract, a and he was inspired by suggested that yogurt might not scientific publications. The project financed by the European Metchnikoff’s research into only be a significant contributor studied benefits of probiotic Commission, 2008–2012) and dairy ferments. Through in the provision of micronutrients products range from reducing the Human Microbiome Project experimentation and by trial but is also associated with a incidence or duration of digestive (2007–2013), respectively, and error, Carasso mixed fresh reduced risk of weight gain and discomfort symptoms, intestinal which have led the way and milk with ferments isolated at increased satiety and that yogurt transit, common infection and developed bioinformatics tools the Institut Pasteur to create in consumption might be linked to illness, respiratory infection, and concepts that have unlocked 1919, exactly 100 years ago, what an overall healthier dietary and gastrointestinal infection and microbiome research. Inspired by became the first Danone yogurt. lifestyle pattern8. prevention of diarrhoea following its microbiology heritage, Danone He named the yogurt after his Building on Pasteur ’s heritage, the use of antibiotics. Specifically, Nutricia Research contributed to son, Daniel, and in reference to scientists in the twentieth the results accumulated for this frantic endeavour by joining his nickname ‘Little Daniel’. The century isolated other health- BFMP showed a consistent the MetaHIT consortium, which yogurt was packaged in porcelain promoting strains from the and significant improvement was seen by many as a scientific pots (Fig. 1), which Carasso human intestine among which of outcomes related to gamble at the time.

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Building on the emerging gut- centred science, Danone Nutricia Research rapidly focused its research efforts on understanding the mode of actions of its major probiotic-containing product targeting gut health: BFMP. After a decade of a broad range of collaborations with leading academics including those from Washington University at St. Louis, U.S., Harvard T.H. Chan School of Public Health in Boston, U.S., the University of California, Los Angeles, U.S. (UCLA), Institut National de la Recherche Agronomique, headquartered in Paris, and the University of Gothenburg, Sweden, we are able to provide a working model capturing the different potential mode of actions of BFMP11 (Fig. 2). The evidence supports the hypothesis that BFMP confers health benefits by modulating the activity of the gut microbiome and the components of the gut–brain axis. On the gut microbiome, we have evidence showing that BFMP stimulates the pathways leading to the production of beneficial short-chain fatty acids and decreases the production of intestinal gas13,14. On the gut–brain axis, results obtained in different studies support the idea that this product decreases the visceral hypersensitivity and modulates activity of the brain10,15. During our research we found that not all individuals respond to BFMP to the same extent. Recently, we have Figure 2. The potential mode of action of BFMP (Activia® ). Source: Danone / Boris Le Nevé. shown that the decrease in intestinal gas production by the results open the avenue for but many aspects of health, from change and continuous BFMP was observed only the ‘precision probiotics’ era. In the neurological to the immune interconnections, human health is in individuals exhaling high other words, probiotics that will system, from paediatrics to interconnected through effects of quantities of hydrogen14. We be selected and tailored to an geriatrics. the environment, especially diet, also observed evidence for individual’s phenotype, genetics the microbiome and the intrinsic two types of microbiomes: and microbiome. 100 YEARS FROM NOW: and specific background of each permissive and resistant16. Future investigations should CHALLENGES AND HOPES individual. The permissive microbiome focus on the mechanistic In today’s world, just as Isaac was more susceptible to be understanding of the benefits of Carasso found 100 years ago, HEALTH THROUGH THE GUT modulated by BFMP than the probiotics. Such understanding we face many challenges. In a For decades, the scientific resistant microbiome. Together, will not just impact gut health world in constant and accelerated approach to health was

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compartmentalized and focused in collaboration with scientists are lactose intolerant to consume to their fullest potential. The on studying specific organs or cell showing that a four-week intake of yogurt by providing the lactase strains could help to address types. Today, we are witnessing BFMP by healthy women affected (an enzyme missing in people a series of health, societal and the emergence of a new era with the activity of brain regions that who are lactose intolerant) environmental challenges20. the rise of integrative science, control central processing of to convert lactose into well Additionally, and due to the which defines health as the result emotion and sensation. More tolerated glucose and galactose. complexity and diversity of the of the adequate functioning of recently, we published a meta- In the future, key species or microbiome, Danone Nutricia interconnected organs, organ analysis of 105 publications functions of the gut microbiome Research decided to collaborate systems or cell types. The and demonstrated that the will be identified by the scientific with world citizens and open intestine has been highlighted as consumption of probiotics is community, and probiotics will the possibility for citizens to one of the most interconnected associated with improvements be a natural way to restore or help understand the complexity organs because it is involved in several metabolic risk factors support some of these functions. and diversity of the world’s gut in mental, cardiovascular, in subjects with metabolic Probiotics could originate microbiomes. Traditionally, metabolic, immune and diseases18. Probiotics seem to be from our traditional lactic acid research on the gut microbiome musculoskeletal health and is relevant candidates to bring health bacteria or Bifidobacterium focused on populations from essential for health and plays an through the gut. but they will also come from the Western world because we important part in disease17. In line with our findings, we bacteria isolated from the gut. know the diet and how a variety Scientists are (re)discovering firmly believe in the concept of Akkermansia municiphila is a of foods can modulate the gut the gut as a cornerstone of human ‘Health through the gut’, which gut-isolated bacterium that holds microbiome. Danone Nutricia health and well-being because places the gut and its microbiome promises in the area of metabolic Research partnered with the the function of the gut goes way as an important target for health. health because research suggests University of California, San beyond its primary function of More than one hundred years it improves several metabolic Diego, U.S. to understand the digesting and absorbing nutrients. after Metchnikoff’s insights, parameters in obese and best ways of nourishing the gut The gut is mediated by four the idea that small molecules overweight individuals19. microbiome. By launching The different mechanisms: i) signalling produced by the gut microbiome Human Diets & Microbiome molecules produced by the gut can modulate health is highly OPEN SCIENCE Initiative (THDMI) we aim to make it a virtual endocrine organ, relevant and has catalysed a new There is huge potential discover the best diets and foods arguably the largest that can gold rush in the gut microbiome for probiotics and the gut consumed by humans in different contribute to circulating signalling field. The focus on health through microbiome to contribute to parts of the world that can benefit molecules within the host; ii) the gut will allow the development public health, therefore one our guts. Because of the high bacteria-derived compounds (for of new solutions, including company and one research variability in gut microbiome example, short-chain fatty acids, probiotics, to improve personal team will not suffice to explore composition between individuals, lipopolysaccharides, vitamins, and hopefully contribute towards and exploit all possibilties. A it is necessary to achieve the and polyphenol metabolites) solving public health challenges. new way of thinking is required, recruitment of several cohorts able to cross the epithelial barrier and that involves multiple across all geographical regions contribute or interfere with the PRECISION PROBIOTICS partners working together. The to enable a full mapping of the functioning of extra-intestinal Scientific and technological Danone vision is collaboration gut microbiome combined with organs or tissues; iii) immune advances in the gut microbiome and openness that allows dietary data. Most importantly, cells primed in the intestine and field hold promises for a new complementary factors to work unlike other similar initiatives, homing in extra-cellular tissues way to select the next generation together towards common goals. this programme is using full and; iv) a nervous system able of probiotics, named hereafter To celebrate 100 years since metagenome sequencing, to transmit signals from the gut ‘precision probiotics’. Precision the creation of its first yogurt, which is the latest sequencing into the brain, interfering with its probiotics will bring to the gut Danone has opened its collection technology, to assess the gut activity. activities or functions that are not of 1,800 strains for research microbiome composition and Because the gut is important to provided by our gut microbiome purposes20. The 193 lactic and function. human health, it is not surprising or our own genes. Precision Bifidobacteriumferment strains, The THDMI programme that more studies suggest the probiotics will be tailored to as well as Danone’s collection of has a public health educational potential benefits of probiotics a recipient’s diet, phenotype, 1,600 other strains, have been vocation and will be conducted beyond the gut to include the lifestyle, age, gender, genetics made available to researchers to contribute to promote healthy brain, cardiovascular, metabolic, and microbiome. around the world, with the sole dietary habits. The THDMI bone, muscular and immune The first precision probiotics aim of sharing our legacy to initiative will give participants the systems. In 2013, Danone Nutricia were L. bulgaricus and benefit all. The bacteria strains in opportunity to become citizen Research and collaborators S. thermophilus, the bacteria Danone’s collection may have a scientists and to contribute from UCLA15 published the first used for yogurt fermentation, range of additional uses, many of to the ‘health through the gut’ gut–brain probiotic clinical trial because they allow people who which have not yet been explored revolution.

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2. Robertson, R. Healthline, 27 June 13. Veiga, P. et al. Sci. Rep. 4, 6328 BRINGING IT ALL TOGETHER: Nutricia Research share the 2017. Available at: www.healthline. (2014). THE GUT MICROBIOME AND same passion for innovation. com/nutrition/gut-microbiome-and- 14. Le Nevé, B. et al. PLoS ONE 14, DANONE SHARED HISTORY Danone researchers use their health [accessed 20 August 2019]. e0214273 (2019). 3. Berche, P. Clin. Microbiol. Infect. 18, 15. Tillisch, K. et al. Gastroenterology The entrepreneurial spirit that scientific and technological 1–6 (2012). 144, 1394–1401.e1394 (2013). inspired Isaac Carasso to search expertise to create products 4. Cavaillon, J. M. & Legout, S. Microbes 16. Zhang, C. et al. ISME J. 10, for solutions for malnourished that best fit the Danone mission Infect. 18, 577–594 (2016). 2235–2245 (2016). 5. Viader, J. HMiC: Història Moderna i 17. Hills, R. D. et al. Nutrients 11, 1613 children is as essential today as to bring health through food Contemporània 8 (2010). (2019). it was 100 years ago. And it is to as many people as possible. 6. van Hylckama Vlieg, J. E. T., Veiga, P., 18. Koutnikova, H. et al. BMJ Open 9, this spirit that propels us into the The science and technology for Zhang, C., Derrien, M. & Zhao, L. Curr. e017995 (2019). Op. Biotechnol. 22, 211–219 (2011). 19. Depommier, C. et al. Nat. Med. 25, future at Danone. Entrepreneurs, developing probiotics has moved 7. Savaiano, D. A. Am. J. Clin. Nutr. 99, 1096–1103 (2019). in the purest sense, are those at the same pace as the science 1251S–1255S (2014). 20. Marking 100 years since the creation who identify a need – any need in the field of the microbiome. 8. Fernandez, M. A., Panahi, S., Daniel, of its first yogurt, Danone opens access N., Tremblay, A. & Marette, A. Adv. Nutr. to its historical collection of 1,800 – and fill it. Every entrepreneur The gut microbiome history 8, 812–829 (2017). strains. Available at: www.danone.com is a problem solver, someone refects the Danone history for 9. Parker, R. B. Anim. Nutr. Health 29, [accessed 20 August 2019]. who sees a problem affecting food and health. 4–8 (1974). people and is driven to find a 10. Waitzberg, D., Quilici, F., Miszputen, REFERENCES S. & do Carmo Friche Passos, M. Nutr. solution. Inspired by Carasso’s 1. McGill University. ScienceDaily, Hosp. 32, 501–509 (2015). entrepreneurship, openness 31 May 2018. Available at: 11. Eales, J. et al. Therap. Adv. and curiosity, research and www.sciencedaily.com/ Gastroenterol. 10, 74–88 (2017). releases/2018/05/180531114611.htm 12. Agrawal, A. et al. Aliment. Pharmacol. innovation teams at Danone [accessed 20 August 2019]. Ther. 29, 104–114 (2009).

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