Understanding immune-microbiota interactions in the intestine

Abstract

The past two decades have seen an explosion in research that aims to understand how the dynamic interplay with the gut microbiota impacts host health and disease, establishing a role for the gut microbiota in a plethora of pathologies. Understanding how health-promoting microbiota are established and how beneficial host-microbiota interactions are maintained is of immense biomedical importance. Despite the enormous progress that has been made, our knowledge of the specific microbiota members that mediate these effects and the mechanisms underlying these interactions is rudimentary. The dearth of information regarding the nature of advantageous host-microbiota interactions, and the factors that cause these relationships to go awry, has hampered our ability to realize the therapeutic potential of the microbiota. Here we discuss key issues that limit current knowledge and describe a path forwards to improving our understanding of the contributions of the microbiota to host health.

Keywords: immune homeostasis; microbiome; microbiota; mucosal immunology; tolerance.

Figure 1

Identifying immunomodulatory microbes within the gut microbiota: As depicted above, newer strategies employ intensive culturing and microbiota subsetting, and/or IgA‐based identification of immunomodulatory microbes, followed by selective reconstitution of germ‐free mice, to map phenotypes to defined microbiota components. These efforts should provide key insights into the prominent modifiers of host immune phenotypes and help to develop next‐generation probiotics that beneficially manipulate immune function.

Figure 2

Optimizing microbial communities to model microbiota–host interactions: The best source of gut microbiota to allow faithful modeling in mice of human host–microbiota interactions remains an important question. Recent work suggests that human‐derived microbiota do not fully recapitulate the immune phenotype seen using murine‐derived communities. In addition, the gut microbiota harbored by ‘wild' (feral) mice may imprint a mature immune phenotype more comparable to that of adult humans than to the immature immune system found in common laboratory mice, priming development of more activated CD8⁺ T cells and providing increased resistance to weight loss induced by treatment with azoxymethane plus dextran sodium sulfate. Identification of the mechanisms that underlie these phenomena will facilitate the development of microbial consortia that allow more accurate representation of human physiology in laboratory mice.