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Understanding how the microbiota forms a stable, resilient state would allow strategies to be devised to increase the resilience of healthy states or decrease the resilience of unhealthy states. For example, a healthy state with a high resilience to exogenous microbes might mean one person at a dinner party escapes food poisoning but their companions with lower resilience fall ill. A degraded microbiota with high resilience can contribute to chronic diarrhoea or inflammation, as is inherent with CDAD, IBD and IBS.

Species and functional response diversity

The aspects of diversity that are crucial for conferring resilience in elton macroecosystems are probably the same features that are important in microbial ecosystems. One such parameter is the number of species present in a given system, or species richness. (In culture-independent studies, this number depends on the number of sequences collected per sample.) Species-rich communities are less susceptible to invasion because they use limiting resources more efficiently, with different species specialized to each potentially limiting resource64. An excess of nutrients in water, or eutrophication, often decreases ecosystem diversity because a small number of species overgrow and outcompete everything else, with a concomitant decrease in resilience67. In a similar way, decreased diversity has been linked to obesity and to a diet that is high in fat and sugar compared with one that is low in fat and plant-based4, 7. Whether this decrease in microbiota diversity results in a decrease in resilience is not known. Low microbiota diversity also correlates with IBD51 and recurrent CDAD49, but the effects on microbiota resilience are not known.

Functional response diversity is the degree to which species in a community that contribute to the same ecosystem function vary in their sensitivity to ecosystem changes68. High functional response diversity may, for instance, allow a species that is relatively rare but functionally similar to fill a niche when an abundant species is compromised by an environmental disturbance68. In a macroecology example, a compromised coral reef that was in a healthy state changed to an unhealthy, algal-dominated state only when both the algal-grazing fish were overfished and the sea urchins that had increased in numbers to fill this niche were compromised by a pathogen68. The same principle is also likely to apply to the gut microbiota. Following antibiotic treatment, a previously rare microbe may increase in abundance to fill a niche that had been dominated by a microbe with higher antibiotic sensitivity, leading to persistence of the same stable state but with a decreased resilience because of the decrease in functional redundancy.

Human-gut-adapted bacteria are likely to have high functional response diversity because phylogenetically disparate microbes often perform similar metabolic functions. For example, methanogenic Archaea, sulphate-reducing bacteria and phylogenetically diverse acetogens in humans and mice all consume hydrogen generated by other microbes during fermentation69. Butyrate producers of the Clostridiales order can have different ecological strategies, such as adaptation to different stages of community succession, oxygen tolerance and substrate preference. The abundance of Anaerostipes caccae peaks in infancy, whereas Eubacterium hallii and R. intestinalis are more abundant in adults. A. caccae is able to survive 10–60-minute periods of exposure to air better than E. hallii or R. intestinalis70. Furthermore, E. hallii but not F. prausnitzii can use lactate as a substrate71. Thus, butyrate production in the gut can also continue through different successional and metabolic states.

Competition and feedback loops

The densely populated gut environment means that microbes compete to use the same resources or inhibit each other directly using antimicrobial products. Phylogenetically related bacteria could be expected to compete because of their overlapping functional roles, habitats or both, yet contrary to this expectation, phylogenetically similar species tend to appear in the same samples72. For example, analysis of bacteria with complete or draft genome sequences from 124 individuals from Europe found that the abundance of related Enterobacter species, including E. coli, Salmonella enterica, Citrobacter koseri and Enterobacter cancerogenus were positively correlated across individuals53. These related species may share environmental preferences so that they are selected for simultaneously. The abundance of closely related species can also predict the susceptibility to intestinal colonization by both pathogenic and commensal bacteria in mice73.

Feedback loops can either stabilize or destabilize the microbiota (Fig. 6). Stable physiological states are preserved by negative feedback, in which a change to the gut environment results in opposing changes that maintain homeostasis. This feedback is likely to be controlled by a tight interplay between microbial metabolic activities and host pathways. For example, microbial metabolites might induce changes in the expression of the host pathways that control gut retention time so that it rises above or below the optimum, causing diarrhoea or constipation. This deviation probably induces host signalling pathways to correct it. This is similar to body temperature regulation, in which a rise above the optimum induces thermoregulatory mechanisms such as sweating, and a fall induces mechanisms such as shivering. Stabilizing the physiological parameters that are controlled by negative feedback from the host could therefore promote resilience of the microbiota.

Figure 6: Compositional transitions in the human gut microbiota.
Compositional transitions in the human gut microbiota.

Primary succession of the gut microbiota during early development involves a systematic turnover of species until a stable adult state is reached. Positive- and negative-feedback loops probably have a role in driving primary succession and in conferring resilience to healthy stable equilibrium states. Acute disturbances, such as antibiotic administration, are often followed by an unstable state that progresses to a stable state through secondary succession. In some cases, a complete recovery occurs, in which the stable state highly resembles the pre-disturbance state, but sometimes the post-recovery stable state is distinct. Post-disturbance stable states may be both degraded and resilient; for example, IBS that forms after an initial acute disturbance of the microbiota from an enteropathogen can persist in some individuals for years and even decades78. Resilience of degraded states is probably driven by unique positive- and negative-feedback loops that occur both in concert with and independently of the host. Degradation to a stable state may also occur as a result of persistent stressors, such as poor diet, that slowly degrade resilience of a healthy state until a threshold is passed so that new feedback mechanisms are needed to maintain community composition and stability. Developing therapies that encourage transition from degraded to healthy stable states, or complete recovery to a healthy stable state following disturbance, may involve identifying species or combinations of species, and drivers of feedback loops. Whether interventions are more effective early in succession, when communities are more unstable but possibly stochastic, or later in succession, when convergence to the end point is more certain but the trajectory may be more difficult to change, will be important to investigate.

Negative-feedback loops that promote microbiota resilience could also operate independently of the host. For example, if the abundance of a particular microbe exceeds a certain threshold, this would result in a change in the gut environment that would decrease the growth of that microbe relative to other species. These feedback loops may involve the accumulation of a phage specific to that microbe or the accumulation of a specific toxic metabolite. Negative feedback is thought to promote high ecosystem diversity, which can promote resilience74.

Positive feedback is thought to induce an ecosystem change because a difference from a point in one direction produces further change in the same direction. However, positive-feedback mechanisms could support stability at the individual microbe level or of the microbial consortia that promote each other's growth. Metabolic activities or interactions with host pathways in microbes may induce a physiological state that favours their growth over the growth of potential competitors, promoting resilience. The microbiota is likely to contain both important functional drivers of physiological status and microbes that co-occur with these drivers because they are able to thrive in such an environment. Invasion by microbes that do not thrive in that particular physiological state would be prevented, for example if a microbiota containing functional drivers of a low inflammatory state resists colonization by pathogens, and microbiota with functional drivers of a relatively high inflammatory state resists colonization of beneficial microbes (Fig. 6).

Positive- and negative-feedback loops are also likely to have a role in destabilizing the microbiota during regime changes, such as during succession in early development and following a disturbance (Fig. 6). Negative feedback, whereby an organism's activity alters the environment so that fitness is decreased, can induce a directional change when microbes induce a physiological state that favours their competitors. For instance, the higher redox potential in the gut of infants is probably one of the factors that explains the relative success of facultative anaerobes such as E. coli or some Lactobacillus in early development75, but the reduction of oxygen that results from their metabolism favours their eventual replacement by a consortium dominated by strict anaerobes.

The importance of feedback for successional changes is also likely to involve a complex interplay between the microbiota and its host. For example, the same change in redox potential that directly affects microbial fitness can also affect the expression of host factors in the gut epithelium, such as hypoxia-inducible factor, in early development and inflammatory diseases of the gut76. Manipulating positive and negative feedback at the level of the host, the individual microbes and the entire gut ecosystem will be essential to maintaining healthy stable states and switching from an unhealthy to a healthy state.


Source: http://www.nature.com/nature/journal/v489/n7415/full/nature11550.html


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