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Possibilities for the Future

Although research on the microbiome is considered an emerging science, with some areas of research still in their infancy, the field is progressing rapidly. Researchers are making significant headway in understanding not just what the microbiome does, but how the microbiome influences human health and disease—especially through its interaction with diet. Evidence suggests that gut microbes and their human host share much of the same metabolic machinery, with bacteria influencing which dietary components and how much energy their human host is able to extract from its diet. What we eat and drink, in turn, influences the microbiome, with significant implications for disease risk. This growing understanding of the role of diet in microbiome-human interactions is driving interest and investment in probiotic and prebiotic food products as a means to help build and maintain health. Indeed, probiotics are one of the fastest-growing sectors in the global functional food market. Yet, despite this early scientific and market progress, the field faces significant scientific and regulatory challenges. During the last session of the workshop, participants debated ways to move the science forward and drive continued industry investment in microbiome-related product development. This chapter summarizes that discussion. The chapter concludes with a summary of a panel discussion on research priorities that took place earlier in the workshop.



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7 Possibilities for the Future A lthough research on the microbiome is considered an emerging sci- ence, with some areas of research still in their infancy, the field is progressing rapidly. Researchers are making significant headway in understanding not just what the microbiome does, but how the microbiome influences human health and disease—especially through its interaction with diet. Evidence suggests that gut microbes and their human host share much of the same metabolic machinery, with bacteria influencing which di- etary components and how much energy their human host is able to extract from its diet. What we eat and drink, in turn, influences the microbiome, with significant implications for disease risk. This growing understanding of the role of diet in microbiome-human interactions is driving interest and investment in probiotic and prebiotic food products as a means to help build and maintain health. Indeed, probiotics are one of the fastest-growing sectors in the global functional food market. Yet, despite this early scientific and market progress, the field faces significant scientific and regulatory challenges. During the last session of the workshop, participants debated ways to move the science forward and drive continued industry investment in microbiome-related product development. This chapter summarizes that discussion. The chapter concludes with a summary of a panel discussion on research priorities that took place earlier in the workshop. 147

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148 THE HUMAN MICROBIOME, DIET, AND HEALTH MOVING THE SCIENCE FORWARD: STUDYING HEALTH VERSUS DISEASE Moderator Fergus Clydesdale initiated the open discussion by observ- ing that the science of the microbiome is focused mostly on associations between the microbiome and disease, not health, and that most dietary interventions intended to have an impact on host biology via their influence on the microbiome (e.g., probiotics) are being studied for their potential to prevent disease, not promote health. He predicted that unless action is taken, the science will continue in that direction—not that it should not. Clydesdale expressed how impressed he was with the science described over the course of the 2-day workshop. The question is, How can additional studies be designed to yield the kind of information needed to substantiate allowable health claims on food products? The challenge to studying health end points, as opposed to disease end points, is the lack of funding for conducting research in healthy popula- tions, according to Clydesdale. He noted that the National Institutes of Health (NIH) funds disease research, not health research, and that the food industry does not have the kind of money that the pharmaceutical industry has to fund the large clinical studies that would be needed to substantiate health claims. “We have to come up with better ways,” he said. He sug- gested that a public-private partnership might be a good place for dialogue and that the NIH Program on Public-Private Partnerships might be a good place to initiate the conversation. Another participant suggested that some of the many European public-private partnerships might serve as models. The significance of studying the microbiome in healthy populations extends beyond the health (versus disease) claim implications of doing so. Dan Levy commented on the “huge opportunity” being missed to gain a better understanding of the important role that the microbiome plays in nutrition, by focusing so much on disease. He mentioned the important role that microbially produced short-chain fatty acids play in maintaining colon health. Susan Crockett of General Mills pointed to the “amazing things” that the food industry can do to help people meet recommended nutrition guidelines, implying that the same would be true if there were authorita- tive guidance on maintaining a healthy microbiome. For example, with respect to fiber, cereals have been reformulated “bit by bit over a period ­ of years” to include more fiber-containing whole grains in an effort to help Americans meet the recommended guidelines for fiber intake. George Fahey agreed that Americans are doing better than in the past, but noted that most Americans still fall short of the recommended daily intake for fiber. Fiber-like prebiotics (i.e., oligosaccharides) could help close that gap. He said, “We have a great opportunity here to meet the guidelines, but we are going to have to be strategic about it.” Clydesdale urged the inclusion

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POSSIBILITIES FOR THE FUTURE 149 of nutrition in the Human Microbiome Project 2 (HMP2), if and when HMP2 is funded. There was also some discussion about the usefulness of better under- standing the impact of the microbiome on host energetics. Fahey suggested that there might be lessons to be learned from studying microbial metabo- lism in cows and pointed to work done in that area by Marvin Bryant and Robert Hungate. Johan van Hylckama Vlieg suggested that simplified systems models might help to better understand the microbial role in en- ergy metabolism in humans. He said that probably a few core metabolic pathways are major determinants for the impact of the microbiome on host metabolism. Building a systems-level model of gut ecosystem that functions with these core pathways could reduce some of the puzzlement caused by the vastness of the microbiome metagenome and help to better understand clinical observations. CHANGING THE REGULATORY FRAMEWORK FOR FOOD CLAIMS With respect to the challenge of health (versus disease) food claims, not all workshop participants agreed that the next best step is to shift the sci- ence toward collecting data in healthy populations in order to substantiate those health claims. One audience member agreed that all of the disease- related research on the microbiome described over the course of the 2-day workshop is “great science” and that “the science will continue to go forward,” but the greater challenge, he said, is that “we are still left with a 1938 regulatory environment” and regulatory authorities are “hamstrung by whatever the law tells [them]. That is all [they] can act on.” He referred to Sarah Roller’s suggestion that “maybe we should think about how to change that law.” (See the Chapter 6 summary of Sarah Roller’s presenta- tion for a description of her views on what she perceives as an outdated regulatory framework for food claims.) Especially given that the science is moving in the disease direction and there will probably come a point when “we may be able to treat or mitigate disease by virtue of foods,” the speaker urged that steps be taken now to change the regulatory framework in preparation for the future. Otherwise, how will the value of what scien- tists discover be communicated? Stuart Craig agreed and said, “The current regulatory environment is paralyzing for industry … we need to start now” (see Figure 7-1). Peter Turnbaugh cautioned that drawing a hard line between disease and health is “a very dangerous way to think about the way we study” the microbiome. In his opinion, most biologists are interested in funda- mental mechanisms. While they hope that their research findings will have helpful applications, that is not the underlying goal of science. Clydesdale

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150 THE HUMAN MICROBIOME, DIET, AND HEALTH Target population for food industries and public health care Population numbers Target population for pharma industries FIGURE 7-1  A key distinction between the food and pharmaceutical industries is that the food industry targets healthy people and people at risk, and the pharma- ceutical industry treats unhealthy people. The green arrow represents a desired shift toward health where food can play an important role. Figure 7-1 SOURCE: Green and van der Ouderaa, 2003. only some text editable responded, “I know all scientists are searching for the truth, and I agree with that goal and that motivation.” Yet, the current regulatory environ- ment demands that the “truth” be interpreted in a certain way. Craig added that if a study is conducted on a population of individuals with irritable bowel syndrome, for example, but the food industry cannot communicate that information to consumers, then the information is “stuck.” He went on: “If it is great research, but it cannot translate to public health … what value does it truly have?” Changing the legal regulatory framework for food claims would entail a tremendous challenge. Seppo Salminen commented on the situation in the European Union (EU), where changing regulation would require influencing several hundred EU Members of Parliament. Clydesdale opined that in the United States, he would rather make a recommendation to NIH to “tackle the science” than try to influence Congress. He clarified, “I don’t think that there is anyone in the room who would disagree with the fact that we should start talking about it,” but he warned not to expect changes in the near future. Craig expressed concern that industry will lose interest if ac- tion is not taken. He said that someone needs to start the conversation and “charge forward, instead of just reacting.… It might take 5 or 10 years. Fine. We are in it for the long haul.” So who could start the conversation? An audience member asked whether there were any mechanisms in place to help. For example, what is

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POSSIBILITIES FOR THE FUTURE 151 the role of the Institute of Medicine’s (IOM’s) Food Forum? What is the role of the International Life Sciences Institute? What is the role of the Codex Alimentarius Commission? Another audience member referred to Roller’s suggestion that lessons might be learned from environmental law. He also mentioned Roller’s remarks about potential opportunities in the current law to consider prebiotics or probiotics as food for special dietary use or medical food. Salminen reminded the workshop audience to include the European Union in the dialogue. In a sense, this IOM workshop itself may have served as a starting point. As one audience member said, “I do not recall these conversations really going on seriously at any other meeting.” One audience member suggested that a congressional champion be found in the United States, and perhaps a parliamentary champion in the European Union, to partner with industry and academia as a first step toward renovating the regulatory framework. To attract interest, an argu- ment can be made that being unable to communicate the results of scientific research on food labels is not just a disservice to public health, but also to national competitiveness and global welfare. Another audience member wondered about the role of industry in initiating the conversation. Yet an- other participant wondered whether the World Health Organization might have a program in place that can serve as a model. Mary Ellen Sanders agreed that “something needs to be done, some- thing fundamental.” However, she cautioned that efforts to change the regulatory framework will take a long time and may not even be successful. Meanwhile, what can be done? Are there ways to approach the regula- tory authorities and “nudge” their interpretations of the law around food claims? Roller replied that, yes, there are places in the existing legal frame- work where the Food and Drug Administration (FDA) has “some running room.” However, given all of the other responsibilities that FDA has right now, she predicts that it “is quite doubtful” that it would take this on as well. Historically, solutions to these sorts of problems have come from third parties, where someone else finds the solution and then educates the parties. She concluded, “That is what I would recommend here.” THE MICROBIOME, ENVIRONMENT, AND HEALTH: FUTURE RESEARCH NEEDS At the end of the first day of the workshop, speakers from the after- noon sessions were asked to identify priorities for future research. This section summarizes their responses. Their responses were not intended to reflect a comprehensive examination of gaps in knowledge, nor do they reflect consensus. The list below reflects individual opinions of workshop speakers.

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152 THE HUMAN MICROBIOME, DIET, AND HEALTH • Find shared interest across broad areas of expertise that can drive analysis and interpretation of the massive amounts of sequencing data that are accumulating. o  Advances in sequencing technology have generated tremendous amounts of sequencing data, a fact that Karen Nelson, Lita Proctor, and Jennifer Russo Wortman all addressed in different ways. Vincent Young emphasized the importance of finding com- mon ground among broad areas of expertise where experts can work together to drive analysis and interpretation of those data. Too often, he said, sequencing projects end up “half-baked” be- cause researchers are unsure how to proceed. • Supplement sequencing studies with mechanistic studies. o  Peter Turnbaugh noted that sequencing studies should be com- plemented with mechanistic studies in animal or perhaps even non-animal model systems. Regardless of the specific research question, without knowing anything about fundamental mecha- nisms, it is difficult to know what to measure in human studies. • Collect prospective data that can inform causality. o  Many comments were made throughout the workshop about the abundance of data showing correlations, but not causality, be- tween the microbiome (both composition and activity) and health or disease. Johanna Lampe expressed concern that not enough attention is being directed toward causality. In many cases, it is not clear if a microbial community known to be associated with a disease is a consequence of that disease or a contributing factor. She has been pushing the cancer community to start collecting fecal samples, but the need exists across multiple disease areas, not just cancer. • Continue to explore not just the microbiome, but also the metabo­ lome and its role in human health and disease. o  Josef Neu urged more studies aimed at understanding the meta- bolic consequences of the microbiome. For example, researchers have identified microbes associated with necrotizing enterocolitis and other phenomena in preterm babies, but they do not under- stand the metabolic implications of this association. Johanna

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POSSIBILITIES FOR THE FUTURE 153 Lampe agreed that researchers, especially nutrition researchers, need to focus more on “who is really active and doing what.” • Continue to explore the role of commensal microbes in disease. o  Both Vincent Young and Richard Darveau touched on the no- tion that pathogenic disease ensues not just from the presence of a “bad bug,” but rather from an imbalance in the indigenous microbial community. Darveau suggested expanding microbiome studies to explore this phenomenon in greater depth. • Continue to explore fetal, infant, and pediatric microbiome biology. o  Josef Neu urged continued exploration of the relationship be- tween fetal microbial ecology and prematurity. Evidence suggests that contrary to conventional thought, some infants acquire their initial microbiome prior to birth during the third trimester. What microbes are present in the amniotic fluid, and what is their im- pact on fetal physiology? o  Neu also urged continued exploration of microbiome differ- ences between cesarean section (C-section) and vaginally deliv- ered infants, given the growing prevalence of C-section deliveries worldwide and the growing number of diseases being associated with C-section delivery (e.g., celiac disease, type 1 diabetes). For example, how does mode of delivery impact development of the immune system in the first year of life? o  Sharon Donovan urged expanding sample collection in pediatric populations, but in a well-controlled manner. She suggested that research on the infant microbiome could perhaps “piggyback” onto some ongoing or planned large national studies to get a bet- ter sense of what is happening in the infant microbiome over time (e.g., the National Children’s Study)—for example, by including a fecal sampling protocol. Also, as the Human Microbiome Project moves forward, the inclusion of younger individuals should be considered, Donovan emphasized. Another workshop participant suggested that perhaps some of the longitudinal studies being un- dertaken around the world, outside the United States, might offer alternative opportunities to collect that type of information. She suggested looking into one of the Scandinavian countries, Japan, or other countries with unified health systems that might make it easier to track study subjects. o  Donovan also encouraged collection of nutrient intake data as part of any pediatric microbiome study. In her opinion, nutrition

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154 THE HUMAN MICROBIOME, DIET, AND HEALTH is usually an afterthought. She remarked how “struck” she was by Johanna Lampe’s work with phytochemicals. Results from Lampe’s work, combined with observations by Peter Turnbaugh that the microbiome can be altered so dramatically in such a short period of time, underscore the important role that nutrition plays. REFERENCE Green, M. R., and F. van der Ouderaa. 2003. Nutrigenetics: Where next for the foods indus- try? Pharmacogenomics Journal 3(4):191-193.