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Personalized Nutrition for Better Health: Targeting the Human Microbiome Posted 02 July 2019 | By Kathleen D’Hondt, PhD, Jim Kaput, PhD, Manfred Ruthsatz, PhD, RPh, DABT, RAC, FRAP
Personalized Nutrition for Better Health: Targeting the Human Microbiome This article describes the strategic role of nutrition and the human microbiome in personalizing health and disease management and the need for diligent regulatory and policy action in light of the rapid pace of science and technology development and application of these fields. The authors cover the need for biomarkers for personalized targeting the micobiome, bringing innovations to the market, avoiding industry “hype,” creating the right regulatory framework for personalized nutrition and building confidence and trust among consumers and health care providers.
Introduction
Healthcare systems are under continuous pressure due, in part, to the increasing incidence of non-communicable diseases, often linked to changing demographics and modified dietary patterns. The underlying causes of complex and chronic diseases, such as obesity, metabolic syndrome, type 2 diabetes, allergies, food intolerances, Alzheimer’s and other neuro-psychiatric disorders, are still not well understood at a molecular level. Consequently, effective treatments, such as targeting mechanisms, are lacking. A growing body of evidence demonstrates that, in many cases, such diseases are associated with disturbances in the gut microbiome (dysbiosis).1-5 The human gut microbiome is now recognized as an important biological interface between human genetics, lifestyle, and environmental conditions which all interact with, involve, or are affected by nutrition. The impact of nutrition on the microbiome begins before birth and has a determining role during one’s lifetime, particularly in the development of many complex pathologies.6,7
Microbial ecosystems were largely ignored in human studies in the pre-genomic era, but this has changed with the availability of high throughput omics technologies in the post-genomic era. Since new research insights may have transformed the way medicine is practiced, there has been growing interest in the functioning of the gut microbiome and had attracted the attention of the OECD Working Party on Biotechnologies, Nanotechnologies and Converging Technologies (BNCT). Innovative applications targeting the microbiome are expected to impact health outcomes. To better understand these developments, and identify possible policy needs, the OECD, along with the department of Economy, Science and Innovation of the Flemish government in Belgium, organized two international workshops in Brussels. The first workshop, in May 2016, focused on ‘The Microbiome, Diet and Health: Assessing Gaps in Science and Innovation.’
The results of this workshop were published by the OECD8 and have served as input for the follow-up workshop in October 2017. While the first workshop emphasized the broader needs to advance the field, the second workshop on ‘Personalized Nutrition for Better Health: Targeting the Microbiome,’ addressed whether health solutions focused on changing the composition or function of microbiome are imminent, and how microbiome-targeted interventions may be developed.
Both workshops provided a forum for scientists from academia and industry, experts in regulatory issues, and policy makers, to identify challenges across science, regulation and application. The workshops also focused on how new knowledge about the gut microbiome may lead to innovative approaches based on diet and food, not only for preventive medicine, but perhaps for new therapeutic applications.9 The emerging insights, the complexity and high potential to develop novel informed manners to maintain or restore health, became the basis for a ‘call-for-action’ for scientists, regulators and policymakers.10,11
Toward Personalized Nutrition Targeting the Microbiome
Although the intestinal microbiome is influenced by diet, and disturbances in the microbiome are associated to certain diseases, it remains unclear whether dysbiosis is a cause or result from such diseases. Nevertheless, dietary fiber has been shown to be important for maintaining a high biodiversity in the microbiome. In turn, high biodiversity has been correlated with a healthy status and with increased production of beneficial metabolites. These results indicate that, in addition to the amount of fiber, the increased accessibility of substrates for bacteria are also important.12 The physiological response to dietary nutrients was shown to be highly individualistic, although the mechanisms are not well understood.13-15 “Omics” technologies (e.g., genomics, transcriptomics, metabolomics, and epigenomics) provide a means to address interactions between dietary components, the human genomic make-up, microbial genomes, and eventually for regulating human protein levels and metabolic pathways. Metabolomics is used to identify the bioactive components generated by gut microbes. Some of these components have signaling functions within the microbial ecosystems, others regulate gene expression, or control physiological conditions of the host in other ways.
A well-studied example of how food components influence gene expression is through epigenetic mechanisms, which may be heritable or temporary and, therefore, uninheritable modifications of DNA or proteins involved in regulating messenger RNA production. The best-known example of such a modification is DNA methylation. The essential components in the methylation pathway include choline, betaine, folate and other B vitamins, all provided from nutrition.16 The gut microbiome contains conserved basic metabolic pathways17,18 that generate essential compounds for epigenetic modifications through digestion.19 Microbial metabolites can, thus, influence epigenetics by altering the pool of compounds used for modification, or by directly inhibiting enzymes involved in epigenetic pathways.
Understanding the complex interactions between signaling from and through the microbiome, and how these processes may be influenced by nutritional interventions, is opening ways to develop personalized nutrition for health purposes, or preventing the development of chronic diseases.20-22
Personalized medicine, as defined by the European Council in 2015, refers to a medical model based on genomic and phenotypic characterization to offer the right treatment, to the right person, at the right time, and/or determines the predisposition to disease and/or delivers timely and targeted prevention. Personalized nutrition is understood in this context as relying on genomic and phenotypic characterization of the person and their individual response to diet. While targeted nutritional interventions may address certain chronic conditions and provide an important contribution as preventive approaches, nutrigenomics is the study of the relationship between human genome, nutrition, and health.
The impacts of the human microbiome on health, and the influence of external factors, such as nutrition and lifestyle, add additional layers of complexity into maintaining health. Moreover, it is still unclear what a healthy microbiome is, whether each individual may have their own “healthy” microbiome, how it is kept in balance, which factors influence its composition, what confounding factors should be taken into account, and how the microbiome interacts with the host. Such primary knowledge is required before therapies targeting the microbiome can be developed.
Need for Biomarkers
The personalization of medicine and nutrition relies on the identification of biomarkers associated with physiologies or phenotypes that can be linked to an increased risk to a disease and relevant clinical endpoints to measure the effect of interventions. The development of nutrigenomics, with the extensive use of omics technologies for in depth profiling at genomic, proteomic, metabolomic, microbial and nutritional levels, is invaluable for identifying novel biomarkers to monitor health and the effect of nutritional interventions. The implementation of personalized nutrition will depend on integration of these various types of data.24
The development of dietary biomarkers poses specific challenges, however. Dietary studies often use self-reported dietary intake assessment methods, which are subjective and, therefore, not very reliable.25-26 Validating and ensuring sensitive, specific, cost-effective, and non-invasive dietary biomarkers are needed to impact both preventive and medical care. Metabolomics and food metabolome databases are required to both achieve these goals and to establish dietary biomarkers as indicators of specific food intake.27-28
A study from the Institute for the Future (IFTF) predicted that by 2010, one-third of consumers would rely on nutrigenomics to choose what they eat.29 Although that prediction remains unrealized, the foresight study sketched how the market would develop and which drivers and barriers were envisioned. Technological evolution was identified as a major driver, while the complexity of this type of research, the limitations of animal studies, and the difficulties of implementing human studies, were identified as major barriers.
Despite intensive research efforts over the past two decades, the promises of nutrigenomics have not been fulfilled. The European-funded Food4me project exemplified the challenges of implementing personalized nutritional recommendation. That proof-of-principle project tested whether a fully internet-delivered personalized nutrition advice could make a difference in peoples’ lifestyle. In 2015, the consortium published a white paper titled “Personalized Nutrition: Paving a way to Better Population Health.”30 The main conclusion of this study was that personalized advice was most impactful, regardless of including phenotypic or genomic information for the individual. Nevertheless, the growing consumer interest in food and health, as well as the role of personal devices to keep track of well-being and health (predicted in the IFTF foresight study), has become a reality. A simple, web search counted over 300,000 health-related apps as of March 2018. In addition, genomic and microbiomic analyses are now inexpensively available from a growing number of companies. Although data created from these different sources are usually unconnected, they provide potential valuable resources to identify new biomarkers and may advance research to understand the interaction of nutrition and lifestyle in an individual genetic background and with specific microbiome composition.
With the addition of computational methods, omics technologies, and the self-quantified movement, these developments are opening opportunities for new applications and new markets. However, these new data and opportunities require a regulatory framework that does not impede development but, rather, ensures safety and efficacy for consumers and health care providers. Currently, no regulations exist for academic or commercial entities offering various omics-technologies for monitoring human condition and health. Hence, the quality of the data gathered from various applications and genomic providers is not guaranteed and is sometimes questionable.
This regulatory gap may result from the need to clinically validate biomarkers in order to justify reimbursement. Thus, regulatory agencies have been hesitant to regulate diagnostic biomarkers developed within single laboratories. The recommendations made by the US National Academy of Sciences Committee on Policy Issues in the Clinical Development and use of Biomarkers for Molecular Targeted Therapies may be used to address the barriers to developing personalized medicine.31
Bringing Innovation to Market
Although expectations are high, nutritional genomics has yet to prove the potential to lead to personalized health recommendations that integrate microbiomics. Nevertheless, companies are offering new services based on the individual genome and microbiome information and other physiological parameters to develop personalized nutrition and promise better health.32
The food industry is following these advancements and is exploring the development of novel food products to target the microbiome for positive health effects. These food products include prebiotics and probiotics. Prebiotics serve as a nutritional source favoring certain bacterial genera to colonize the digestive tract, or may function as a matrix for adherence of certain microbes; probiotics contain live organisms to bring beneficial health effects when (temporarily) colonizing the digestive tract upon ingestion.
Apart from general health benefits, personalized diets or nutrition-based solutions may treat specific chronic conditions. A classic example for managing inborn error of metabolism diseases is phenylketonuria, a monogenetic autosomal recessive disease, requiring a balanced intake of the amino acids, phenylalanine, and tyrosine via medical foods and diet.33
The pharmaceutical industry and innovative biotechnology companies have identified the microbiome and the mechanisms of microbiome-host interactions as a potential target to address chronic diseases. The microbiome may also be a source of novel antibiotics or other bioactive molecules and shown to sometimes modify drugs, thereby altering the drug activity.34,35 In addition to industries directly thriving on the opportunities offered from expanding insights, this field also holds promise for diagnostic companies and tech providers, such as app developers, wearables developers, and “big data” informatics and analytics.
A growing number of companies offer nutritional advice based on full genome analysis and information on biomarkers and biochemical testing. However, the recommendations they provide to consumers are often generic and could provide a false sense of security. As these companies are not offering specific clinical advice, they do not qualify for regulation beyond the accuracy of the genetic or omic test methodologies. The validity of advice provided by private companies may be questioned given the current lack of knowledge linking single genetic variants to the highly complex chemical content of foods along with the obvious profit motive that may skew recommendations based on laboratory results. Objections to such testing kits in the UK led to the voluntary suspension of commercial testing activity, while US governmental bodies also raised criticism against various testing companies.36 While these events occurred over a decade ago, the U.S. Office of Inspector General posted a fraud alert on genetic testing scams as recently as June 2019. An article in Business Insider (UK) warned against the “hype” in this field and pointed out that some of the companies offering genome analysis to provide advice on personalized diets are not building this advice on clinical data, data essential to building a foundation for substantiating recommendations.37
Creating the Right Framework
Both personalized medicine, as well as personalized, targeted or stratified nutrition, hold great promises, with unquestionable benefits for healthcare and well-being.38-40 New investigative techniques, such as system biology approaches, consider multiple levels of biological information to capture functional interactions of the microbiome, rather than focusing on a particular strain or molecule.41 Although major gaps remain in our understanding of how nutrition interacts on and with the microbiome, and how this controls health conditions, new applications based on this interplay are emerging. An example of this was developed on the findings of Zeevi and colleagues.42 They developed an algorithm to predict glucose response based on analyses of the gut microbiome. This academic research led to the establishment of a company providing personalized dietary advice based on the analyses of stool samples.
A solid regulatory framework guaranteeing the science base and quality of new applications is a prerequisite to ensure clinical utility, uptake by healthcare professionals, and public confidence. Novel insights into how diet, microbiome and health are interconnected will support the development of solutions to address chronic diseases, prevent or postpone the occurrence of such diseases, and may help to make personalized nutrition for better health a reality. Thorough and targeted assessment studies should document the potential benefits for healthcare systems and new ways to create evidence may be required.43,44 The development and use of personalized nutrition targeting the human microbiome for health, as part of personalized and preventive medical practice, may succeed only when the health-cost-benefit ratio for healthcare systems and the public can demonstrate added value. The speed of development in this field demands regulatory frameworks able to respond quickly and with flexibly and better harmonization across countries, including agreements on terminologies.45 Complex and stringent regulatory frameworks without global harmonization hamper investments in this field.
One of the challenges for regulatory frameworks is the biological fact that health and disease are on the opposite sides of a continuum. Given the sensitivity of diagnostics and the ability to identify physiologies defined as pre-disease that require nutritional or drug interventions, using dichotomous health versus disease states are no longer valid. The same reasoning applies to the boundaries between food, nutrition, and drugs, which also have become blurred - personalized nutrition underlies personalized medicine. Food products and drugs are governed under different regulatory frameworks. Because foods for personalized health fall between these regulatory frameworks, a hybrid regulatory framework may account for the reality of a food-drug continuum.46
In addition, if individualized nutrition to improve health is to become part of personalized and preventive health, dietary studies focusing on the complex interactions through the intestinal microbiomes are needed. Indeed, the importance of the gut microbiome for health is becoming generally accepted, but it remains unclear how a healthy gut microbiome should be maintained, or how specific health outcomes may be generated through dietary interventions. In this respect, the current population-based dietary guidelines do not sufficiently account for the effects of the gut microbiome. Future dietary guidelines should similarly address the nutritional needs of the gut microbiota in order to promote a healthy state of this ecosystem.47
A regulatory framework is essential to ensure novel applications are adopted. In addition, an awareness and understanding by the public and healthcare providers is also indispensable. Specific communication strategies to inform the public on new insights related to diet and microbiome should support the adoption of beneficial dietary habits, which may ultimately be developed into personalized nutritional recommendation for better health outcomes. Educating the public with respect to the role of human microbiomes and their potential importance for maintaining health is an important challenge for policymakers.
In this context, specific training programs dedicated to dieticians, genetic councilors, and health practitioners should focus on a holistic understanding of health influenced by food, microbiome, and human characteristics (genetics, physiology, social conditions). Specifically, the novel insights of how diet can influence the gut microbiome, its role, functioning, and interaction with the host requires health practitioners to have sufficient genetic and nutritional knowledge.
The current public environment on the role of the microbiome and the potential benefits of novel foods is, however, subject to a significant level of hype. Social media, influencing a new generation of well-connected consumers, as well as cross-border, digital or e-commerce, are developing certain dynamics of their own, beyond established regulated or policy frameworks aimed at protecting consumer health. Hence, the need for science-based, swift and proportionate regulatory and policymaking action. Yet, our understanding of the functioning of the gut microbiome and the interactions with the host is still limited; too, the mode of action of diet and lifestyle in an individual genetic context is extremely complex and the evidence base has not been replicated or validated. Therefore, a balance between rigid regulatory demands and a certain level of acceptable uncertainty may be agreeable to experts and decision-makers to support this promising field to advance, while at the same time ensuring a certain amount of trust, for both the public and healthcare providers. The emerging understanding in this field is expected to become part of a holistic approach in personalized and preventive medicine. Such knowledge may contribute to an increase in healthy life years and also reduce healthcare costs associated with aging.
Conclusion
Establishing the right framework conditions is foundational to realizing the concept of personalized nutrition for better health by targeting the microbiome as part of personalized and preventive healthcare. A reliable and trustworthy science base is a major criterion for health care systems to support novel interventions or to take up in novel dietary guidelines. Regulatory systems should accept the concept of a continuum between health and disease and food or drug, and should address these issues with a holistic approach. Advancing this field also requires the adoption by the public through (and with) health care providers. Creating awareness and understanding for citizens and healthcare providers is essential, while - at the same time - not encouraging the hype currently associated to this field.
Some of the major recommendations that followed the OECD workshops mentioned in 2016 and 2017 toward personalized nutrition are summarized in Table 1.48
