Studies enabled by high-throughput sequencing over the past five years suggest that each individual’s microbiota has some resistance to perturbation, but that this resistance could potentially be overcome by therapies that alter the microbiota composition via diet, drugs, prebiotics or probiotics. For example, dietary changes may cause regime changes in the gut over long timescales. The surprising success of whole community transplants in healthy rats and in humans with CDAD reveals that exogenous microbes can colonize despite resistance from an entrenched microbiota. However, we do not yet understand which microbes will best colonize once introduced, or how particular microbial configurations and their functional attributes change in response to specific dietary components or exogenous microbes. Just like gardeners, we must learn what conditions promote the health of desired species and exclude undesirable weeds.
The landscape of stable states of the microbiota and its implications for resilience is an important research direction. Current evidence suggests that small perturbations, such as short-term dietary changes, may allow a return to the same state, but larger perturbations, such as antibiotic administration, may cause movement to a different state. The long-term implications for such changes for health are not yet well understood. Furthermore, perturbation of the landscape of stable equilibrium states of the gut microbiota through long-term changes, such as inflammation, diet, or repeated antibiotic administration, might make new states reachable even with smaller perturbations. Factors such as host genetics, the process of development, diet, and long-term drug administration might all contribute to differences in the landscape among individuals. Consequently, both the general landscape and the current community state may be important for determining individual responses to a given intervention.
The exhibited degree of resilience to diet, disturbances including antibiotics, and challenge with exogenous microbes has important implications for health care. The degree to which repeated applications of broad-spectrum antibiotics degrade the microbiota and its ability to provide ecosystem services needs to be studied, especially in children because early development is a crucial time for interactions between microbiota and host5
. However, the identification of suitable controls is challenging given the large intra- and interpersonal variation in the gut microbiota during early development. As indicated by studies of resilience to dietary changes, regime change is not always instigated by acute disturbances and can occur gradually. Individuals with a ‘degraded’ microbiota from long-term consumption of a high-fat/high-sugar Western diet may need long-term dietary changes to restore their microbiota to a healthy state.
The decreased taxonomic diversity of individuals in Western cultures raises concern about the maintenance of important microbial symbionts in the broader population, and whether global trends in diet can result in the permanent loss/extinction of bacterial species that can provide important health benefits. Maintaining culture collections from individuals in the developing world or specifically in agrarian cultures may help to preserve potentially important components of the microbiota.
Given that gut microbes often produce unique states in the gut through their collective activities and cooperative metabolism, it will be important to understand associations between disease states and sets of species rather than single taxa 53
. A central problem of culture-independent metagenomic analyses is that identified phylotypes (or collections of phylotypes) often represent species for which little is known biologically. Therefore, the field of gut microbial ecology has come full circle, with increasing attention being paid to developing methods for culturing the majority of diversity present in a community so that hypotheses about the contributions of community members can be further explored. Encouragingly, the human fecal microbiota is largely composed of readily cultured bacteria 77
. In vitro
experiments with these isolates will be extremely valuable for exploring specific hypotheses about the metabolic attributes of a particular microbe or set of microbes and the genes involved. However, because microbiota composition and function are also controlled by feedbacks from the host, in vivo
studies in gnotobiotic mice will be particularly valuable. Indeed, the culturable component of the microbiota exhibits similar colonization dynamics, biogeographical distribution, and responses to dietary perturbations compared to the full microbiota when transplanted into gnotobiotic mice77
. A translational science pipeline is thus developing where particular phylotypes and interactions between phylotypes that are important for health and/or that contribute to disease can first be identified based on distribution patterns with disease. Furthermore, biological attributes that may be driving these patterns can be predicted based on the expression or prevalence of functional genes in whole communities and in genomes. These specific hypotheses can then be tested and verified in culture and in animal models before application to humans. Tools for this pipeline are now in place. Although the path ahead will be difficult, the direction is becoming clearer.