The resilience of the intestinal microbiota influences health and disease

Journal name:
Nature Reviews Microbiology
Year published:
DOI:
doi:10.1038/nrmicro.2017.58
Published online

Abstract

The composition of the intestinal microbiota varies among individuals and throughout development, and is dependent on host and environmental factors. However, although the microbiota is constantly exposed to environmental challenges, its composition and function in an individual are stable against perturbations, as microbial communities are resilient and resistant to change. The maintenance of a beneficial microbiota requires a homeostatic equilibrium within microbial communities, and also between the microorganisms and the intestinal interface of the host. The resilience of the healthy microbiota protects us from dysbiosis-related diseases, such as inflammatory bowel disease (IBD) or metabolic disorder. By contrast, a resilient dysbiotic microbiota may cause disease. In this Opinion article, we propose that microbial resilience has a key role in health and disease. We will discuss the concepts and mechanisms of microbial resilience against dietary, antibiotic or bacteriotherapy-induced perturbations and the implications for human health.

At a glance

Figures

  1. Schematic representation of resilience phenomena in health and disease.
    Figure 1: Schematic representation of resilience phenomena in health and disease.

    a | The structure of the microbial community of an individual is established during the first months of life. During this period of time, larger fluctuations may occur and the individual is particularly vulnerable to external perturbations. Usually, an equilibrium state (stable state A) is attained in adolescence, which remains relatively stable over the lifetime of a healthy host. The depicted stability in the absence of perturbations is, in reality, also subject to constant minor fluctuations. Even in the face of catastrophic external perturbations (n perturbations), the intestinal microbiota has a remarkable ability to restore its functional state (stable state A), owing to a marked capacity for self-regeneration (the resilience phenomenon). b | Permanent shift to a detrimental equilibrium state (stable state D) termed 'dysbiosis' can occur when resilience of the original community fails. Dysbiosis represents an ill-defined loss of the typical intestinal host–microbial balance and is associated with numerous systemic and local human disorders, from chronic infections or inflammatory diseases (for example, inflammatory bowel disease) to metabolic syndrome. c | Disturbances during the vulnerable period may potentially exert long-lasting changes to the structure of the microbial ecosystem, possibly causing a predisposition to chronic disease, which manifests after a lag phase. It is conceivable that such early changes could lead to especially strong resilience of the dysbiotic communities, which would make attempts to restore a normal physiological state particularly difficult.

  2. Conceptual elements that govern the stability of the intestinal ecosystem.
    Figure 2: Conceptual elements that govern the stability of the intestinal ecosystem.

    Several principles contribute to stable ecosystem services of the intestinal ecosystem. a | The microbial community withstands an external short-term perturbation ('pulse') without any noticeable change in composition or functional genetic elements (such as a change in gene expression). This theoretical case would refer to a perfectly 'resistant' community. b | A short-term 'pulse' disturbance, such as inflammation, infection, acute diarrhoea, dietary life events or antibiotic treatment, disrupts community composition. After a lag phase or recovery, a resilient community returns to normal function and composition (stable state A). c | A long-term 'press' perturbation requires the community of microorganisms to adapt its function and can lead to the community adopting an alternative stable and beneficial state (stable state B). It can be assumed that if the selection pressure is released, the alternative state will shift to another stable equilibrium that reflects the plasticity of the ecosystem. d | Failing resilience of the initial microbial community (stable state A) facing a perturbation may also lead to an alternative stable but detrimental state ('resilient dysbiosis'; stable state D). The latitude of change describes the threshold of no return, past which the microbial community cannot return to its initial compositional state (stable state A). Precariousness is defined as the magnitude of community shift that is necessary to reach the threshold (for example, the point of no return will be easier to reach in a community that has non-redundant functions, as loss of a function cannot be compensated for). Panarchy is another important layer of resilience that is not depicted in the scheme, as it refers to the spatial and temporal organization of the microbiota, which may be very different in the gut under different conditions; for example, owing to changes in transit time.

  3. Mechanisms of resilience.
    Figure 3: Mechanisms of resilience.

    Several selection mechanisms guide the stability and resilience of microbial consortia in the intestinal habitat. This includes positive selection from the faecal stream, or by host–bacteria or bacteria–bacteria cooperation. Negative selection mechanisms comprise direct bacteria–bacteria antagonism and the context-dependent expression of antibacterial effectors by the host (for example, reactive oxygen species (ROS) and antimicrobial peptides from specialized Paneth cells). The matrix of the interaction is delivered mainly by intestinal epithelial cells, which secrete the mucus layer. Their regeneration (stem cells (blue) and proliferating zone (red)) and differentiation potential (goblet cells (grey), enterocytes (light brown) and Paneth cells (green)) influence positive and negative selection. Biological rhythms, such as nutrient intake (positive selection) and expulsion by defecation (negative selection; reduction of bacterial load), lead to physiological fluctuations in the microbial communities and are an important principle of the ecosystem.

  4. Faecal microbiota transplantation as a perturbation to a resilient dysbiotic community.
    Figure 4: Faecal microbiota transplantation as a perturbation to a resilient dysbiotic community.

    The interaction between two microbial consortia during bacteriotherapy (for example, faecal microbiota transplantation (FMT)) may be regarded as a complex pulse perturbation, which is carried out to transfer the functional properties of the donor community to a recipient host. a | Several hypothetical outcomes are possible. First, the host communities return to their initial dysbiotic state (stable state I and stable state A), as the perturbation is too weak and the transferred microorganisms do not permanently succeed. Second, owing to host intrinsic or environmental factors, the final outcome is the selection of an alternative, but still dysbiotic, state (stable state B). Although distinct in composition, the microbial community would still carry out the detrimental ecosystem service. Third, resilience of the donor community (stable state C) in the new habitat would define a new interaction with long-term transfer of the beneficial properties. b | Hierarchical level of the definition of resilience. Resilience can be defined at the species or taxonomical level. In this sense, full recovery would only be obtained if the abundance and composition of the microbiota are identical to its initial state after a perturbation. In conventional β-diversity analyses (left panel; this visualizes the similarity in the composition and abundance of species between different samples), the alternative dysbiotic state B or the eubiotic (healthy) state C would simply be recognized as two distinct distant community types. At the functional level (right panel), the communities in state B and state C are clearly separated. In turn, a functional definition of resilience could hypothetically mean complete elimination of initial bacterial taxa from the microbiota, but full recovery of biological functions and symbiotic interactions with the host. Understanding the functional elements that are necessary for stable homeostasis and correct ecosystem services will thus be important for designing rational bacteriotherapy approaches.

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Affiliations

  1. Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, Rosalind-Franklin-Straße 12, 24105 Kiel, Germany.

    • Felix Sommer,
    • Jacqueline Moltzau Anderson,
    • Richa Bharti &
    • Philip Rosenstiel
  2. Department of Microbiology and Immunology, Rega Institute, KU Leuven - University of Leuven, Leuven 3000, Belgium; at the Vlaams Instituut voor Biotechnologie (VIB), Center for Microbiology, Leuven 3000, Belgium; and at the Department of Bioengineering Sciences, Research Group of Microbiology, Vrije Universiteit Brussel, Brussels 1050, Belgium.

    • Jeroen Raes

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Author details

  • Felix Sommer

    Felix Sommer is a senior postdoctoral researcher in the laboratory of Philip Rosenstiel at the Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts University Kiel, Germany. After finishing his Ph.D. thesis in zoology and comparative immunology in the laboratory of Thomas Bosch at Christian-Albrechts University Kiel, he moved to the laboratory of Fredrik Bäckhed at the University of Gothenburg, Sweden, where he worked on the interactions between gut microorganisms, metabolism and immune responses. He subsequently moved back to Christian-Albrechts University Kiel, where he now concentrates on molecular selection mechanisms that shape the intestinal ecosystem, their contribution to host metabolism and immune responses, and on a potential exploitation as therapeutic principle.

  • Jacqueline Moltzau Anderson

    Jacqueline Moltzau Anderson is a Ph.D. student in the laboratory of Philip Rosenstiel at the Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts University Kiel, Germany, and the international Max-Planck Research School, Germany, with a specialization in microbiology. She is interested in faecal transfers and the effect of inflammatory bowel disease (IBD) risk genes on the resilience phenomenon of the gut microbiota.

  • Richa Bharti

    Richa Bharti is a Ph.D. student in the laboratory of Philip Rosenstiel at the Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts University Kiel, Germany, and has worked on the characterization of the gut microbiota in response to genotype variation. Being a bioinformatician and biostatistician by training, she is interested in longitudinal patterns in both 16S ribosomal DNA (rDNA) and ribosomal RNA (rRNA), as well as metagenomic data sets.

  • Jeroen Raes

    Jeroen Raes is a professor at Vrije Universiteit Brussel, Belgium, and a group leader at Vlaams Instituut voor Biotechnologie (VIB), Flanders, Belgium. His laboratory uses a combination of high-throughput metagenomics and computational approaches to investigate microbial ecosystems, both in environmental and human settings. An important focus of his laboratory is the study of the impaired functionality of the human microbiome to ultimately discover diagnostic markers and therapeutic principles, which can be used in microbiome-associated human diseases, such diabetes, obesity or chronic inflammatory diseases.

  • Philip Rosenstiel

    Philip Rosenstiel studied medicine in Kiel, Germany, and at Tufts University, Medford, Massachusetts, USA. During a research scholarship at the Jackson Laboratory, Bar Harbor, Maine, USA, and his doctoral thesis in the Laboratory of Jobst Sievers at Christian-Albrechts University Kiel, Germany, he worked on the effect of inflammation on neurodegenerative diseases. He received clinical training in gastroenterology and his focus since then has been on functional genomics and animal models to study host–microbiota interactions in the gut and inflammatory bowel disease. He holds a professorship in molecular medicine and is director at the Institute of Clinical Molecular Biology at the Christian-Albrechts University Kiel, Germany.

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