M cell maturation and cDC activation determine the onset of adaptive immune priming in the neonatal Peyer's patch.

Early-life immune development is critical to long-term host health. However, the mechanisms that determine the pace of postnatal immune maturation are not fully resolved. Here, we analyzed mononuclear phagocytes (MNPs) in small intestinal Peyer's patches (PPs), the primary inductive site of intestinal immunity. Conventional type 1 and 2 dendritic cells (cDC1 and cDC2) and RORgt+ antigen-presenting cells (RORgt+ APC) exhibited significant age-dependent changes in subset composition, tissue distribution, and reduced cell maturation, subsequently resulting in a lack in CD4+ T cell priming during the postnatal period. Microbial cues contributed but could not fully explain the discrepancies in MNP maturation. Type I interferon (IFN) accelerated MNP maturation but IFN signaling did not represent the physiological stimulus. Instead, follicle-associated epithelium (FAE) M cell differentiation was required and sufficient to drive postweaning PP MNP maturation. Together, our results highlight the role of FAE M cell differentiation and MNP maturation in postnatal immune development.

The Microbiota-Gut-Brain Axis in Health and Disease and Its Implications for Translational Research.

Over the past decades, microbiome research has evolved rapidly and became a hot topic in basic, preclinical and clinical research, for the pharmaceutical industry and for the general public. With the help of new high-throughput sequencing technologies tremendous progress has been made in the characterization of host-microbiota interactions identifying the microbiome as a major factor shaping mammalian physiology. This development also led to the discovery of the gut-brain axis as the crucial connection between gut microbiota and the nervous system. Consequently, a rapidly growing body of evidence emerged suggesting that the commensal gut microbiota plays a vital role in brain physiology. Moreover, it became evident that the communication along this microbiota-gut-brain axis is bidirectional and primarily mediated by biologically active microbial molecules and metabolites. Further, intestinal dysbiosis leading to changes in the bidirectional relationship between gut microbiota and the nervous system was linked to the pathogenesis of several psychiatric and neurological disorders. Here, we discuss the impact of the gut microbiota on the brain in health and disease, specifically as regards to neuronal homeostasis, development and normal aging as well as their role in neurological diseases of the highest socioeconomic burden such as Alzheimer's disease and stroke. Subsequently, we utilize Alzheimer's disease and stroke to examine the translational research value of current mouse models in the spotlight of microbiome research. Finally, we propose future strategies on how we could conduct translational microbiome research in the field of neuroscience that may lead to the identification of novel treatments for human diseases.

The Mammalian Metaorganism: A Holistic View on How Microbes of All Kingdoms and Niches Shape Local and Systemic Immunity.

The field of microbiome research has developed rapidly over the past decades and has become a topic of major interest to basic, preclinical, and clinical research, the pharmaceutical industry as well as the general public. The microbiome is a complex and diverse ecosystem and defined as the collection of all host-associated microorganisms and their genes. It is acquired through vertical transmission and environmental exposure and includes microbes of all kingdoms: bacteria, archaea, prokaryotic and eukaryotic viruses, fungi, protozoa, and the meiofauna. These microorganisms co-evolved with their respective hosts over millions of years, thereby establishing a mutually beneficial, symbiotic relationship on all epithelial barriers. Thus, the microbiome plays a pivotal role in virtually every aspect of mammalian physiology, particularly in the development, homeostasis, and function of the immune system. Consequently, the combination of the host genome and the microbial genome, together referred to as the metagenome, largely drives the mammalian phenotype. So far, the majority of studies have unilaterally focused on the gastrointestinal bacterial microbiota. However, recent work illustrating the impact of viruses, fungi, and protozoa on host immunity urges us towards a holistic view of the mammalian microbiome and the appreciation for its non-bacterial kingdoms. In addition, the importance of microbiota on epithelial barriers other than the gut as well as their systemic effects via microbially-derived biologically active compounds is increasingly recognized. Here, we want to provide a brief but comprehensive overview of the most important findings and the current knowledge on how microbes of all kingdoms and microbial niches shape local and systemic immunity in health and disease.