Causal effects of the microbiota on immune-mediated diseases

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Science Immunology  09 Feb 2018:
Vol. 3, Issue 20, eaao1603
DOI: 10.1126/sciimmunol.aao1603


  • Fig. 1 Demonstrating causality in host-microbe interactions.

    Germ-free mice colonized with specific microorganisms or microbial communities have emerged as the gold standard for demonstrating causal roles for the microbiota in shaping host physiology and disease. These approaches range from highly reductionist models, such as monocolonization, all the way to colonization with complete microbial communities from human patients. Each of these methods has particular advantages and limitations. (A) Monoassociation of germ-free animals with a single microorganism. Germ-free mice can be monocolonized with bacteria from many sources including, most commonly, isolates from human or mouse gut microbial communities. Advantages: It allows for precise interrogation of the activity of a single organism, it may reveal the functions of low-abundance organisms that are masked in the presence of a complex community, and bacterial mutants can be used to understand gene-function relationships. Limitations: It ignores the complexity of the human microbiota and the importance of microbe-microbe interactions, it is highly nonphysiological, and it is often difficult to choose proper controls for comparison. (B) HMA mice. Complete gut microbial communities obtained from individuals with a particular disease (such as IBD and Parkinson’s disease) and healthy controls can be used to colonize germ-free mice. Advantage: Conferral of a given phenotype proves microbial causation. Limitation: Xenotransplantations of microbial communities face multiple hurdles, including loss of species because of oxygen sensitivity, an inability of certain or particular human gut microbes to colonize rodent hosts, and mechanisms of host-microbe interaction that are specific to the human host. (C) Introduction of culturable isolates into germ-free mice. Recent studies have taken the HMA model one step further by colonizing germ-free mice with culturable isolates from the human gut microbiota. Advantages: It allows for determination of the effects of specific groups of microbes on the host, defined subsets of the microbiota can be assembled rationally according to phylogenetic or functional profiling and predictions, and cultured microbes can be studied in vitro and in vivo to determine mechanisms by which a given organism affects the host. Limitations: Certain gut microbes are difficult or impossible to culture in vitro, and isolate-based experiments are very low throughput due to the effort and time needed to construct culture collections. (D) Replacement of “beneficial” bacterial taxa. Conventional mice or HMA mice with dysbiosis or microbiota-driven disease are ideal tools to test the ability of beneficial species to correct dysbiosis and prevent disease. The advantages and limitations of these models are similar to those described for HMA mice and culturable isolates.

  • Fig. 2 Contribution of microbiota diversity to immune health.

    (A) Higher levels of α diversity (number of different taxa within a given microbiota) are almost invariably associated with reduced incidences of disease both within modern societies and between modern society and the developing world. (B) Potential mechanisms by which reduced microbial diversity may contribute to the development of dysbiosis and increased susceptibility to disease. Loss of balance: This model posits that the impact of the microbiota on disease depends mainly on the relative balance of inflammatory versus immunoregulatory taxa present in a given microbial community. Thus, selected loss of regulatory taxa without concomitant loss of inflammatory taxa might lead to a loss of homeostasis and increased disease development. Loss of community functions: The effects of a complex microbial community can scale owing to additive and synergistic effects, as well as emergent properties. Thus, decreases in microbial diversity may lead to erosion, or even complete loss, of specific beneficial functions of the microbiota. Mismatched niche occupancy: This model posits that particular bacterial taxa have coevolved with the host to inhabit exquisitely defined niches, where they can coexist symbiotically with the host and provide colonization resistance against neighboring species. The loss of a “niche-matched” symbiont would lead to invasion of the newly empty niche by neighboring microbes that have not evolved to occupy that niche. This mismatched niche occupancy might result in the initiation of an inappropriate and potentially pathogenic host response.

  • Fig. 3 Immunological control of microbial diversity.

    (A) Negative selection: kill the winner. Studies in macroecosystems demonstrate that predation increases biodiversity by serving to control particularly abundant and well-adapted species. Controlling population growth of these species can liberate niches and resources that allow other organisms to thrive. The immune system can control gut microbial communities via negative selection through multiple mechanisms. AMPs can mediate direct killing, and IgA can cause aggregation and elimination of specific organisms, as well as down-regulation of proteins involved in bacterial motility, invasion, or toxicity, such as flagellin. (B) Positive selection: immunoselection. The immune system might also serve to select particular organisms for residence within the gut. In addition to mediating negative selection, IgA may also help retain specific bacterial taxa by promoting retention of slow-growing species in the mucus or by enabling residence in protected niches, such as the colonic crypt. The immune system can also support survival and growth of specific taxa by inducing lumenal deposition of specific nutrients; for example, interleukin-22 (IL-22) induces epithelial fucosylation, which nourishes particular beneficial bacterial taxa.

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