DUPONT AND THE HUMAN MICROBIOME

Nutrition & Health

DuPont Nutrition & Health

The Microbiome Venture

• What is the human microbiome?

• The human microbiome and health

• Microbiome science – potential health benefits and global impact

• Consumer interest and response

• Improved molecular biology techniques advancing microbiome science

• DuPont Nutrition & Health – probiotics, HMOs and next generation microbiome solutions

TENS OF TRILLIONSOF MICROBIAL CELLS

A COMPLEX MICROBIAL ECOSYSTEM

>1000 SPECIES

MILLIONSOF MICROBIAL GENES

PRODUCING

OVER 500,000DIFFERENT METABOLITES

30% OF THE METABOLITES FOUND IN YOUR BLOOD ARE COMING FROM THE MICROBIOME

THE SCIENTIFIC COMMUNITY HAS BEEN STUDYING THE

MICROBIOME FOR

10-15 YEARS

THE MICROBIOME:BY NUMBERS

What is the human microbiome?

From birth, humans are exposed to a myriad of microbes that form communities in and on the body. Tens of trillions of microbial cells such as bacteria, archae, fungi, protists, viruses (including bacteriophages) inhabit our bodies and the collective name for these microbes is the “human microbiome” 1.

The human microbiome and health

Together, human cells and the human microbiome have an inseparable collective physiology and changes in the microbial community can make a substantial impact on individual short- and long-term health including immunologic, and metabolic development and function1.

The large intestine or colon is the largest reservoir of microbes in the human body with more than 1,000 species that are encoding millions of microbial genes that together produce thousands of metabolites. It has been estimated that as much as 30% of all metabolites circulating in the bloodstream are produced by the microbes in our gastrointestinal tract. An imbalance in the composition of the microbiome it is said to be in a state of “dysbiosis” typically characterised by a decrease in microbial diversity and, in the extreme case, by an overgrowth of pathogenic microbes.

Whilst it is well known that the microbes in our gastrointestinal tract play a key role in digesting selected food components, synthesising certain vitamins and in the protection against pathogens, it is only in the past 10-15 years that it has been revealed just how important these microbes are in many aspects of health and disease.

In recent years, it has been discovered that many diseases or health disorders are associated with dysbiosis including obesity, the metabolic syndrome, non-alcoholic steatohepatitis, inflammatory bowel disease, irritable bowel syndrome (IBS), atherosclerosis, type 1 diabetes, autism, allergy, asthma and coeliac disease 2. Some probiotics* are already known to improve clinical outcomes for acute infectious diarrhoea, antibiotic-associated diarrhoea, necrotising enterocolitis, cancer therapies, pouchitis and possibly ulcerative colitis 2.

DIVERSITY IS ESSENTIAL TO A HEALTHY ADULT MICROBIOME

HIGH GUT MICROBIAL DIVERSITY IS TYPICALLYASSOCIATED WITH HEALTH IN THE ADULT.

LOW GUT MICROBIAL DIVERSITY IS TYPICALLY ASSOCIATED WITH

DISEASE OR DISORDERS IN THE ADULT.

GUT MICROBIOMESYMBIOSISContributing to digestion, immune system regulation, gut barrier integrity, protection from infections.

GUT MICROBIOMEDYSBIOSIS

Associated with gut, immune, metabolic and

behavioural disorders.

OTHER MICROBIOMES: ORAL, NASAL, SKIN, VAGINAL

Probiotics such as Lactobacilli or Bifidobacteria have long been established as playing a key role in maintaining good health most prominently by supporting the immune system and improving intestinal function 3.

A key question moving forward is whether dysbiotic microbiomes can be remodelled to be more robust, resilient and disease free with the use of probiotics as either a prevention or intervention strategy for improved health. In the future, probiotics developed to address microbiota-associated conditions will probably move beyond the micro-organisms commonly used as probiotics today 2, 4 ; these are referred to as “next generation probiotics”

*Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” 5

Microbiome Science – potential health benefits and global impact

Probiotics are often seen as an approach to restore or improve dysbiotic microbiota and are an effective treatment for a wide range of gastrointestinal conditions.

A research and development team from DuPont Nutrition & Health 6 has suggested that these benefits can also be expected to contribute to a reduced spread or evolution of antibiotic resistance in humans (and animals). It has been postulated by this research team that probiotics may provide opportunities for reducing the spread of resistances by:

• Reducing the risk for certain infectious diseases and thereby reduce the need for antibiotics• Reduce the risk of antibiotic-associated diarrhoea (AAD)• Reduce the spread of antibiotic resistance.

The DuPont Nutrition & Health team have recognised the potential health benefits of probiotics in reducing antibiotic resistance and have summarised important potential mechanisms including 6:

• The production of bacteriocins to decrease the pathogenic bacterial populations at mucosal sites as well as for disruption of biofilms which would improve the function of the antibiotic

• The improvement of the mucosal immunity, which in turn assists in the eradication of the pathogenic organisms at the mucosal site

• Improving competitive exclusion e.g. by reducing adherence to cells, coaggregation, competition for nutritional resources, as well as production of organic acids which antagonize pathogenic bacteria

• The production of antimicrobials such as short chain fatty acids, hydrogen peroxide and nitric oxide – these characteristics may enhance the probiotics ability to compete against other gastrointestinal microorganisms and could potentially inhibit pathogenic bacteria

• The improvement in resilience of the microbiota. Antimicrobial treatment has a substantial effect on the composition and functional characteristics of intestinal microbiota potentially elevating risk of AAD and C.difficile infection (CDI).

The role of probiotics in preventing drug-resistant infection in humans has not yet been established. What evidence is available is not sufficiently conclusive to issue specific recommendations, however the revolution in biological molecular techniques applied to microbiome science will help determine more clearly the mechanistic understanding of gut ecology. The hope is that this will enable the development of new therapeutic strategies, including probiotics, to help limit the use of antibiotic compounds and contribute to the control of antibiotic resistance 7.

Human milk oligosaccharides (HMOs) are another area of interest for DuPont Nutrition & Health and particularly their role in shaping early microbiome including certain types of Bifidobacteria. The early microbiome is known to protect the infant from microbial pathogens at a time of life when the immune system is not fully developed and research over recent years has revealed some interesting facts about how a healthy microbiome can be established early in life 1:

• At birth, the infant acquires its microbiota from the mother by transfer to the infant of microbes’ resident in the birth canal, gut, breast milk and skin

• At about 2 years, a mature microbiome develops in the infant with immune system development linked to that of the microbiome

• The infant’s microbiome composition is influenced by birth mode, antibiotic use and breast milk components including HMOs.

The development of non-traditional treatments, such as pro- or pre-biotics, that specifically reduce the capacity of pathogens to cause disease while leaving commensals unharmed, in all age-groups, is an important focus of microbiome science 7. Any breakthrough in this field of research would have a very positive global impact for human health and well-being.

Consumer interest and response

The benefits of probiotics have wide recognition particularly in Europe and Asia, and is growing rapidly in other markets including the USA. The consumer understands the importance of a healthy microbiome most often via the concept of maintaining “friendly” or “good” bacteria in the gut. This situation is positively impacting market demand for probiotic-containing foods, beverages and supplements globally 8.

Improved molecular biology techniques advancing microbiome science

Applying the same molecular biology tools as those used in the Human Genome Project has enabled and opened-up many aspects of biology including the field of the microbiome. Closer collaboration between research groups has led to quicker advances in the techniques and science.

Rapid technological development in combined “omics” approaches is enabling not only the characterisation of complex microbial communities but has also helped to understand their biological function. Molecular technologies have revolutionised the identification and our understanding of the composition, diversity and activity of the microbiome.

The molecular approaches include metagenomics, metatranscriptomics, metaproteomics and metabolomics which allow analyses of DNA, RNA, proteins and metabolites respectively within microbial communities like the human gut. In this way, it is now possible to gain a deeper insight into the human microbiome and allows the identification of changes that are associated with disease states 1, 9.

The Microbiome Venture - improving human and animal health

The potential of microbiome based science has been recognised by governments, venture-capital investors and the food and pharmaceutical industries. The growth potential is evident in the increased number of scientific publications and investment-related activities since 2000.

With this in mind DuPont Nutrition & Health established the Microbiome Venture to plan for projects through appropriate and co-ordinated partnerships in order to accelerate the delivery of new microbiome science-based products to the market place. The Microbiome Venture is designed to engage in strategic partnerships with leaders in academia and industry to accelerate product development that complements DuPont’s existing product portfolio and business goals, especially in the areas of probiotics and prebiotics, including human oligosaccharides (HMOs).

Applying a microbiome based science approach enables discovery of new health benefits for existing probiotics strains and also discovery of new microbial strains. Overall the goal is to harness the key microbes as new probiotics and find ways to support their growth and metabolism.

The Microbiome Venture was established in 2016 and a full Microbiome Venture team is in place. This highly focused, entrepreneurial team from DuPont Nutrition & Health has a strong connection to the entire DuPont organization, tapping into valuable internal knowledge and capabilities as needed, including research and development, manufacturing, regulatory, legal and marketing capabilities.

DuPont Nutrition & Health – Probiotics, HMOs and Next Gen Microbiome Solutions

DuPont is a leader in probiotic science and technology with significant investments over many years in health efficacy science and probiotic manufacturing supporting clinical efficacy documentation, large scale manufacturing, formulation, stability and application of its extensive range of HOWARU® and FloraFIT® probiotic strains 10. With well over 100 clinical trials on probiotics having been conducted and many ongoing studies, DuPont has an extensive offering of products for different applications along with a robust pipeline. DuPont’s extensive range of probiotics include building on its capabilities and positioning probiotics, DuPont is investing in several new platforms within the field of the microbiome.

Human Milk Oligosaccharides: HMOs are the third-most-abundant solid component of human milk after lactose and fats, and a growing body of evidence suggests they promote infant health by supporting digestive, immune, and cognitive development through changes to the microbiome. But their benefits may extend beyond infancy: Initial research shows support for a healthy microbiome in adults, and DuPont is uncovering ways in which the health benefits of HMOs can be used in dietary supplements (singularly or in combination with probiotics), extending the advantages of HMOs from infancy into adulthood.

More than 130 HMOs are found in breast milk, with 2’-fucosyllactose (2’-FL) being the most abundant. At >98% 2’-FL, CARE4U™, which is produced through microbial fermentation, is the highest-purity product available on the market today, with superior powder properties that allow for ease in formulation.

Next Generation Microbiome Solutions: Through its Microbiome Venture, DuPont aims to develop new microbiome solutions by combining microbes and molecules (Next Generation Probiotics, Prebiotics and Postbiotics) with diagnostic and digital solutions with a focus on Mother/Infant, Gut, Metabolic, Brain and Onco-Therapy Potentiation. The Microbiome Venture is driving microbiome solution development through partnering with world class research organizations and highly innovative start-ups. Partnerships include strategic collaborations with the APC Microbiome Institute in Ireland and the TFTAK Centre for Food & Fermentation Technology in Estonia and mostly recently announced with INRA (French National Institute for Agricultural Research), through both the Micalis Institute and MetaGenoPolis in France. There are others in the pipeline. This is just the beginning!

DuPont has been bringing world-class science and engineering to the global market place in the form of innovative products, materials, and services since 1802 and DuPont is consistently recognised as a world-leading innovator 11. Through its leadership and investments in the field of Probiotics, HMOs and Microbiome Venture, DuPont aims to improve health and wellness by bringing leading microbiome science innovations to the world for years to come. For further information regarding the current microbiome projects and Microbiome Venture partnerships please visit https://www.dietarysupplements.dupont.com/microbiome-venture.html.

References

1. Patrick C Seed. The Microbiome and Pediatric Health. Nelson Textbook of Pediatrics. ed Robert M. Kliegman & Bonita M.D. Stanton & Joseph St. Geme & Nina F Scho . Elsevier. Chapter 171, 1237-1242.

2. Sanders, ME et al., An update on the use and investigation of probiotics in health and disease. Gut. 2013, Vol. 62, 787-796.

3. Technical Memorandum. Lactobacillus Acidophilus NCFM® - A Probiotic With Proven Efficacy. s.l. : Dupont Danisco, 2016.

4. Strous, M and Sharp, C. Designer microbiomes for environmental, energy and health biotechnology. Current Opinion in Microbiology. 2018, Vol. 43, 117-123.

5. Hill, F et al., Expert consensus document. The Interantional Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat. Rev. Gastroenterol Hepatol., 2014, Vol. 11. 506-514

6. Ouwehand, A et al., Probiotic approach to prevent antibiotic resistance. Annals of Medicine. [Online] 2016. http://dx.doi.org/10.3109/07853890.2016.1161232.

7. Langdon, A et al., The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation. Genome Medicine. 2016, Vol. 8, (39) DOI 10.1 186/s13073-016-0294-2.

8. Schultz, H. Awareness of probiotics growing worldwide, expert says. Food Navigator-USA.com. [Online] 29 March 2013. [Cited: 19 March 2018.] https://www.foodnavigator-usa.com/Article/2013/03/29/Awareness-of-probiotics-growing-worldwide-expert-says.

9. Alonso, VR and Guarner, F. Linking the gut microbiota to human health. British Journal of Nutrition. 2013, Vol. 109, S21-S26.

10. Anon. Probiotics. DuPont Nutrition & Health. [Online] [Cited: 27 March 2018.] http://www.danisco.com/product-range/probiotics/.

11. Anon. Clarivate Analytics. DuPont. [Online] [Cited: 27 March 2018.] http://top100innovators.clarivate.com/content/dupont.

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DuPont Nutrition & Healthwww.dietarysupplements.dupont.com

About DuPont Nutrition & Health DuPont Nutrition & Health, a DowDuPont Specialty Products Division business, combines in-depth knowledge of food and nutrition with current research and expert science to deliver unmatched value to the food, beverage, pharmaceutical and dietary supplement industries. We are innovative solvers, drawing on deep consumer insights and a broad product portfolio to help our customers turn challenges into high-value business opportunities. More information is available at www.dupontnutritionandhealth.com.