With this issue of The Journal of Immunology we expand our annual topical review series by introducing a smaller set of topical reviews. I am delighted to serve as the inaugural guest editor of this collection on the microbiome, featuring speakers from the IMMUNOLOGY2021tm Major Symposium “Modern World Influences on the Microbiome and Their Consequences for Immune-Mediated Diseases.”

It is increasingly clear that our microbiomes, defined as the collective genomes of the microbes (including bacteria, bacteriophage, fungi, viruses, protozoa, and helminths) that populate our bodies, profoundly influence all aspects of our physiology. Humans have coevolved with the microbes that inhabit their skin and mucosal surfaces (1). Twenty-first century human microbiomes differ substantially from those that colonized our ancestors, as demonstrated by sequence analysis of ancient paleofeces (2) or of samples collected from living indigenous populations (3). In particular, the lifestyle changes associated with industrialization, including increased sanitation, antibiotic use, consumption of processed foods, and urban living, have reduced microbial diversity and altered both community structure and function (4). Some losses may be more consequential than others; it is now clear that the depletion of microbial metabolites beneficial to host health is associated with a rapid rise in noncommunicable chronic diseases (NCCDs) (5). To stem the tide of NCCDs, we need a better understanding of how microbes, and their metabolites, influence host immunity. Much of the current literature is based on associations of bacterial taxa and disease with little evidence for causality. Because the diets and geocultural practices of human societies are highly diverse, we don’t even have a clear definition for a healthy microbiome. In keeping with the focus of The Journal of Immunology, the outstanding contributions to this special collection add to our understanding of the microbiome’s influence on immunity.

We begin our special collection with a review from Oh and Rehermann (6), who point out that standard laboratory mice are problematic for modeling human health and disease. In fact, preclinical animal studies on treatments for inflammatory diseases are often not successful in predicting clinical outcome, placing important limitations on drug development. Oh and Rehermann explain that mice from ultraclean mouse colonies, which have often been rederived specific-pathogen-free, have microbiomes that are substantially different from those found in wild-caught mice. Working directly with wild-caught mice is inherently difficult and there are, of course, many advantages to using inbred and genetically mutant mouse lines. Oh and Rehermann argue that investigators can have the best of both worlds by creating “wildling” mice through the transfer of inbred laboratory mouse embryos into pseudopregnant wild mice. Because the microbiome is vertically transmitted from the mother, the offspring inherit the wild microbiome. Shaped from birth by the wild microbiome, the immune response of the wilding mice more closely resembles that of humans in predicting the response to various anti-inflammatory drugs, emphasizing the utility of this approach for translational research (7).

Cathryn R. Nagler, Ph.D., is the Bunning Family Professor in the Biological Sciences Division and the Pritzker School of Molecular Engineering at The University of Chicago.

Cathryn R. Nagler, Ph.D., is the Bunning Family Professor in the Biological Sciences Division and the Pritzker School of Molecular Engineering at The University of Chicago.

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Next, Tan, Ramirez, and Surana (8) examine the influence of the microbiome on infectious disease from a modern-world point of view. Mechanisms by which the microbiota can modulate the response to pathogens are both direct (such as niche exclusion and production of bacteriocins) and indirect (such as secretion of metabolites and induction of antimicrobial peptides). Along with the rise in NCCDs noted above, increasing susceptibility to infectious disease is another consequence of the reduced functional diversity of the 21st century microbiota. The authors compare the commensal microbiota to a protective shroud against infection and point out that the microbiome can also influence the response to vaccination against infectious disease. One long known but poorly understood example is the comparatively poor efficacy of oral vaccines, prepared and tested in industrialized countries, in developing-world settings. The modern-world reduction in our commensal microbial shroud therefore impacts not only an effective response to pathogenic infection but also vaccine-induced protective immunity.

Klag and Round (9) then describe the mechanisms by which homeostatic immune responses in the gut mucosa shape the microbiota to regulate metabolic disease. Like other NCCDs, metabolic diseases are increasing in prevalence and can include diseases of both undernutrition and overnutrition (obesity and type 2 diabetes). Numerous studies have shown that the gut microbiota can profoundly impact both nutrient intake and energy expenditure, which, when dysregulated, can result in metabolic dysfunction. The authors argue that, in its homeostatic interactions with the microbiota, the immune system is critical to preventing metabolic dysfunction. They focus on the role of IgA. All mucosal surfaces are bathed in IgA, where it is produced at concentrations that exceed those of all the other Ig isotypes combined. The barrier protective function of IgA has been well described; more recent work suggests that IgA also plays a critical role in shaping both the composition and function of the commensal microbiota. For example, flagellin-specific IgA regulates bacterial motility; the impairment of this response in tlr5−/− mice is associated with increased inflammation and metabolic dysfunction (10, 11). Mice that bear T cells that are conditionally mutant for the TLR adaptor protein MyD88 lack T follicular helper cells critical to the formation of germinal centers in small intestinal Peyer’s patches, where much of class switching to IgA takes place. Consequently, these T-MyD88−/− mice are deficient in IgA, which normally targets components of the microbiota important for the maintenance of homeostasis. The authors propose that mucosal Abs (predominantly IgA) interact with the commensal microbiota to shape its composition. This Ab targeting regulates the microbiota’s ability to absorb nutrients and produce metabolites that control inflammation and prevent metabolic dysfunction.

Finally, Bishai and Palm (12) remind us that up to 50% of all serum metabolites are produced or modulated by commensal microbes. Rather than simply catalog known metabolites, the authors categorize the different types of interactions at the host–microbiota interface by their roles in microbial physiology. These include attainment of nutrients, detoxification, signaling (to other microbes or the host), and competition. The specific examples provided in each category emphasize both the complexity and biological importance of the metabolites described. Clearly there is much new information to be mined from the analysis of the biochemicals produced by commensal bacteria. The authors discuss both existing and emerging strategies to identify novel bioactive microbial metabolites. Comparative metabolomics can be used to link metabolites associated with a specific biological phenotype. Causality can then be demonstrated by a combination of in vitro and in vivo assays. Functional metagenomics is a high-throughput screening tool to identify bioactive clones of DNA that can be sequenced to identify the gene (or genes) producing the metabolite of interest. Finally, culture-based methodologies can be used to fractionate populations of microbes that can be screened for a bioactivity of interest. Some combination of all of these strategies will be needed to reveal the thousands of microbial metabolites yet to be discovered.

A common thread weaving through all the reviews in this collection is the translation of basic science findings into the development of microbiome modulating therapeutics. The use of “bugs as drugs” and the creation of drugs from microbial products is an area of enormous interest (13). A better understanding of how our resident microbes regulate immunity will be central to any efforts to reverse the deleterious consequences of industrialization and achieve a new normal for our 21st century microbiomes that is better adapted to protect us from both noncommunicable and infectious disease.

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