Recent advances in understanding how the mammalian immune system and intestinal microbiota functionally interact have yielded novel insights for human health and disease. Modern technologies to quantitatively measure specific members and functional characteristics of the microbiota in the gastrointestinal tract, along with fundamental and emerging concepts in the field of immunology, have revealed numerous ways in which host-microbiota interactions proceed beneficially, neutrally or detrimentally for mammalian hosts. It is clear that the gut microbiota has a strong influence on the shape and quality of the immune system and correspondingly, the immune system guides the composition and localization of the microbiota. In the following review, we examine the evidence that these interactions encompass homeostasis and inflammation in the intestine and, in certain cases, extraintestinal tissues. Lastly, we discuss translational therapies stemming from research on host-microbiota interactions that could be utilized for the treatment of chronic inflammatory diseases.

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Multiple Sclerosis (MS) is a complex disease of the CNS thought to require an environmental trigger. Gut dysbiosis is common in MS, but specifically causative species are unknown. To address this knowledge gap, we used sensitive and quantitative PCR detection to show that people with MS were more likely to harbor and show a greater abundance of epsilon toxin (ETX)producing strains of C. perfringens within their gut microbiomes compared to healthy controls (HC). MS patient-derived isolates produced functional ETX and had a genetic architecture typical of highly conjugative plasmids. In the active immunization model of experimental autoimmune encephalomyelitis (EAE), where pertussis toxin (PTX) is used to overcome CNS immune privilege, ETX can substitute for PTX. In contrast to PTX-induced EAE, where inflammatory demyelination is largely restricted to the spinal cord, ETX-induced EAE caused demyelination in the corpus callosum, thalamus, cerebellum, brainstem, and spinal cord, more akin to the neuroanatomical lesion distribution in MS. CNS endothelial cell transcriptional profiles revealed ETX-induced genes that are known to play a role in overcoming CNS immune privilege. Together, these findings suggest that ETX-producing C. perfringens strains are biologically plausible pathogens in MS that trigger inflammatory demyelination in the context of circulating myelin autoreactive lymphocytes.

Pro-inflammatory T cells in the central nervous system (CNS) are causally associated with multiple demyelinating and neurodegenerative diseases, but the pathways controlling these responses remain unclear. Here we define a population of group 3 innate lymphoid cells (ILC3s) that are uniquely enriched in the CNS during a mouse model of multiple sclerosis. CNS-associated ILC3s exhibit distinct transcriptional profiles, localize in proximity to infiltrating T cells, and express major histocompatibility complex class II (MHCII) and co-stimulatory molecules. Critically, antigen presentation by ILC3s was required to selectively promote pro-inflammatory T cell responses in the CNS and the development of multiple sclerosis-like disease. In contrast, antigen presenting ILC3s in the periphery lack co-stimulatory molecules and did not appear to contribute to disease induction, but rather could induce tolerance in autoimmune T cells and prevent multiple sclerosis-like disease when experimentally targeted to present myelin antigen. Collectively, our data demonstrate an essential role for CNS-associated ILC3s in promoting T cell-dependent neuroinflammation and reveal the potential to harness peripheral ILC3s for the prevention of autoimmune disease.