The healthy human microbiome

Abstract

Humans are virtually identical in their genetic makeup, yet the small differences in our DNA give rise to tremendous phenotypic diversity across the human population. By contrast, the metagenome of the human microbiome-the total DNA content of microbes inhabiting our bodies-is quite a bit more variable, with only a third of its constituent genes found in a majority of healthy individuals. Understanding this variability in the "healthy microbiome" has thus been a major challenge in microbiome research, dating back at least to the 1960s, continuing through the Human Microbiome Project and beyond. Cataloguing the necessary and sufficient sets of microbiome features that support health, and the normal ranges of these features in healthy populations, is an essential first step to identifying and correcting microbial configurations that are implicated in disease. Toward this goal, several population-scale studies have documented the ranges and diversity of both taxonomic compositions and functional potentials normally observed in the microbiomes of healthy populations, along with possible driving factors such as geography, diet, and lifestyle. Here, we review several definitions of a 'healthy microbiome' that have emerged, the current understanding of the ranges of healthy microbial diversity, and gaps such as the characterization of molecular function and the development of ecological therapies to be addressed in the future.

Fig. 1

Possible definitions of a healthy microbiome: composition, function, dynamics, and ecology. a Early definitions of a “healthy” microbiome generally focused on sets of taxa that might be expected to be found prevalently in healthy people. While purely taxonomic cores of any type have remained elusive, even in relatively narrowly defined populations, each body-site habitat possesses strong phylogenetic enrichments. Typical genera (or families in the gut) in healthy populations at different sites are shown here [, , , –35]. b Metagenomic measurements have allowed the functional potential of the microbiome at different sites to be assessed. These studies have yielded more consistently shared functional cores of body-wide and niche-specific pathways that are maintained in health [6, 7, 9, 98]. LPS lipopolysaccharide, PAMP pathogen-associated molecular pattern. c Ecological assembly patterns provide another possible definition of a healthy microbiome, because each host may draw from a “typical” meta-population of potential microbes through a mix of partially stochastic processes. These processes may include the order in which microbes colonize their respective human habitat (affected by geography and early exposures, for example), the prolonged availability of each microbe in the host’s local environment, and host selection (through diet or genetics, adapted from Fig. 1 of [101]). d The healthy microbiome can also be characterized in terms of its dynamics, depicted here in a simplified model as a conceptual energy landscape. The infant microbiome (yellow point) starts out in an unstable state and gradually descends towards one of potentially several healthy adult attractor states. Perturbations (dashed red arrows) can either be resisted (green point) or can move the microbiome out of the healthy state, after which a resilient microbiome will return to a healthy state (not necessarily the original healthy state) or fall into an unhealthy state (red)