Overview

The Food Forum convened a public workshop on February 22-23, 2012, to explore current and emerging knowledge of the human microbiome, its role in human health, its interaction with the diet, and the translation of new research findings into tools and products that improve the nutritional quality of the food supply. This report summarizes the presentations and discussions that took place during the workshop.1 Box O-1 provides definitions of the human microbiome and other key terms used throughout this report.

Several major overarching themes emerged over the course of the 2-day dialogue:

  • The microbiome is integral to human physiology, health, and disease.
  • The microbiome is arguably the most intimate connection that humans have with their external environment, mostly through diet.
  • Given the emerging nature of research on the microbiome, some important methodology issues might still have to be resolved with respect to undersampling (i.e., some workshop participants expressed

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1 The workshop was organized by an independent planning committee whose role was limited to designing the workshop program and identifying goals, topics, and speakers. This workshop summary has been prepared by the rapporteurs as a factual summary of the presentations and discussions that took place at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants and are not necessarily endorsed or verified by the Food Forum or the National Academies; they should not be construed as reflecting any group consensus.



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Overview T he Food Forum convened a public workshop on February 22-23, 2012, to explore current and emerging knowledge of the human microbiome, its role in human health, its interaction with the diet, and the translation of new research findings into tools and products that improve the nutritional quality of the food supply. This report summarizes the presentations and discussions that took place during the workshop.1 Box O-1 provides definitions of the human microbiome and other key terms used throughout this report. Several major overarching themes emerged over the course of the 2-day dialogue: • The microbiome is integral to human physiology, health, and disease. • The microbiome is arguably the most intimate connection that hu- mans have with their external environment, mostly through diet. • Given the emerging nature of research on the microbiome, some important methodology issues might still have to be resolved with re- spect to undersampling (i.e., some workshop participants expressed 1  The workshop was organized by an independent planning committee whose role was limited to designing the workshop program and identifying goals, topics, and speakers. This workshop summary has been prepared by the rapporteurs as a factual summary of the presentations and discussions that took place at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants and are not necessarily endorsed or verified by the Food Forum or the National Academies; they should not be construed as reflecting any group consensus. 1

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2 THE HUMAN MICROBIOME, DIET, AND HEALTH concern not just about underpowered studies, but also tissue under- sampling) and a lack of causal and mechanistic studies. • Dietary interventions intended to have an impact on host biology via their impact on the microbiome are being developed, and the market for these products is seeing tremendous success. However, the cur- rent regulatory framework poses challenges to industry interest and investment. In her keynote address, Karen Nelson, president of the J. Craig Venter Institute (JCVI), touched on all of these themes. With respect to the in- BOX O-1 Definition of Key Terms Commensal: An organism participating in a symbiotic relationship in which one species derives some benefit while the other is unaffected Enterotype: The concept that distinct communities of bacteria are defined by their bacterial composition (Arumugam et al., 2011) Metabonomics: The quantitative measurement of the multiparametric (time-­ related) metabolic responses of complex systems to a pathophysiological stimulus or genetic modification (Nicholson et al., 1999); often used synonymously with metabolomics (Fiehn, 2002) Metagenomics: The study of the gene content and encoded functional attributes of the gut microbiome in healthy humans (Gill et al., 2006) Microbiome (human): The full complement of microbes (bacteria, viruses, fungi, and protozoa), their genes, and genomes in or on the human body Prebiotic: A substance that (1) is resistant to gastric acidity, to enzymatic hydro- lysis, and to gastrointestinal absorption (i.e., not hydrolytically digestible); (2) is fermented by cecal-colonic microflora; and (3) selectively stimulates growth and/ or activity of those bacteria that contribute to colonic and host health (Gibson et al., 2004) or a nonviable food component that confers a health benefit on the host associated with modulation of the microbiota (Pineiro et al., 2008) Probiotics: Living microorganisms that when administered in adequate amounts confer a health benefit on their host (FAO-WHO, 2002) Resistome: The collective informational resources available to the microbiome for responding to antimicrobial pressure (Wright, 2007)

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OVERVIEW 3 tegral role of the microbiome in human physiology, health, and disease, she described some of the findings that JCVI scientists have made in their studies on gut microbiome-disease associations (Fouts et al., 2012; Yan et al., 2011). For example, JCVI scientists are working in collaboration with researchers from New York University to examine how the microbiome changes over time in individuals with esophageal cancer. The researchers are detecting unique microbial signatures associated with different stages of esophageal cancer. She also described some of the work that JCVI research- ers have been doing on fundamental microbiome functioning (e.g., how mi- crobial gene expression varies depending on what other species are present) and JCVI efforts to access once-inaccessible genomic information that can be used to help develop novel nutritional (e.g., probiotic) tools. Nelson’s talk prompted a lively discussion about methodology, mostly about the limitations of undersampling. JCVI researchers are credited with laying much of the conceptual and technological groundwork for contemporary research on the microbiome (e.g., Eckburg et al., 2005; Gill et al., 2006; Human Microbiome Jumpstart Reference Strains Consortium, 2010; Rusch et al., 2007; Venter et al., 2004; Wu et al., 2011a; Yooseph et al., 2007). STUDYING THE MICROBIOME While study of what is now known as the human microbiome can be traced as far back as Antonie van Leeuwenhoek (1632-1723), advances in genomics and other areas of microbiology are driving the field in a direc- tion van Leeuwenhoek could not have imagined. Although scientists are increasingly shifting their attention toward studying not just what microbes are present in (and on) the human body, but also what those microbes are doing, the field still revolves around genomics. A major goal of the Human ­ Microbiome Project (HMP) is to characterize the genomic makeup of all microbes inhabiting the human body. Lita Proctor, coordinator of the N ­ ational Institutes of Health Common Fund HMP, explained how HMP re- searchers are building a publicly available reference database of ­ icrobiome m genomes from “healthy,” or “normal,” individuals, with the intention of providing researchers with “healthy cohort” information for use in com- parison studies. The HMP is also coordinating a series of “demonstration projects” aimed at identifying characteristic microbial communities associ- ated with certain human diseases (e.g., an enrichment of Fusobacteria with colorectal cancer). Based on what the HMP and other investigators have observed, Proctor elaborated on what she views as “universal” properties of the microbiome, that is, properties shared by all hosts. In her opinion, most universal proper- ties identified thus far have to do with the dynamic nature of the microbi- ome over time, or the way the microbiome changes in composition over the

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4 THE HUMAN MICROBIOME, DIET, AND HEALTH course of a human lifetime. For example, one key universal property is that unlike the human genome, the human microbiome is acquired anew each generation, with vaginally born babies acquiring different microbiomes than cesarean section (C-section) babies (Dominguez-Bello et al., 2010). Meanwhile, Proctor questioned whether certain other phenomena—namely, enterotypes, the notion of a “core” microbiome, and the idea that the presence of a pathogen indicates disease—are universal properties. None of these, in her opinion, are universal properties based on the evidence to date (e.g., Wu et al., 2011a). Following Proctor’s presentation, Jennifer Russo Wortman, director of microbial informatics at the Broad Institute, described methodologies that HMP Consortium investigators are using to analyze the massive amount of genomic data that are accumulating. Most researchers are using one of two types of data: (1) 16S ribosomal ribonucleic acid (rRNA) data to determine what microbes are present (i.e., by using operational taxonomic units, or OTUs, as proxies for species) and (2) whole-genome shotgun reads to get a sense of what these microbes might be doing (i.e., by comparing sequences to functional databases). The data reveal varying levels of microbial diver- sity, depending on taxonomic level, among body sites (e.g., vaginal samples have less genus-level microbial diversity than other body sites, but more species-level diversity). Among individual hosts, scientists are observing greater compositional diversity (based on 16S rRNA reads) than putative functional diversity (based on shotgun reads). One of the greatest challenges in moving forward will be interpreting the massive amount of sequencing data that are accumulating, especially with respect to function, by integrat- ing them with transcriptomic, proteomic, and metabolomic data into a systems-level approach to studying the microbiome. Jeremy Nicholson, head of the Department of Surgery and Cancer at the Imperial College London, argued that not only is an integrative, systems-level approach necessary for understanding human health and dis- ease, but studying the microbiome is central to that approach (Mirnezami et al., 2012; Nicholson, 2006). Only by understanding how gut microbes are signaling and otherwise functioning, especially with respect to their impact on their human host, will scientists ever be able to tease apart hu- man biocomplexity enough to realize the vision of personalized health care. Nicholson discussed some of the ways that gut microbes influence human host metabolism and generate differential metabolic phenotypes (Holmes et al., 2008). For example, mouse and rat studies have demonstrated what Nicholson described as a “massive effect of the microbiome on bile acid metabolism,” with gut microbial activity impacting liver and colonic disease risk as a result (Martin et al., 2007; Swann et al., 2011).

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OVERVIEW 5 THE MICROBIOME, HEALTH, AND DISEASE While demonstrated associations between the human microbiome and health or disease were an overarching theme of the workshop, with most speakers at least touching on the topic, some speakers homed in on it. Josef Neu, professor of pediatrics in the Division of Neonatology at the Univer- sity of Florida, provided an overview of recent microbiome-disease research in pediatric populations. First, he described evidence suggesting that a fetal microbiome exists; that is, babies are born with microbiomes acquired dur- ing the last trimester of pregnancy (DiGiulio et al., 2008; Goldenberg et al., 2000; Koenig et al., 2011). The existence of a fetal microbiome has clinical implications, with greater microbial diversity being associated with prema- turity (DiGiulio et al., 2008; Mshvildadze et al., 2010). Then he summa- rized recent evidence of associations between microbiome composition and two diseases prevalent among babies in neonatal intensive care units (ICUs): necrotizing enterocolitis and late-onset sepsis (Alexander et al., 2011; Mai et al., 2011). Neu also explored in more detail a topic that Lita Proctor had mentioned, that is, microbiome differences between babies born vagi- nally and babies born via C-section (Dominguez-Bello et al., 2010). The differences are important not only because of the increasing prevalence of C-section deliveries in many countries, but also because of the wide range of immune-related diseases associated with C-section delivery (Neu and Rushing, 2011). Finally, he remarked on other recent evidence indicating associations between microbial ecology in children and the onset of type 1 diabetes (Brown et al., 2011; Vaarala et al., 2008). Together, these various avenues of research suggest that the early microbiome, from fetal develop- ment through childhood, can influence both short- and long-term health. Researchers have made significant headway in understanding how the oral microbiome contributes to health and disease. Richard Darveau, pro- fessor and chair in the Department of Periodontics at the University of Washington Dental School, described evidence indicating that unlike many other human pathogens, the periopathogen Porphyromonas gingivalis trig- gers disease not by inducing inflammation but by intervening with host immunity in a more subversive manner. In fact, inflammation is a normal part of a healthy oral environment, with neutrophil movement being a sign of healthy “immune surveillance” and cytokine production contrib- uting to healthy tissue development and function (Roberts and Darveau, 2002). Eventually, over time, even a healthy mouth experiences bone loss. However, P. gingivalis accelerates the process. The bacteria interferes with i ­nnate immunity in a way that prevents the host from detecting and clearing not just P. gingivalis, but other oral microbes as well (Burns et al., 2010; Coats et al., 2005, 2007; Hajishengallis et al., 2008a,b, 2011; Liang et al.,

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6 THE HUMAN MICROBIOME, DIET, AND HEALTH 2011; Wang et al., 2010). Darveau said, “It actually takes something that is already functioning and modulates that.” Vincent Young, associate professor at the University of Michigan Medi- cal School, expanded on the theme that disease reflects an imbalance in the microbiome. Using Clostridium difficile as an example, he discussed how medical thinking around infectious disease is shifting. When he was a medical student, the paradigm revolved around finding the lone “bad bug” and the “drug for bug.” Young teaches his students to consider instead bad versus good communities of microbes. He described a series of experi- ments that he and colleagues have conducted to better understand what factors influence whether an indigenous gut microbiota resists or succumbs to C. difficile colonization and disease (Chang et al., 2008). Evidence sug- gests that C. difficile illness is a function of how resilient the indigenous microbiota is following an antibiotic assault, with some communities able to restore balance following withdrawal of the antibiotic and others not. Recurrence is also a common problem with C. difficile, with 25 percent of patients becoming sick again after ending antibiotic treatment due to continued imbalance of the gut microbiota. Restoring balance in the indig- enous microbiota—for example, by adding a “good bug” or combination of “good bugs”—could be the basis for a novel therapeutic approach to managing C. difficile disease. HOW THE MICROBIOME INFLUENCES HOST DIET METABOLISM Although research on the microbiome is considered an emerging sci- ence, scientists already have made tremendous progress in understanding the microbial makeup of the microbiome and associating microbiome diver- sity with human disease. Moreover, they are beginning to make headway in understanding how the microbiome impacts human health and disease. It is likely that much of this impact is mediated through diet. Growing evidence suggests that gut microbes influence what the human host is able to extract from its diet, including energetically. Peter Turnbaugh, Bauer fellow in the FAS Center for Systems Biology at Harvard University, summarized some of what is known about how the gut microbiome influences host energetics based on a series of mouse model studies demonstrating that gut microbes influence obesity (Backhed et al., 2004; Ley et al., 2005; Turnbaugh et al., 2006, 2008). For example, when the gut microbiota of obese mice is transplanted into germ-free mice, the mice gain more body fat compared to initially germ-free mice that receive microbiota transplants from lean mice; furthermore, the obese microbiome has been shown to extract more energy from the same amount of kilocalo- ries compared to the lean microbiome (Turnbaugh et al., 2006, 2008). Other mouse data from Turnbaugh’s lab suggest that the microbiome impacts host

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OVERVIEW 7 metabolism in other ways as well. For example, he described work done in collaboration with Lee Kaplan’s group at Massachusetts General Hospital utilizing a mouse model for gastric bypass surgery. These results highlight dramatic changes in the gut microbiota immediately following surgery. Re- searchers are now investigating which metabolic outcomes of surgery may be influenced by the gut microbiota. Indeed, a growing body of evidence suggests that the microbiome im- pacts a wide range of host metabolic pathways. Using degradation of plant chemicals as an example, Johanna Lampe, associate division director in the Public Health Sciences Division at the Fred Hutchinson Cancer Research Center, explored the many roles that microbes play in host metabolism and how those microbial contributions influence disease prevention and disease risk (Qin et al., 2010; Scalbert et al., 2011). She highlighted the gluco- sinolates (the chemical precursors to a compound in cruciferous vegetables that protects against cancer) (Li et al., 2011; Shapiro et al., 2001), soy isoflavones (which have been associated with a variety of health outcomes in perimenopausal women) (Akaza et al., 2002; Atkinson et al., 2003; Frankenfeld et al., 2004; Fuhrman et al., 2008), and plant lignins (Kuijsten et al., 2005). HOW DIET IMPACTS THE MICROBIOME As the workshop progressed, speakers explored in greater depth the impact of diet on the microbiome; how dietary influences on the micro- biome contribute to human health and disease; and ways to modulate the microbiome to build and maintain health through the use of prebiotics and probiotics in food products. Diet-related diseases have become more prominent in today’s society. For Bruce German, professor in the Department of Food Science and Tech- nology at the University of California, Davis, that raises the question: Is it possible to prevent disease through diet? German’s quest to understand the preventive potential of diet led him to “the one thing” that evolved to promote a reduction in risk: human breast milk. He described work by Carlito Lebrilla, David Mills, and others on the association between human milk oligosaccharides (HMOs) and Bifidobacterium infantis, a dominant member of the breast-fed-infant microbiome. HMOs are the third most predominant component of human breast milk (Wu et al., 2010, 2011b). Yet, they are undigestible by the infant. As it turns out, their role is to serve as a food source not for the infant, but rather for B. infantis (LoCascio et al., 2007; Marcobal et al., 2010; Sela et al., 2011; Ward et al., 2006, 2007). “The mother’s milk is providing a growth medium for the bacteria,” German said. Knowledge of the HMO-B. infantis association is also being used to explore new ways to improve the health of premature infants.

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8 THE HUMAN MICROBIOME, DIET, AND HEALTH Sharon Donovan, professor and Melissa M. Noel Endowed Chair in Nutrition and Health at the University of Illinois, is hopeful that her research on the impact of a breast milk diet on the infant microbiota will help to de- velop new ways to improve the health of formula-fed infants. She wondered whether there might be substances that could be added to infant formula to provide formula-fed infants with the same health benefits afforded by breast-feeding. Using a noninvasive stool sampling methodology, she and colleagues have detected several significant differences in gene expression between breast-fed and formula-fed infants (Chapkin et al., 2010; Davidson et al., 1995). Moreover, they have correlated some of that variation with variation in host gene expression, providing clues about how diet-modulated microbial signaling affects host biology (Schwartz et al., 2012). Although food may be the primary modulator of the microbiome, it is not the only modulator. Ellen Silbergeld, professor in epidemiology, en- vironmental health sciences, and health policy and management at Johns Hopkins University, explained that the way most food animals are raised is another major driver of the microbiome. Specifically, extensive antibiotic use in the modern livestock farm exerts a selective pressure for antibiotic resistance that spreads beyond the farm to the ecosystem at large and eventually to the human microbiome. Silbergeld introduced the notion of a “resistome,” which she defined as the collective informational re- sources available to the microbiome for responding to antimicrobial pres- sure (Wright, 2007). An important feature of the resistome is horizontal gene transfer. Because of the rapid and efficient transfer of resistance genes from one bacterium to another, even nonpathogenic (so-called commensal) bacteria can carry and express resistance genes. Thus, the microbiome is a major part of the resistome; in addition, naked DNA in ecological niches is available for internalization by competent bacteria. Silbergeld elaborated on the way the resistome expands across space—from food animals to the soil environment to the human gastrointestinal (GI) tract—and the implica- tions for human health of antibiotic resistance in bacteria carried by food animals and often transferred to food during processing (Danzeisen et al., 2011; Davis et al., 2011; Martinez, 2009; Nandi et al., 2004). PROBIOTICS AND PREBIOTICS Workshop participants considered two major categories of dietary interventions intended to confer a health benefit: probiotics and prebiot- ics. To set the stage for discussion on each category of intervention, James Versalovic, head of the Department of Pathology and director of the Texas Children’s Microbiome Center at Texas Children’s Hospital, provided an overview of probiotics and George Fahey, professor emeritus of animal sci- ences and Kraft Foods endowed professor emeritus of nutritional sciences

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OVERVIEW 9 at the University of Illinois, an overview of prebiotics. While there are sev- eral potential probiotic mechanisms of action (Neish, 2009; Saulnier et al., 2009), Versalovic elaborated on evidence showing that probiotics can either stimulate or suppress host immunity (Macaubas et al., 2003; Madara, 2004; Prescott et al., 2008; Thomas and Versalovic, 2010; Yamanaka et al., 2003). With respect to host immune suppression, he relayed how his research group made a surprising discovery: the probiotic Lactobacillus reuteri can suppress host immunity by secreting histamine (Thomas and Versalovic, 2010; Thomas et al., 2012). “But the real punch line isn’t histamine,” Versalovic said. “It’s histidine.” L. reuteri bioconverts dietary histidine into histamine. The “other part of the punch line” is that micro- bially produced histamine suppresses immunity only in the presence of an H2 receptor. In the presence of an H1 receptor, histamine stimulates im- munity. He and his team are exploring microbe-derived immunomodulatory molecules. Versalovic speculated that providing enzymatic machinery that converts dietary content into biological signals “may be how the microbi- ome is really contributing to health and physiology.” In his overview of prebiotics, Fahey summarized the major dietary sources of prebiotics and explored evidence showing how prebiotics selec- tively stimulate the growth and/or activity of bacteria that contribute to colonic and host health (Davis et al., 2010; Everard et al., 2011; Hooda et al., 2012; Martinez et al., 2010; Mussatto and Mancilha, 2007). While the effect of a prebiotic on the microbiota depends largely on the type of prebi- otic ingested and its dietary concentration, Fahey noted that a multitude of other factors affected by the prebiotic will also affect the microbiota, such as intestinal transit time and frequency of defecation. Fahey urged more research on the effect of prebiotics on microbial metabolites, not just the microbiome taxonomic composition. There are some key scientific challenges to translating probiotic science into probiotic foods, according to Mary Ellen Sanders, executive director of the International Scientific Association for Probiotics and Prebiotics, beginning with the need for a more substantial evidence base that probiotic- mediated changes in the microbiome confer health benefits on the host. That is, there is plentiful evidence that probiotics impact the microbiome and that they benefit human health, but it is not clear whether the observed human health benefits are actually mediated by the microbiome changes (Sanders, 2011). Strain specificity creates another major challenge to in- terpreting and translating research on probiotics into probiotic-containing food products, with the effectiveness of one strain not necessarily an indica- tion that other strains are equally effective (e.g., see Canani et al., 2007). Yet another challenge is difficulty in demonstrating magnitudes of effect that are meaningful and that make a probiotic intervention worth pursu- ing. Sanders speculated that the public health significance of demonstrated

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10 THE HUMAN MICROBIOME, DIET, AND HEALTH small effects may be underestimated. A final challenge discussed was the issue of mixed results from replicative studies. Sometimes, multiple studies on similar end points yield different conclusions about a probiotic’s effect. These differences may reflect individual-level variation in microbiome com- position or in activity among subjects, or that the study is underpowered (i.e., the sample size is too small to detect an effect). Added to these scien- tific challenges are regulatory challenges. Sanders expressed concern about draft guidance on when human studies require Investigational New Drug (IND) applications, suggesting that, if finalized, the guidance could have a “chilling” effect on probiotic research in humans. Experiments carried out within well-controlled laboratory or clinical settings may suggest that a particular bacterium is a highly effective pro- biotic. Yet if the activity of that probiotic is lost before it reaches a site in the human GI tract where it can exert its beneficial health effects, then that prediction falls flat. David Julian McClements, professor in the Department of Food Science at the University of Massachusetts Amherst, provided an overview of encapsulation technologies that can be used to build delivery systems for probiotics. Embedding a probiotic in some sort of solid or liquid matrix or coating it with some sort of protective layer keeps the pro- biotic safe (i.e., viable and plentiful) as it travels through the stomach and into the colon (Priya et al., 2011). While most of McClements’s research on food delivery systems is with nutraceuticals, he stated that the same systems are amenable to utilization with live bacteria. Despite the many scientific and other challenges to translating probiotic science into probiotic foods, the food industry already has seen tremendous success. Johan van Hylckama Vlieg, scientific director of gut ­ icrobiology m and probiotics at Danone Research Center, discussed how Danone is l ­everaging the microbiome for health with a specific focus on prebiotics and probiotics. He described how microbiome science provides the “rationale” for prebiotic and probiotic interventions. This rationale was illustrated with experimental results from studies on the TRUC mouse model, where the mice were fed a Bifidobacterium animalis subsp. lactis containing fer- mented milk product (FMP) (Garrett et al., 2007; Veiga et al., 2010). TRUC mice spontaneously develop gut inflammation resembling human ulcerative c ­ olitis. Studies have shown that FMPs decrease gut inflammation in TRUC mice by altering the intestinal environment in a way that inhibits the growth of colitogenic bacteria. In addition to its research on FMPs, Danone is also building a culture collection of microbes, mostly lactic acid bacteria, and identifying strain-specific genes and functions (Diancourt et al., 2007; Siezen et al., 2010), which provides an important resource for future innovation. The strain collection is part of Danone’s preparation for what van Hylckama Vlieg predicted will likely bring opportunities to the food industry in com-

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OVERVIEW 11 ing years: the demand for personalized or categorized nutrition based on individual- or group-level microbiome variations. UNDERSTANDING CONSUMER BEHAVIOR AND REGULATORY CHALLENGES Added to the many scientific challenges to realizing the potential of microbiome-targeted dietary intervention as a means to health, speakers also addressed the market and regulatory challenges to realizing that poten- tial. When probiotics were first introduced into the marketplace, consum- ers were confused, according to Darren Seifer, food and beverage industry analyst for the NPD Group. For example, according to data collected by the NPD Group, in 2006 more adults were trying to cut down on or avoid probiotics (13 percent) than to get more probiotics into their diets (10 per- cent). Although the trend has shifted, with more adults in 2010 trying to get probiotics into their diets (24 percent) than avoid them (10 percent), there is still some confusion around the word “probiotic.” “Prebiotic” is even more difficult. This confusion is just one component of the challenge of changing consumer behavior. Although changing consumer behavior around food is difficult, it can be done. Seifer summarized market research showing that consumers respond to changes that make foods easier to prepare, newness, and the idea of enhancing and not restricting one’s diet. According to Peggy Steele, global business director in the Nutrition and Health Division of DuPont, the probiotic market is one of the fastest- growing sectors in the functional food market. Yogurts account for the majority of new products (75 percent) being launched as probiotics. Over the past several years, the probiotic yogurt market has been growing at about 10 percent annually. The question is, Will that growth persist as the regulatory environment becomes more challenging to maneuver and as manufacturers and marketers are no longer able to make the same type of claims about their products that they have been able to make in the past? Steele suggested three general types of actions that industry can take to help drive continued growth in probiotics in the face of a changing regulatory landscape: (1) conduct efficacy studies to help the scientific and regulatory communities recognize the effects of probiotics on human health (e.g., Ouwehand et al., 2008); (2) educate doctors, nutritionists, key opinion leaders, and journalists to communicate the results of human studies con- ducted on probiotics; and (3) explore new end points (e.g., new health end points, effects in different populations) (e.g., Amar et al., 2011; Ibrahim et al., 2010; Makelainen et al., 2009). The changing regulatory landscape around health claims for food prod- ucts is arguably most visible in the European Union. Seppo Salminen, professor of health biosciences and director of the Functional Foods Fo-

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12 THE HUMAN MICROBIOME, DIET, AND HEALTH rum at the University of Turku in Finland, described changes that have taken place since the 2006 European Parliament passed new nutrition and health claim legislation. The new regulation creates several challenges for claim applicants, not the least of which is that evidence for an effect must be demonstrated in the generally healthy population (i.e., not a diseased population). In addition to changing the way the European Food Safety Authority (EFSA) evaluates new claims, the 2006 legislation also required EFSA to assess existing nutrition and health claims. With respect to probi- otics, this new evaluation involves identifying and characterizing the strain being used, evaluating relevant studies on the proposed health relationship, and assessing whether the proposed health relationship is something that consumers can understand. Salminen commented on the difficulty in char- acterizing many of the strains being used in currently marketed probiotic products, let alone evaluating whether the evidence supports the proposed health claims. He acknowledged the difficulty in demonstrating a health effect in a generally healthy population but suggested that in many cases, small changes to standardize approaches and outcome measurements in study design would enable researchers to collect relevant data to demon- strate health effects more clearly. In the United States, a major regulatory challenge for probiotic- containing food products is that many probiotic ingredients require U.S. Food and Drug Administration (FDA) pre-market notification. Dan Levy, microbiologist in the Division of Dietary Supplement Programs at the FDA Center for Food Safety and Applied Nutrition, described draft guidance published in July 2011 to help industry and other stakeholders understand when new dietary ingredient (NDI) notification is necessary and what those notifications should include. He described how FDA evaluates the identity and safety of live microbial ingredients using the same logic it uses to evalu- ate botanical extracts. Research on the microbiome is advancing so rapidly that it is a challenge to develop specific recommendations. The health claim regulatory landscape in the United States is gov- erned not only by FDA, but also by the Federal Trade Commission (FTC). M ­ ichelle Rusk, senior staff attorney in the Bureau of Consumer Protection at FTC, explained how FDA has primary authority for claims appearing on labeling or product packaging, while FTC has primary authority for claims appearing in advertising (with the exception of prescription drugs, over which FDA has authority over both labeling or packaging and advertising). She described the three steps involved in an FTC investigation, noting that FTC uses the same substantiation standard that FDA adopted in its draft guidance for dietary supplement claims. First, FTC examines the internal validity of the studies that support the claim. Second, it examines the con- text of the studies that the company is relying on for substantiation (e.g., Are there any inconsistencies and, if so, how are those resolved?). Third,

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OVERVIEW 13 it examines the relevance of the science to the claim being made. Rusk highlighted two recent FTC actions, one against claims made about two of Dannon’s yogurt products, the other against claims made about a Nestlé probiotic drink. She assured the workshop audience that FTC is not rais- ing its standards, but rather is trying to be more transparent and concrete so that companies know exactly what is expected in terms of compliance. Looking through the lens of DuPont, Stuart Craig, director of regula- tory and scientific affairs for DuPont Nutrition and Health, described how the changing regulatory landscape is affecting the food industry. He noted that the EFSA evaluations in particular have drawn on many of DuPont’s regulatory affairs resources in the past couple of years. The EFSA evalua- tions reflect a general global trend toward a higher scientific standard for safety and efficacy with respect to health claims on food products, but the higher standard creates a significant challenge for the food industry. Not only are human clinical studies expensive, threatening return on investment, but also it is more difficult to demonstrate health maintenance than disease intervention. Compounding the challenge is the fact that there is no global system for scientific substantiation. Different regions, sometimes different countries, operate according to their own rules and standards for scien- tific substantiation, making collaboration and comparison difficult. Craig mentioned some tools that DuPont uses when conducting its own internal scientific substantiation evaluations. Finally, Sarah Roller, partner with the law firm Kelley Drye & Warren LLP, suggested that many of the regulatory challenges addressed by work- shop speakers relate to the fact that “we are struggling to fit” an emerging science into an old legal paradigm. In the United States, the regulatory landscape for health claims on food products was codified in law in 1938, as part of the Federal Food, Drug, and Cosmetic (FD&C) Act. Added to the FD&C Act are the many other federal and, importantly, state laws that gov- ern health claims on food products. Roller explained how an FDA warning letter about a probiotic-containing food product can quickly cascade into a series of state-level actions—namely, class action lawsuits—that have a “chilling” effect not only on the truthful communication of information, but also on industry investment in products that Roller believes have “huge promise for public health.” She wondered whether the type of ecological approach that is used in environmental law might be a more useful way to think about food, health, and the microbiome. MOVING FORWARD Although research on the microbiome is still widely considered an emerging area of science, the field is progressing quickly. Researchers are making significant headway in understanding not just what the microbi-

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14 THE HUMAN MICROBIOME, DIET, AND HEALTH ome does, but how the microbiome influences human health and disease, including through its interaction with diet. What we eat and drink influ- ences the microbiome, with significant implications for human health and disease, and the microbiome in turn influences diet. All of this newfound knowledge about diet-microbiome-host dynamics is being used to develop probiotic and prebiotic food products intended 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. Dur- ing the last session of the workshop, participants debated ways to move the science forward and drive continued industry investment in microbiome- related product development. Moderator Fergus Clydesdale, distinguished university professor in the Department of Food Science at the University of Massachusetts Amherst, initiated the open discussion by observing 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 mi- crobiome (e.g., probiotics) are being studied for their potential to prevent disease, not promote health. However, current regulatory constraints on food claims prohibit communicating to consumers many of the effects that studies focused on disease prevention demonstrate. Participants debated oppor­unities for shifting the science by encouraging more research in t healthy populations versus shifting the regulatory landscape to accom- modate the science. Several suggestions were put forth for how to proceed down each path. REFERENCES Akaza, H., N. Miyanaga, N. Takashima, S. Naito, Y. Hirao, T. Tsukamoto, and M. Mori. 2002. Is daidzein non-metabolizer a high risk for prostate cancer? A case-controlled study of serum soybean isoflavone concentration. Japanese Journal of Clinical Oncology 32(8):296-300. Alexander, V. N., V. Northrup, and M. J. Bizzarro. 2011. Antibiotic exposure in the new- born intensive care unit and the risk of necrotizing enterocolitis. Journal of Pediatrics 159(3):392-397. Amar, J., C. Chabo, A. Waget, P. Klopp, C. Vachoux, L. G. Bermudez-Humaran, N. Smirnova, M. Berge, T. Sulpice, S. Lahtinen, A. Ouwehand, P. Langella, N. Rautonen, P. J. Sansonetti, and R. Burcelin. 2011. Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: Molecular mechanisms and probiotic treatment. EMBO Molecular Medicine 3(9):559-572. Arumugam, M., J. Raes, E. Pelletier, D. Le Paslier, T. Yamada, D. R. Mende, G. R. Fernandes, J. Tap, T. Bruls, J. M. Batto, M. Bertalan, N. Borruel, F. Casellas, L. ­ernandez, L. Gautier, T. Hansen, M. Hattori, T. Hayashi, M. Kleerebezem, F K. Kurokawa, M. Leclerc, F. Levenez, C. Manichanh, H. B. Nielsen, T. Nielsen, N. Pons, ­ J. Poulain, J. Qin, T. Sicheritz-Ponten, S. Tims, D. Torrents, E. Ugarte, E. G. Zoetendal, J. Wang, F. Guarner, O. Pedersen, W. M. de Vos, S. Brunak, J. Dore, H. I. T. C. Meta,

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OVERVIEW 21 Yooseph, S., G. Sutton, D. B. Rusch, A. L. Halpern, S. J. Williamson, K. Remington, J. A. Eisen, K. B. Heidelberg, G. Manning, W. Li, L. Jaroszewski, P. Cieplak, C. S. Miller, H. Li, S. T. Mashiyama, M. P. Joachimiak, C. van Belle, J. M. Chandonia, D. A. Soergel, Y. Zhai, K. Natarajan, S. Lee, B. J. Raphael, V. Bafna, R. Friedman, S. E. Brenner, A. Godzik, D. Eisenberg, J. E. Dixon, S. S. Taylor, R. L. Strausberg, M. Frazier, and J. C. Venter. 2007. The Sorcerer II Global Ocean Sampling Expedition: Expanding the uni- verse of protein families. PLoS Biology 5(3):e16.

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