This article covers policy needs concerning the rapidly evolving field of microbiome and diets with respect to health and disease. It captures some key outcomes of a multi-stakeholder dialogue (Brussels, May 2016), spearheaded by a joint effort of the Organisation for Economic Co-operation and Development (OECD) and the Department of Economy, Science and Innovation of the Flemish Government (Belgium), to help design and/or interpret regulatory frameworks for food and drugs to support innovation to benefit society, while guaranteeing safety and efficacy of products and ensuring the science base.
The combined genomes of the microbial ecosystems that live in symbiosis or as commensals with the human body can be defined as the human microbiome. These microbial ecosystems not only include bacteria and archaea, but also fungi, protozoa, and viruses. Different microbial ecosystems colonise the mouth, the skin, the vaginal and intestinal tract, of which the latter has the highest biodiversity, composed of more than 1000 phylospecies.
An Interface Between Human Genetics and Diet: the Gut Microbiome
The human gut microbiota has been described as a key biological interface between human genetics and environmental conditions, such as diet, that can modify the composition and the functioning of the intestinal microbiome. In that sense, it may be considered a virtual organ which is an integral and essential part of the body.1 Through nutritional intervention, the gut microbiome may be altered to generate better wellbeing and protection against many diseases or even to cure certain conditions.2-4
The gut microbiome can be linked to many Non-Communicable Diseases (NCDs), such as cardiovascular diseases, cancer, diabetes, and metabolic syndrome related to increasing incidence of obesity. More recently, also neurological diseases have been related to gut microbiota and diet and are considered as NCDs.5, 6 The burden of ageing related dementia and other NCDs is exponentially increasing in relation to changing life styles and ageing of the population, conditions that are associated with gut microbiome alterations. Changing demographics worldwide, combined with the broader adoption of the western diet and lifestyle increases the burden of NCDs, creating serious challenges for the public healthcare systems. Prevention and more efficient treatment of NCDs not only offer important economic advantages for healthcare systems, it also contributes to the reduction of poverty as only healthy people can actively participate to society and economies.7-9 Recent scientific studies are linking dietary habits to an array of health conditions in new ways and indicate that nutrition has a determining influence that start even before birth and can influence the development of complex pathologies.10, 11
Opportunities and Hype
New insights about the importance of the intestinal microbiome and the modulating effect of diet are opening new possible ways of treatment and prevention that may contribute to the sustainability of healthcare systems by keeping the increasing healthcare costs under control. Innovations based on better understanding of how the intestinal microbiome functions and regulates our health and how it is impacted by what we eat are expected also to lead to preventative medicine and contributions to longer wellbeing in general.
However, the field is subject to some hype. Although insights are growing fast, at this moment it is still unclear how health or disease is determined by the human microbiomes. In most cases, a certain microbiome composition can at best be associated with certain condition. The causal relation of nutrition, gut microbiome composition and health is not clearly understood yet, such as whether a healthy microbiome can be defined at population level, what determines its resilience when disturbed, or how its composition can be beneficially manipulated. Such primary knowledge is required before therapies targeting the microbiome can be developed.
Nevertheless, there is a clear interest of food and pharmaceutical developers and industries to develop new products that target the gut microbiome, for better well-being or to manage chronic disease conditions. Moreover, microbiomes are also a source of novel bioactive compounds that may be used for innovative applications.
Identifying Policy Needs
To follow the pace of new scientific insights and translate these to innovative applications, there is a need to accelerate policy actions at the national and international level, to address scientific and regulatory challenges as well as to ensure safety and efficacy and efficient take up by consumers and healthcare professionals.12-14
To stimulate innovation based on the new insights of how the human microbiome and the gut microbiome in particular is functioning, in May 2016, the department of Economy, Science and Innovation of the Flemish Government in Belgium organized a workshop on 'The Microbiome, Diet and Health: Assessing Gaps in Science and Innovation' in Brussels in collaboration with OECD and the Business and Industry Advisory Committee (BIAC), the industry association linked to OECD.15
This workshop brought together scientists from academia and industry, experts in regulatory issues and policy makers to identify and discuss on policy needs for this field to progress and deliver upon the promises. The regulatory frameworks in place need to follow fast the new developments and combine a right balance between measures to ensure safety and consumer/patient protection and flexibility to adapt to these new developments.16-18
This article summarizes some of the policy needs that were identified as well as messages from workshop participants, how to address these and help move from hype to solid intervention or prevention. A complete workshop report is published by OECD.
A Healthy gut Microbiome and Dysbiosis
The versatility of the gut microbiome opens the possibility of inducing health benefits, but also adds complexity to understand the influence of environmental changes and other pressures, such as diet or medicines. The gut microbiota changes as well during the lifespan, starting at birth or possibly even already in utero.20-21 Some of these age-related changes in the gut ecosystem are linked to chronic inflammation and age-related reduction of gut motility and permeability or may by itself induce inflammation. Several projects address these issues to develop better guidelines, health recommendations, weaning programs and educational programs for an optimal pregnancy and delivery with improved health outcomes for the infant, supporting early life development and healthy ageing. Dietary guidelines still emphasise mainly on food that is easily digested and absorbed in the upper gastrointestinal tract (small intestine). Requirements to build a healthy gut microbial ecosystem were less considered, except for acknowledging the role of pre- and probiotics for gut health.
Prebiotics, as non-digestible food ingredients, beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon, improving the host health.22 Short Chain Fatty Acids (SCFA) are produced by the gut microbial organisms from dietary fiber. Some SCFA are absorbed in the blood, and butyrate is mainly utilized by colonocytes, and was shown to have potential anti-carcinogenic and anti-inflammatory properties.23 A disturbed or dysbiotic gut microbial ecosystem generally produces less SCFA, hydrogen and methane, while mucus degradation is increased as well as the potential to produce hydrogen sulphide and lipopolysaccharide endotoxins. These characteristics are associated to an increased potential for inflammation.24 So far in most cases, only associations of metabolites with health conditions can be made and although diet clearly determines metabolites patterns, this also depends on the individual's microbiota.25
Probiotics are live microorganisms mostly provided in mixtures believed to provide health benefits when consumed. One of the main challenges is to provide scientific evidence a specific species or strains in such 'cocktails' induce a certain action that generates a health benefit.
It is becoming increasingly clear that the response to nutrition can differ significantly among individuals and that identical foods can produce healthy or unhealthy responses that can be linked to the individual microbiota composition. A recent study led to the development of an algorithm that predicts the individualized post-meal blood sugar response as a function of variables, including anthropometry factors and gut microbiota characteristics.26 Based on such analyses, diets can be adapted to trigger a good or a bad sugar response. Moreover, it could be demonstrated the diet that favored a good sugar response favored growth of microbiome bacteria that are considered beneficial, whereas the diet that generated a bad sugar response led to decreasing numbers of these bacteria. The results of this study support the idea that personalization of diets for a better health is possible and the gut microbiota have an important role in the complex interaction between nutrition, microorganisms, and hosts.
Long-term, multi-centred longitudinal studies are needed to validate outcomes of dietary interventions and to characterise how diet, ageing and gut microbiome are linked and could help to increase healthy life years. Such studies will combine lifestyle information with data from "omics" technologies, including metabolomics, to understand the signalling between host and microbial ecosystem. Such studies will provide validated predictive biomarkers and identify intermediate endpoints toward the development of personalised dietary patterns and the development of novel food products for improving long-term health and reducing the risk of disease to address the current epidemic of non-communicable chronic diseases.
To address all the complexities, large collaborative efforts are needed. The characterization of the complete human microbiomes was one of the next big challenges after the finalization of the human genome project. The availability of novel high-throughput "omics" technologies now for the first time made it possible to characterise complete microbial communities without isolation and pure culturing of individual species.27
The first large initiatives to characterize the human microbiome and analyze the role in human health and disease, were launched in 2008 by the NIH in the US, with the Human Microbiome Project, and in Europe under the Seventh Framework Programme of the European Commission (FP7 – EC) with the International Human Microbiome Consortium.28, 29
In 2015, US scientists pleaded for Unified Microbial Initiative (UMI) that should provide an interdisciplinary platform to develop and advance tools to study microbial ecosystems in general. Such a harmonized effort would lead to better understanding of how the microbial organisms interact with each other and with their hosts and should push the transition from description to understanding causality, which would open ways to modify the microbiomes and develop microbiome-based applications.30 This plea had a prompt result as the US government launched the 'National Microbiome Initiative' in May 2016 to support research, technology development and training of a new workforce with cross-disciplinary skills, by combining biological, technological and computational expertise.31, 32
The European Union has been sponsoring an impressive portfolio of microbiome related research projects, including projects addressing diet, lifestyle and chronic diseases, such as MyNewGut, Metacardis and SYSCID.33-35 The total investment so far reaches up to 600 million Euros (approximately $700 million). Already within the first two years of Horizon 2020, about 400 million Euros (approximately $460 million) were spent. Within the new framework of the 'Food 2030' program, launched in October 2016 by the European Union, an international initiative on the microbiome is being explored.
MyNewGut, a five-year major European project started in 2013 with an estimated total cost of more than 13 million Euros (approximately $15 million) to generate a better understanding of the interaction between diet and the gut microbiome and respective contributions to the host's health. The European Commission supports this project with almost nine million Euros (approximately $10 million).36
MetaCardis is an ambitious project (2012-2018) aiming to understand the effects of gut microbiota on multi-factorial cardiometabolic diseases and their co-morbidities by using systems biology. It brings 14 project partners from six EU countries together and received 12 million Euros (approximately $14 million) in European Commission support.37
Furthermore, national R&D programs are bundled to increase knowledge on how diet affects the gut microbiota and consequently human health and development of NCDs under the Joint Programming Initiative on 'A Healthy Diet for a Healthy Life' (JPI HDHL).38 A joint budget of more than seven million Euro (approximately $8 million) was awarded to six projects that started in March 2016.39
The JPI HDHL is since December 2016 also supported by an ERA-Net Cofund (HDHL-INTIMIC) which is set up to coordinate national and regional programs in the area of diet, intestinal microbiomics and health.40 In addition, to multinational efforts, large national initiatives are being supported in several countries. Challenges to get funding for collaborative projects in which US and European scientists team up, highlight the necessity for more international mechanisms, especially for smaller and medium-sized collaborative projects.
Challenges to Translate Science Into Applications
The translation of new insights in the interactions of the host-microbiome-diet into novel food and health products will need sustained efforts. Not only computational analysis and big data issues are significant hurdles to be taken, also product characterisation and manufacturing are posing specific challenges. To realise the market potential, supporting framework conditions need to be in place. For instance, consumer acceptance not only depends on an appropriate communication, but also a suitable reliable regulatory framework that ensures safety and efficacy of the products with scientifically substantiated health effects.41
One of the major concerns with respect to intellectual property rights is the proprietary status to substantiate food health claims is only for five years.42 Analysis is needed to determine whether this is sufficient, given the significant amount of data and complexity, and developing cost considerations are essential to realize the market potential.
Furthermore, the fact that multiple sets of data is created in large consortia, stored in shared databases, or funded from public and private sources, raises discussions on data ownership. Beyond demonstrating product safety and efficacy, benefits need to be communicated in an understandable way to healthcare workers and consumers.
The Regulatory Framework
A transparent regulatory framework, adapting to recent scientific developments, creates an enabling environment for public and private R&D investments to support better public health and economic outcomes. Innovative products with demonstrated safety and efficacy, should reach the market smoothly. The regulatory framework should ensure that health claims are evidence and science based and protect the consumer against false claims.43
One of the major complications for developers is that regulations and policies differ among countries and continents.44, 45 Companies intending to place products on the market, often act with a global perspective, but the EU and US, which serve as benchmark models, use different regulations and terms referring to food, food additives and ingredients, foods with associated health claims, as well as foods for special dietary uses or for disease management.
A particular challenge is created when food is used for therapeutic purposes. For such a "food-drug continuum" existing regulatory frameworks and established product categories may need to be adapted.46, 47 In this context, food supplements (i.e., dietary supplements in the US) and nutrition and health claims legislation cover products intended for normal healthy population. Besides this, the European legislation also considers the regulation on food for specific groups which includes the Food for Special Medical Purposes (FSMP).48 FSMPs (i.e., medical food in the US) are only for patients who have specific disease or medical condition related nutritional requirements. Any food that claims to treat, cure, or prevent a disease, e.g., via a pharmacological effect, is no longer considered a food, but a drug by presentation or function, which has significant implications on, among others, development and production costs, related to Chemistry, Manufacturing and Controls (CMC) under pharmaceutical regulation.49 The current regulations are not adapted for therapies based on food products and do not take these considerations into account. Development and production costs may be kept under control when an ingredient would be defined or characterized by its quality and safety properties and not by the usage within a regulated product category or by the global geography.
In some cases, different regulations apply for the same product or ingredient, such as for vitamin C or ascorbic acid, which may switch from nutrition to drug or chemical, depending on the amounts or sourcing implicated. This has important consequences to meet global compliance requirements as different rules in terms of analytics, clinical research, production environment, etc., apply for each product category. Drug related rules have undergone intensive efforts of global harmonization, led by the International Conference on Harmonization (ICH).50 Although the respective rules for food ingredients or products are also designed to be fit-for purpose, they differ from the rules that apply for drugs, and are not harmonized to the same level as those that apply for drugs. In general, the different sets of rules for food products and drugs are not compatible.
Further regulatory barriers to develop dietary solutions are generated because a food or ingredient may become a drug by definition in the US, simply when clinical disease endpoints are investigated. Drug products, typically containing only one active ingredient, require, among others, dose-response studies to determine the risk-benefit ratio for their intended use. For nutrient 'cocktails,' that contain multiple 'active' ingredients, i.e., nutrients, such analyses for each component is virtually impossible and not reasonable. The need for better harmonization of regulations is illustrated also in the case of medical food, which - in contrast to drugs - requires a documented patho-mechanism of action, as well as proof that the dietary disease management of these medically determined 'distinctive nutrient requirements' cannot be achieved by modification of the normal diet alone.51
Health Claims From the EFSA Perspective
In the European Union, health claims for food, including food supplements fall under the Nutrition and Health Claim Regulation (NHCR).52 A so-called positive list summarizes the nutrition and health claims on food products that are allowed. It is the European Food Safety Authority (EFSA) that reviews the scientific assessment of the food products with health claims as a basis for advice on approval. The purpose of this procedure is to protect consumers and at the same time ensure innovation and fair competitiveness. The assessment is based on the highest scientific standards and focuses on three important criteria. Not only should the food or food ingredient be sufficiently characterized, the claimed health effect should be defined and measurable, and the causal effect of the food or food product should be demonstrated. The food label should contain the information for the consumer on the claimed effect.
The health claims fall under three categories and are addressed accordingly in three articles of the regulation: 1. claims related to effects on a function of the body (Article 13.1, 13.5), 2. claims of reduction of disease risk (Article 14) and 3. claims on children health and development (Article 14).
One of the specificities of the regulation is that health beneficial claims should be demonstrated in a healthy population. The food products should not be used to treat a patient population. However, to prove effectiveness, the study population often needs to be in a gradient between health and disease. Hence, the formulation of health claims also may conflict with the messages from professional associations such as the World Gastroenterology Organisation (WGO), which established guidelines for the use of pre- and probiotics for the treatment of different diseases (2011).53 The WGO guidelines and claims are not eligible in the European regulation on foods. On the other side, according to Regulation (EU) 2015/2283, commensal indigenous human bacteria can be considered as novel foods.
An important part of the work of EFSA involves communication and dialogue with stakeholders. Further to several public consultations, a set of guidance documents on the scientific assessment of health claims, were published in 2015-2016, including guidance for specific requirements for health claims related to the immune system, the gastrointestinal tract and defence against pathogenic microorganisms. Guidance is also provided on the use of new molecular tools according to state of the art technologies (like multi-locus sequence typing, optical mapping, whole genome sequencing etc.) for the characterisation of microorganisms. In addition, examples of dossiers that received favourable opinions are provided as a source of inspiration to design and report studies.54-56
The EFSA guidance documents should bring more clarity on appropriate outcome variables, and explain procedures on the validation of questionnaires. They include advice on the duration of the interventions and emphasises on the importance of biological plausibility-mechanisms. The updated guidance document advises further on the appropriate study population, the design of the study and how to deal with risk factors, like LDL-cholesterol and blood pressure, but also the presence of toxic pathogens or toxins as risk factors. More recently, the EFSA guidance on health claims related to antioxidants, oxidative damage and cardiovascular health has been updated, under public consultation until September 2017.
The claim evaluation process includes a stop clock procedure, used when additional information is needed from applicants. Although the EFSA guidance documents and previous scientific opinions are available for consultation, it is mostly the design of the studies, the statistical analysis, and the reporting that are the cause of 'stopping the clock'. Nevertheless, every claim dossier is unique, and the guidance documents can serve merely as a source of information, yet not covering all aspects of future methods, claimed effects, or outcomes.
In this discussion, also the concept of disease prevention should be addressed as prevention may contribute significantly to keeping healthcare costs under control.57 The regulatory and policy framework should support preventative approaches. However, it is not always clear when disease prevention is considered as medicinal target, and when it is merely part of lifestyle. The sensitivity of novel diagnostics, often relying "omics" technologies, and the identification of novel biomarkers lead to early and predictive diagnosis, which make it difficult to determine where health and homeostasis end and disease starts, i.e., distinguishing between a consumer and patient. When evaluating claims on products focussing on early intervention, early diagnosis, and prevention these issues will have to be addressed.58, 59
Despite intensive research efforts, health claims based on microorganisms so far have had very little success to get approval in Europe. The only product on the market today is related to the starter cultures in yoghurt that improve lactose digestion in individuals who have difficulties in digesting lactose. Associated to the claim, yoghurt should contain a defined minimum concentration of live starter microorganisms (Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus).
Regulatory frameworks for drugs and food should be designed to support innovation at the benefit of society, while guaranteeing safety and efficacy of products and ensuring the science base. Frameworks need to be better matched to incentivize for investing into nutritional solutions for disease management. For instance, product classifications, definitions, terminology, endpoints and standards, used across different regulatory systems, as well as the health claims assessments procedures should converge or be harmonized.60
The outcome of the workshop in May 2016 specified that regulations and regulatory processes should be science based, predictable, clear, transparent, efficient, and include precise timetables, be enforceable and facilitate free movements of goods and innovation. To achieve this, a concerted action is required between the different stakeholders from scientists, nutritionists, regulators, policymakers, patients, and NGOs, and importantly also payers, as indeed, a value based reimbursement is a powerful incentive to stimulate innovation in this field to provide healthcare solutions to all vested stakeholders. Participants to the workshop welcomed opening up this multi-stakeholder dialogue to address gaps in policy and regulation, a significant challenge.
A follow-up workshop in October 2017 on "Personalised Nutrition for Better Health – Targeting the Microbiome," again in a joint effort of OECD and the Department of Economy, Science and Innovation of the Flemish Government (Belgium), emphasised further the respective impact on healthy living and ageing, and the control of healthcare costs. Personalised nutrition and the role of the microbiome in health and disease may ultimately become part of a holistic approach including precision medicine, to realize the concept of positive health and move from healthcare to prevention. Beyond above-mentioned issues, ongoing developments with respect to m-health and e-health solutions for lifestyle monitoring open new challenges, especially related to big data. These new applications are also producing a wealth of information that may help to understand how nutrition influences the microbiome and thereby host health.
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- Giordano-Schaefer, J., Ruthsatz, M. and Schneider, H. "Overcoming Distinctive Regulatory Barriers for the Development of Medical Foods." Regulatory Focus. October 2017. Regulatory Affairs Professionals Society.
- Nutrition and Health Claim Regulation (NHCR). Regulation EC No 1924/2006. http://ec.europa.eu/food/safety/labelling_nutrition/claims/index_en.htm. Accessed 22 October 2017.
- World Gastroenterology Organisation (WGO) Practice Guideline - Probiotics and Prebiotics. www.worldgastroenterology.org/guidelines/global-guidelines/probiotics-and-prebiotics. Accessed 22 October 2017.
- EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). "General Scientific Guidance for Stakeholders on Health Claim Applications." EFSA Journal, 14. n/a-n/a. DOI:10.2903/j.efsa.2016.4367. (2016).
- EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). "Guidance on the Scientific Requirements for Health Claims Related to the Immune System, the Gastrointestinal Tract and Defence Against Pathogenic Microorganisms: Guidance for Claims on the Immune System, GI, and Defence Against Pathogens." EFSA Journal, 14: 4369. DOI:10.2903/j.efsa.2016.4369 (2016).
- EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) "Scientific and Technical Guidance on Foods for Special Medical Purposes in the Context of Article 3 of Regulation (EU) No 609/2013." EFSA Journal, 13, 4300-4324 (2015).
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About the Authors
Kathleen D'Hondt was trained as a molecular cell biologist both in academia and in industry. She earned her PhD at the University of Ghent and spent several years as a postdoc in Belgium, the Netherlands (WAU) and the Biozentrum in Basel. In 2006, she joined the Department of Economy, Science and Innovation of the Flemish government as a Policy Analyst and joined in 2013 the OECD as a policy analyst in the Working Party on Bio-, Nano- and Converging Tech (BNCT). Since 2016, she is back at the Department of Economy, Science and Innovation of the Flemish government. She may be contacted at firstname.lastname@example.org.
Yolanda Sanz holds a PhD in pharmacy, is professor of Research of the National Research Council (CSIC) and is head of the Research Unit on Microbial Ecology, Nutrition and Health at the Institute of Agrochemistry and Food Technology (IATA) of CSIC in Spain. Her scientific field of interest is the human microbiome and its influence on the nutritional and health status. Currently, she coordinates a large collaborative 7FP EU project on the human microbiome and its role in obesity and brain development and function (MyNewGut.) She has also been a member of the Panel on Dietetic Products, Nutrition and Allergies (NDA) of the European Food Safety Authority (EFSA) from 2009 to 2018. She can be contacted at email@example.com.
Manfred Ruthsatz, PhD, RPh, DABT, RAC, FRAPS, is the global head regulatory advocacy at Nestlé Health Science, Epalinges, Switzerland. His healthcare regulatory experience, rounded out by quality, safety, vigilance, health economics and reimbursement, spans more than 25 years in diverse healthcare industry settings, US FDA's CDER and NIH. His publishing and speaking activities in Europe, US, Asia and Latin America include a wide array of regulatory and policy related healthcare topics with a focus on the health and disease continuum, global convergence. He may be contacted at firstname.lastname@example.org.
Disclaimer: this article reflects the personal opinion and experience of the authors. It should not be construed as an official position by any organization with which the authors are affiliated. It underlines the importance to expeditiously work on and create an environment to engage with all vested parties to help investing into sustainable solutions in healthcare, including nutrition, considering the pace, demographics and diversity based needs in our environments are shifting.