Nestlé's Research on Nutrition and the Human Gut Microbiome

Nestlé’s research on nutrition and the human gut microbiome

NESTLÉ IS COMMITTED TO ENHANCING THE QUALITY OF CONSUMERS' LIVES THROUGH nutritional products that promote health and wellness. It is with this mindset that the company actively pursues research on the human microbiome (the collection of microorganisms that inhabit specific parts of the human body) with the aim to develop functional products that provide microbial-mediated health benefits (see Fig. 1). Nestlé pioneered research on beneficial microorganisms – so called ‘probiotics’, i.e. “live microorganisms that, when administered in adequate amount, confer a health benefit to the host” (WHO expert group, 2011) – identifying lead Lactobacillus sp. and Bifidobacterium sp. strains to be included in a variety of food products such as infant formulae. This approach was further enriched by the development of nutritional products containing blends of microbiome-modulatory substances such as short-chain oligosaccharides (i.e. prebiotics), tailored to promote health through promotion of endogenous beneficial bacteria.

The association between multi- of extensive investigation among the ADVERTISER cellular organisms and prokaryotic scientific community. In mammals, FEATURE microorganisms is not the exception, it data accumulated so far indicate that is the rule. All organisms – from simple the microbiome influences a wide range nematodes to complex humans – coexist of physiological processes, including with a population of microorganisms. digestion, the innate and adaptive These associations might be parasitic, immune response, the gastrointestinal commensalistic or mutualistic. The endocrine system, or even the central nature of the interaction might change nervous system – to name a few. In over time, depending upon host or humans, nutrition plays a significant environmental factors. The dynamics part in all of these aspects and over of host–microbe interactions raises recent years much research has been interesting questions. Did these associa- directed to this area. tions impart an evolutionary advantage to the host or to the microbe? Can an From calories to bioactives: existing interaction between a host and Increasing expectations a microbial system be modulated in a from nutrition way beneficial to the host? What are PUBLIC AWARENESS OF the importance the predominant factors that influence of nutrition to maintain health and pre- the equilibrium between the host and vent disease has significantly increased AUTHORS the microbiome? These questions may over the past few decades, paralleled by a Enea Rezzonico1, Annick Mercenier1, Ed Baetge2, Scott Parkinson2, Thomas Beck1, remain at least partially unanswered significant expansion of research activi- Johannes le Coutre1 & Harald Brüssow1 for the next few years, but based on data ties in nutritional sciences. In response accumulated so far it is already generally to these social developments, and some- accepted that nutrition plays a major part times preceding them, the food industry 1 Nestlé Research Center, Lausanne, SWITZERLAND in influencing this dynamic equilibrium. has changed as well. The concept that 2 Nestlé Institute of Health Sciences, The spectrum of biological activi- appetizing food can also be good for your Lausanne, SWITZERLAND ties that are affected by host-associated health is at the same time visionary and microorganisms is currently the subject simple. Instead of treating disease with

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drugs alone, the nutrition and health industry is providing an increasing range of food-based products with the appropriate nutritional composition to help decrease the risk of developing diseases or improve recovery from illness. With the introduction of food-based nutritional approaches the health sector has more access to diversified solutions spanning from preventative to therapeutic approaches. Growing scientific consensus converges on the idea that contemporary nutritional habits in developed countries, sometimes loosely defined as a ‘Western diet’, characterized by an overconsumption of refined sug- ars, salt and saturated fat, together with lifestyle changes that include reduced physical activity, contribute to major diseases such as obesity, diabetes and cardiovascular disease. Public health scientists and health economists also argue for prevention as a complementary strategy to treatment with the benefit of reducing healthcare costs. In view of the constantly increasing interest in the microbiome, the state of FIGURE 1 Nestlé approach to microbiome research: from hypothesis the science of nutrition and the human generation to development of targeted nutritional interventions. gut microbiome was reviewed and dis- cussed by leading scientists in the field at who described it in his book “The category he classified bacteria that ADVERTISER the 11th Nestlé International Nutrition Prolongation of Life: Optimistic Studies.” digest animal proteins which leads to FEATURE Symposium in Lausanne in October 2014. Metchnikoff’s hypothesis started with an harmful metabolic waste products in a epidemiological observation of his time: process he called “putrefaction”. These Beneficial gut microbes Bulgarian people live longer than other products in his hypothesis accelerate DIETARY FIBRES ARE known to be ben- Europeans; and Bulgarians eat more the aging process. eficial to human health, particularly yoghurt. Hence one might search for A 2014 Nature paper analyzing gut plant fibres that humans cannot digest. a life-prolonging principle in yoghurt. microbiome in the faeces of human Scientists realized that the reason for However, Metchnikoff went a step fur- volunteers fed alternatively with a car- this perplexing observation is because ther and offered a visionary concept that bohydrate-rich, plant-derived diet or a part of our food is also food for bacteria tried to explain the effects of nutrition on protein-rich, animal-derived diet came colonizing the human gut. The com- health. He defined two main types of gut essentially to the same conclusions when plex microbial world living in us (some bacteria, which digest food in the colon using an impressive battery of contempo- researchers refer to the 2kg bacterial in two fundamentally different ways. rary ‘omics’ analytical approaches, based mass as a major human organ) had until The first category includes saccharolytic on state-of-the-art nucleic acid sequenc- recently defied explanation. However, bacteria, which can digest carbohydrates ing technologies2. thanks to new analytical developments from plant sources into small organic largely based on characterization of acids. Among those, the lactic acid Nestlé’s interest in probiotics nucleic acid sequences, the scientific bacteria, which ferment lactose into NESTLÉ RESEARCH SCIENTISTS build on community was able to study the totality lactic acid during yoghurt production, Metchnikoff’s hypothesis for several of the gut microbes and these organisms were for Metchnikoff the main bacteria reasons. Nestlé manufactures a large have become a new target for the develop- responsible for the above epidemiological quantity of dairy products. For the pro- ment of beneficial dietary interventions. observations. Short-chain fatty acids such duction of yoghurt, our scientists and The original hypothesis that host- as acetate, propionate and butyrate – the technologists have a sound knowledge associated microbes play an important metabolic end products of the majority of of industrial milk fermentation by lactic part in our health is more than 100 years saccharolytic colonic bacteria – are the acid bacteria; they curate large collec- old and dates back to Elie Metchnikoff focus of much current research linking tions of bacterial starter strains, many of (1908 Nobel Prize in Medicine), the gut to other organs1. In the second which are close relatives of gut bacteria.

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Nestlé is also a leading producer of end products of the gut microbiome may mechanisms of interaction between infant formula – our paediatricians and be beneficial to the mammal host. the gut-associated microbes and our nutritionists strive to develop formulae The identification of bacterial genes physiology. As part of its efforts to fill that are close to human breast milk. that encode health-promoting proper- this knowledge gap, Nestlé collaborated For more than fifty years it has been ties is necessary to build greater insight with scientists at McMaster University known that breast milk contains factors into the mechanisms underlying pro- in Ontario, Canada, to characterize the that facilitate the establishment of the biotic functions. However, for the food role of gut microbes in an experimen- Bifidobacterium-dominated gut micro- industry it is even more important to tal model of irritable bowel syndrome biome typically observed in breastfed explore the range of health effects that (IBS). Oral supplementation of a probiotic babies. By association (‘breast is best’) can be achieved with probiotics and the B. longum strain (NCC3001) led to a reduc- beneficial health effects were attributed ecoystems they influence. tion of anxiety-like behaviours, such as fear to bifidobacteria. A Nestlé-sponsored clinical trial pub- to explore the environment11. This was par- The next goal became to find lished 20 years ago demonstrated that alleled by normalization in the level of candidates for promising probiotic feeding a blend of bifidobacteria and lac- brain signalling molecules involved in (‘health-promoting’) bacteria. With the tic streptococci protected children against the response to environmental stimuli. pioneering work of Minoru Shirota, rotavirus diarrhoea6. In a randomized Those data, together with several inde- a Japanese microbiologist who took controlled trial at the International pendent studies reporting an alteration Metchnikoff’s ideas at face value, the Center for Diarrhoeal Diseases Research of the intestinal microbiome composi- first commercial developments took place in Bangladesh (ICDDR,B), Nestlé scien- tion in IBS patients as compared to with a probiotic drink that was introduced tists demonstrated that Lactobacillus healthy subjects, suggest a role for the to the market in 1935, kick-starting the paracasei strain NCC2461 (also named gut-associated microbes in the patho- search for health-promoting bacteria. A ST11) had a significant therapeutic effect physiology of this disease. few decades later, Nestlé and a handful of on children hospitalized with bacterial, This hypothesis is further supported other companies that became interested but not with viral, diarrhoea7. Notably, by recently obtained results (unpub- in this area of research screened bacte- the same strain also mediated a lower lished) demonstrating transfer of several rial strains for candidate probiotic strains nasal congestion in adults with allergic IBS-related intestinal and behavioural with specific properties using a panel of grass-pollen rhinitis in a small proof of characteristics to germ-free mice after preclinical tests. Nestlé scientists pub- concept trial. The effect was attributed colonization with faecal microbiome from lished the first Bifidobacterium sp.3 and to a decrease in allergen-specific anti- IBS patients, which was not observed in ADVERTISER the second Lactobacillus sp.4 genome bodies8. In a different clinical setting, germ-free mice colonized with healthy FEATURE sequence, which allowed genome-based Bifidobacterium lactis NCC2818 (see Fig. volunteers’ faecal microbiome. insights into the potential mechanisms 2) was also shown to reduce allergic reac- of action of beneficial microbes. Genomic tions in patients suffering from allergic Nestlé’s research on prebiotics comparisons between bacterial strains rhinitis9. Moreover, L. paracasei NCC2461 AS AN ALTERNATIVE to providing beneficial of the same species that displayed dif- was shown to decrease skin sensitivity to microbes directly by means of the probi- ferent characteristics were conducted environmental stresses by increasing otic approach, food compounds can be on microarrays, enabling scientists to the skin barrier function10. Thus, one introduced that specifically support the make preliminary associations linking probiotic strain can have effects on more growth of intestinal health-associated genes with phenotypes (i.e. bacterial than one organ system (in this example bacteria. These substances are called characteristics). In collaboration with NCC2461, on gut and nasal mucosa and prebiotics. Many plant-derived materi- the Karolinska Institute in Sweden, we skin), and different probiotics can affect als have been explored, including inulin linked only hypothetical open reading the same organ while using different (fructo-polysaccharides present in fibers frames of the sequenced Bifidobacterium effector pathways. While these results pro- from many fruits and vegetables), fructo- longum strain NCC2705 with protection vide further evidence that the described oligosaccharides (FOS, derived from against rotavirus diarrhoea in a mouse health benefits may be attributed to the chicory root) and galacto-oligosaccharides model (unpublished data). Japanese introduction of a given probiotic strain, (GOS from soybeans or synthesized from researchers succeeded in linking carbo- much remains to be investigated about milk sugar). A recent Nestlé clinical trial hydrate transporter genes of the same their mechanism of action especially with in children demonstrated that prebiotic NCC2705 strain with protection against respect to their direct and or indirect roles supplementation of infant formula with toxigenic Escherichia coli infection5. in biological outcomes. FOS/GOS led to an increase in faecal Comprehensive analyses of bacterial bifidobacteria, which was also associated metabolic products revealed that acetic Nestlé’s research with increased faecal acetate, butyrate and acid excreted by the NCC2705 strain in to understand mechanisms propionate, and decreased concentration the gut inhibited the activity of a toxin of action: The case of IBS of pathogenic Clostridium difficile12. produced by the pathogenic E. coli A RATIONALIZATION OF the differen- Recent technological developments (Shiga toxin). This validated the concept tial effects mentioned is complicated in analytical sugar chemistry have proposed by Metchnikoff that metabolic by a limited understanding of the identified new and potentially bioactive

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FIGURE 2: Electron micrograph showing bacterial cells (Bifidobacterium lactis NCC2818) adhering to a monolayer of epithelial colonic cells (Caco-2 cell line).

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compounds in human breast milk. that the correct microbiome establishes enters the circulation. Propionate acti- Advances in synthetic chemistry ena- itself in early life. Nestlé is conducting vates receptors (more precisely FFAR3, bling large-scale production of these controlled nutritional intervention tri- free fatty acid receptor 3) on the nerves compounds have opened up opportuni- als with uniquely supplemented infant surrounding the portal vein, which ties to improve the nutritional quality of formula to test the hypothesis. transports the nutrients absorbed in infant formulae. These innovations are the gut to the liver13. The peripheral based on a very intriguing concept: the Short-chain fatty acids and the nerves connect to the brain, which reg- “glycan code” in breast milk. In short, human gut microbiome ulates gluconeogenesis in the intestine, this concept tries to explain why oli- WHAT ELSE CAN human gut microbes do? illustrating the existence of an active gosaccharides – which are indigestible Several studies have shown that soluble bi-directional gut–brain axis making to babies – are the third-most promi- dietary fibers such as fructooligosaccha- a positive contribution to our energy nent component in milk, are complex rides (FOS) can have beneficial effects on balance. Notably, feeding propionate in structure and are variable between body weight and glucose control. FOS instead of FOS induced similar effects, species. The hypothesis states that is a prebiotic, indigestible by the gut illustrating the importance of metabo- lactating mothers produce breast milk enzymes, but metabolized by bacteria in lites produced by the gut microbiome. sugar components that help an optimal the colon, i.e. food to our gut commen- However, our connection with gut gut microbiome to develop in the intes- sals. These bacteria produce acetate, bacteria is more intricate than just tines of the newborn soon after birth. propionate and butyrate as metabolic providing extra calories. Metabolites Babies acquire gut microbes from their endpoints. Butyrate feeds the colon and of gut bacteria have other important mother and the environment, and it is induces glucose synthesis in the intes- physiological functions, as revealed by important for the health of the infant tine (intestinal gluconeogenesis), which a collaborative study between Lausanne

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University, Novartis, CHUV, EPFL and NCC4007 strain induced decreased who can associate the findings in their Nestlé14. Using a mouse model of allergic plasma lipoprotein levels16. Interestingly, areas of expertise. airway inflammation, it was demon- germ free mice are resistant to weight Experimental therapies such strated that a diet rich in plant fibers gain when on a high fat diet. Compared as faecal transplants, which have reduced the pathological manifestations to conventional mice, germ-free mice on been effective in fighting recurrent in the lung, while these were increased a high-fat diet consumed fewer calories, Clostridium difficile intestinal infec- upon feeding mice with a diet low in excreted more faecal lipids, weighed less, tions, demonstrate the importance of fiber content. Also in this case, propion- showed enhanced insulin sensitivity and gut microbiome equilibrium for human ate ingestion reproduced the protective an altered cholesterol metabolism17. health. Microbial transplantation is still effects of a high-fibre diet on the lung, The metabolic events were also studied in an experimental stage and clinicians linking health beneficial effects of diets shortly after the establishment of gut would benefit from a better under- rich in plant fibres to metabolic products bacteria in germ-free mice. The acqui- standing of the mechanisms involved, of gut bacteria. Similarities in the two sition of a gut microbiome resulted in which might allow future interventions systems described above go even further: rapid increase of body weight; it stimu- with defined microbial communities the first relay in the gut–lung axis is the lated glycogenesis and then triglyceride or microbiome-derived compounds. same as in the gut–brain axis: propion- synthesis in the liver. Encouraged by Perhaps the best way to summarize the ate activates FFAR3. Then, however, the these metabolomics results, we asked future for microbiome research is that pathways deviate: FFAR3 activation leads whether the knowledge acquired in there will be a progressive integration to glucose regulation in one case, yet it animal experiments could be applied to into the mainstream of epidemiological reduces the capacity of immune cells humans. The data acquired in human and medical research while concen- to mount pro-allergenic properties in subjects indicate interesting parallels. trating on microbiome function rather the second case. It could be argued that A 2014 study published by Nestlé scien- than its composition. The challenge high-fibre diets may produce multiple tists reported different urine and stool will be the application of new analytical physiological benefits on both glucose metabolome profiles between breastfed tools to couple patient populations with regulation and immune function. and milk formula-fed infants, revealing treatments or clinical decision-making. a relationship between processing of die- Therefore, the microbiome has the Nestlé’s initiative to unravel the tary proteins by intestinal bacteria and potential to play a part in the evolution microbial metabolome host protein metabolism18. At the other of personalized medicine. In the future, IN COLLABORATION WITH Imperial extreme of the lifespan, centenarians microbiome characteristics may be used ADVERTISER College London, Nestlé research has showed an increased urinary excretion to indicate whether a subject might react FEATURE initiated a series of comprehensive of bacterial metabolites, suggesting positively to a medical or dietary inter- metabolite profiling studies (metabo- links between gut microbiome compo- vention, or which treatment might be lome studies) to identify key functional sition and longevity19. best adapted to a person’s physiology. molecules produced by the gut micro- The microbiome is currently being biome. In one of these studies the Developing tangible perspectives associated with a range of conditions, metabolome of germfree mice was com- WHERE IS THE future of microbiome including anxiety, autism, inflammation pared with the metabolome from mice research leading? Some microbiologists and obesity. How can we intervene to colonized with a bacterial community now see humans as a multi-organism change microbial ecology in a way that isolated from the stools of a human consortium. For more doubtful scien- would provide a therapeutic benefit? If baby. Colonized mice showed higher gut tists it remains to be proven to what we consider the human microbiome as concentrations of tauro-conjugated bile extent our phenotype is co-determined an ecosystem, there will be underlying acids and reduced plasma levels of lipo- by the microorganisms that inhabit our principles defined in ecosystems such as proteins15, suggesting that the energy gut. Skeptics have already voiced their soil, lakes, rivers, and oceans that will harvest from the diet depended on the opinions. William P. Hanage is a Harvard serve as guides. It seems certain that presence and the type of gut microbi- epidemiologist who, in a 2014 Nature as our understanding of human micro- ome. It was subsequently investigated comment, called for a good dose of cau- bial ecology develops, we will be able how the bacterial-host interaction was tion towards the conclusions of many to identify the molecular mechanisms influenced after feeding pre-, pro- or published microbiome studies, underlin- underlying associations, determine key symbiotics to mice. Differential effects ing that association is not causation20. points of intervention and demonstrate could be assigned to pre- or probiotic It is safe to predict that the microbiome efficacy in randomized clinical trials. modulation of the gut microbial metab- field will be progressively integrated into Overall, the field of microbiome olism, some features being exacerbated established health research and applica- research and its impact on human health upon symbiotic (probiotic + prebiotic) tions. As molecular mechanisms start is too important for scientists interested administration. For instance, prebiotic to be identified in the context of human in nutrition and health to be ignored. At galacto-oligosaccharides (GOS) reduced disease, the field will probably move Nestlé we have selected two approaches. lipogenesis and triglyceride concentra- away from having its own identity and be Scientists at the Nestlé Research Center tions, while the probiotic L. rhamnosus incorporated by scientists and clinicians in Lausanne are conducting prospective

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nutritional and health studies with fre- References quent sampling of diverse microbiome together with a detailed documenta- 1. Brussow,H. & Parkinson,S.J. You are what you 12. Holscher,H.D. et al. Effects of prebiotic- tion of health outcome (selected studies eat. Nat. Biotechnol. 32, 243-245 (2014). containing infant formula on gastrointestinal to be found in ClinicalTrials.gov under 2. David,L.A. et al. Diet rapidly and reproducibly tolerance and fecal microbiota in a randomized controlled trial. JPEN J. Parenter. Enteral Nutr. the following registration identifi- alters the human gut microbiome. 36, 95S-105S (2012). ers: NCT01276626, NCT01715246, Nature 505, 559-563 (2014). 13. De Vadder,F. et al. Microbiota-generated NCT01581957, NCT01983072, 3. Schell,M.A. et al. The genome sequence of metabolites promote metabolic benefits NCT02031887, NCT01880970, Bifidobacterium longum reflects its adaptation to the human gastrointestinal tract. Proc. Natl. via gut-brain neural circuits. 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With these prospective data and ameliorates the outcome of nonrotavirus 18. Martin,F.P. et al. Impact of breast-feeding by taking advantage of existing cohorts diarrhea in children from Bangladesh. and high- and low-protein formula on the in Europe and beyond, we will test pre- Pediatrics 116, e221-e228 (2005). metabolism and growth of infants from dictions of the literature concerning 8. Wassenberg,J. et al. Effect of Lactobacillus overweight and obese mothers. Pediatr. Res. microbiome-health associations. For paracasei ST11 on a nasal provocation test 75, 535-543 (2014). ADVERTISER those associations, which we can con- with grass pollen in allergic rhinitis. 19. Collino,S. et al. Metabolic signatures FEATURE firm for the investigated population, we Clin. Exp. Allergy 41, 565-573 (2011). of extreme longevity in northern Italian centenarians reveal a complex remodeling will design nutritional intervention tri- 9. Singh,A. et al. Immune-modulatory effect of of lipids, amino acids, and gut microbiota als targeting microbiome changes and probiotic Bifidobacterium lactis NCC2818 in individuals suffering from seasonal allergic metabolism. PLoS. One. 8, e56564 (2013). test for predicted health benefits. rhinitis to grass pollen: an exploratory, 20. Hanage,W.P. Microbiology: Microbiome At the Nestlé Institute of Health randomized, placebo-controlled clinical trial. science needs a healthy dose of scepticism. Sciences Lausanne, which is the bio- Eur. J. Clin. Nutr. 67, 161-167 (2013). Nature 512, 247-248 (2014). analytical arm of Nestlé Research, 10. Gueniche,A. et al. Randomised double-blind we are investigating microbe–host placebo-controlled study of the effect of interactions for the promising microbi- Lactobacillus paracasei NCC 2461 on skin ome–health associations with respect to reactivity. Benef. Microbes. 5, their mechanisms of action by deploy- 137-145 (2014). ing state-of-the-art ‘omics’ technologies 11. Bercik,P. et al. Chronic gastrointestinal and informatics systems approaches inflammation induces anxiety-like behavior and alters central nervous system for multiple data analytics integration. biochemistry in mice. Gastroenterology. 139, With this double-pronged approach, we 2102-2112 (2010). are excited by the prospect of delivering new knowledge in food compositions and nutritional interventions that promote human health by working in concert with host-associated microbes.

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