Establishing What Constitutes a Healthy Human Gut Microbiome: State of the Science, Regulatory Considerations, and Future Directions

Abstract

On December 17, 2018, the North American branch of the International Life Sciences Institute (ILSI North America) convened a workshop “Can We Begin to Define a Healthy Gut Microbiome Through Quantifiable Characteristics?” with >40 invited academic, government, and industry experts in Washington, DC. The workshop objectives were to 1) develop a collective expert assessment of the state of the evidence on the human gut microbiome and associated human health benefits, 2) see if there was sufficient evidence to establish measurable gut microbiome characteristics that could serve as indicators of “health,” 3) identify short- and long-term research needs to fully characterize healthy gut microbiome–host relationships, and 4) publish the findings. Conclusions were as follows: 1) mechanistic links of specific changes in gut microbiome structure with function or markers of human health are not yet established; 2) it is not established if dysbiosis is a cause, consequence, or both of changes in human gut epithelial function and disease; 3) microbiome communities are highly individualized, show a high degree of interindividual variation to perturbation, and tend to be stable over years; 4) the complexity of microbiome-host interactions requires a comprehensive, multidisciplinary research agenda to elucidate relationships between gut microbiome and host health; 5) biomarkers and/or surrogate indicators of host function and pathogenic processes based on the microbiome need to be determined and validated, along with normal ranges, using approaches similar to those used to establish biomarkers and/or surrogate indicators based on host metabolic phenotypes; 6) future studies measuring responses to an exposure or intervention need to combine validated microbiome-related biomarkers and/or surrogate indicators with multiomics characterization of the microbiome; and 7) because static genetic sampling misses important short- and long-term microbiome-related dynamic changes to host health, future studies must be powered to account for inter- and intraindividual variation and should use repeated measures within individuals.

Improving natural product research translation: From source to clinical trial

“…134,168,195,209 When known, relevant genetic variants exist, for example, in metabolism, specimens for genetic analyses should at least be collected and saved. • Age, sex, race/ethnicity, body size and composition, health status (especially with respect to outcomes of interest), co-medications, smoking, geography.…”

“…For example, taurine is an essential nutrient for cats, 135 but synthesized by humans and rodents, while ascorbic acid is essential for humans, but synthesized by most other animals. 133,134,137,138 Both background diet and bioactive NPs affect host physiology directly, as well as through modulation of the microbiota, and the microbiota in turn contribute to modulation of NP processing. 133,134,137,138 Both background diet and bioactive NPs affect host physiology directly, as well as through modulation of the microbiota, and the microbiota in turn contribute to modulation of NP processing.…”

“…Human microbiota are generally much more varied than those of lab animal models, reflective of both genetic diversity 133 and differences in past exposures. 134 Run-in periods prior to pharmacokinetic and metabolic assessments can increase the relevance of preclinical animal models to longterm dietary patterns and provide important information for comparison with post-intervention metabolite profiles. A critical consideration is that, even where preclinical in vivo studies are designed to better model (CTs), the models usually differ from humans in their greater uniformity of background diet, control of prior exposures to the relevant NP, dietary requirements, and metabolic capacities ( Table 4).…”

“…136 Human genetic differences and variations in gut microbiota cannot be considered to be independent, as both direct and indirect effects of host genetics on gastrointestinal ecology have been reported. 133,134,137,138 Both background diet and bioactive NPs affect host physiology directly, as well as through modulation of the microbiota, and the microbiota in turn contribute to modulation of NP processing. 139,140 Nonabsorbed polymeric polyphenols may, for example, modulate absorption of polyphenol monomers in humans, such that history of exposure significantly influences pharmacokinetics.…”

Diet Affects the Gastrointestinal Microbiota and Health

“…Over the past decade, projects across the globe, including the Human Microbiome Project in the United States, 24,25 the MetaHIT (Metagenomics of the Human Intestinal Tract) project in the European Union, 26 and others through the International Human Microbiome Consortium 27 set out to characterize microbiomes and pave the way for our understanding of a "healthy microbiome." Although there is still not a consensus on what constitutes a healthy microbiome, 28 we are beginning to better understand the microbial organ that is the gastrointestinal microbiome and how diet plays a key role in modulating it for human health benefit. Indeed, advances in sequencing technologies now allow us to sequence microbiomes more deeply for a fraction of the cost.…”