Laboratory mouse studies are paramount for understanding basic biological phenomena but also have limitations. These include conflicting results caused by divergent microbiota and limited translational research value. To address both shortcomings, we transferred C57BL/6 embryos into wild mice, creating “wildlings.” These mice have a natural microbiota and pathogens at all body sites and the tractable genetics of C57BL/6 mice. The bacterial microbiome, mycobiome, and virome of wildlings affect the immune landscape of multiple organs. Their gut microbiota outcompete laboratory microbiota and demonstrate resilience to environmental challenges. Wildlings, but not conventional laboratory mice, phenocopied human immune responses in two preclinical studies. A combined natural microbiota- and pathogen-based model may enhance the reproducibility of biomedical studies and increase the bench-to-bedside safety and success of immunological studies.

Intestinal fungi are an important component of the microbiota, and recent studies have unveiled their potential in modulating host immune homeostasis and inflammatory disease. Nonetheless, the mechanisms governing immunity to gut mycobiota remain unknown. We identified CX3CR1+ mononuclear phagocytes (MNPs) as essential for the initiation of innate and adaptive immune responses to intestinal fungi. CX3CR1+ MNPs express antifungal receptors and activate antifungal responses in a Syk dependent manner. Genetic ablation of CX3CR1+ MNPs led to changes in the gut fungal communities and to severe colitis that was rescued by antifungal treatment. A missense mutation in the gene encoding CX3CR1 led to impaired antifungal responses in Crohn’s Disease patients. These results unravel the role of CX3CR1+ MNPs as mediators of the interactions between intestinal mycobiota and host immunity during health and disease.

Fungi and mammals share a co-evolutionary history and are involved in a complex web of interactions. Studies focused on commensal bacteria suggest that pathologic changes in the microbiota, historically termed as ‘dysbiosis’, are at the root of many inflammatory diseases of non-infectious origin. Yet, the importance of dysbiosis in the fungal community— the mycobiota — was only recently acknowledged to have a pathological role as novel findings suggest that mycobiota disruption can have detrimental effects on host immunity. Fungal dysbiosis and homeostasis are dynamic processes that are probably more common than actual fungal infections, and therefore constantly shape the immune response. In this Review, we summarize specific patterns associated with fungal dysbiosis, and discuss how mucosal immunity has evolved to distinguish fungal infection from dysbiosis and how it responds to these different conditions. We propose that gut microbiota dysbiosis is a collective feature of complex interactions between prokaryotic and eukaryotic microbial communities that can affect immunity and influence health and disease.

The mammalian intestine is colonized by a wealth of microorganisms-including bacteria, viruses, protozoa, and fungi-that are all integrated into a functional trans-kingdom community. Characterization of the composition of the fungal community-the mycobiota-has advanced further than the much-needed mechanistic studies. Recent findings have revealed roles for the gut mycobiota in the regulation of host immunity and in the development and progression of human diseases of inflammatory origin. We review these findings here while placing them in the context of the current understanding of the pathways and cellular networks that induce local and systemic immune responses to fungi in the gastrointestinal tract. We discuss gaps in knowledge and argue for the importance of considering bacteria-fungal interactions as we aim to define the roles of mycobiota in immune homeostasis and immune-associated pathologies.

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Summary Sensing of the gut microbiota, including fungi, regulates mucosal immunity. Whether fungal sensing in the gut can influence immunity at other body sites is unknown. Here we show that fluconazole-induced gut fungal dysbiosis has persistent effects on allergic airway disease in a house dust mite challenge model. Mice with a defined community of bacteria, but lacking intestinal fungi were not susceptible to fluconazole-induced dysbiosis, while colonization with a fungal mixture recapitulated the detrimental effects. Gut resident mononuclear phagocytes (MNPs) expressing the fractalkine receptor CX3CR1 were essential for the effect of gut fungal dysbiosis on peripheral immunity. Depletion of CX3CR1+ MNPs or selective inhibition of Syk signaling downstream of fungal sensing in these cells ameliorated lung allergy. These results indicate that disruption of intestinal fungal communities can have persistent effects on peripheral immunity and aggravate disease severity through fungal sensing by gut resident CX3CR1+ MNPs.

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Absence of GPR4 ameliorates colitis in IBD animal models, indicating an important regulatory role in mucosal inflammation, thus providing a new link between tissue pH and the immune system. Therapeutic inhibition of GPR4 may be beneficial for the treatment of IBD.