Early life host regulation of the mammalian enteric microbiota composition

The enteric microbiota exerts a major influence on the host. It promotes food degradation, nutrient absorption, immune maturation and protects from infection with pathogenic microorganisms. However, certain compositional alterations also enhance the risk to develop metabolic, inflammatory and immune-mediated diseases. This suggests that the enteric microbiota is subject to strong evolutionary pressure. Here, we hypothesize that endogenous, genetically determined mechanisms exist that shape and optimize the enteric microbiota. We discuss that the postnatal period as the starting point of the host-microbial interaction bears the greatest chance to identify such regulatory mechanisms and report on two recently identified ways how the neonate host favours or disfavours colonization by certain bacteria and thereby manipulates the postnatally emerging bacterial ecosystem. A better understanding of these mechanisms might ultimately help to define the features of a beneficial enteric microbiota and to develop interventional strategies to overcome adverse microbiota alterations

Gut-liver axis: barriers and functional circuits

The gut and the liver are characterized by mutual interactions between both organs, the microbiome, diet and other environmental factors. The sum of these interactions is conceptualized as the gut-liver axis. In this Review we discuss the gut-liver axis, concentrating on the barriers formed by the enterohepatic tissues to restrict gut-derived microorganisms, microbial stimuli and dietary constituents. In addition, we discuss the establishment of barriers in the gut and liver during development and their cooperative function in the adult host. We detail the interplay between microbial and dietary metabolites, the intestinal epithelium, vascular endothelium, the immune system and the various host soluble factors, and how this interplay establishes a homeostatic balance in the healthy gut and liver. Finally, we highlight how this balance is disrupted in diseases of the gut and liver, outline the existing therapeutics and describe the cutting-edge discoveries that could lead to the development of novel treatment approaches.In this Review, Pabst and colleagues discuss the gut-liver axis, with an emphasis on the establishment and regulation of structural and functional barriers, dynamics within the axis (immune responses and microbiome) and clinical implications

Supplementary Material for: Interleukin-13-Mediated Paneth Cell Degranulation and Antimicrobial Peptide Release

Paneth cell-derived enteric antimicrobial peptides significantly contribute to antibacterial host defense and host-microbial homeostasis. Regulation occurs by enzymatic processing and release into the small intestinal lumen, but the stimuli involved are incompletely understood. Here, the capacity of various microbial and immune stimuli to induce antimicrobial peptide release from small intestinal tissue was systematically evaluated using antibacterial activity testing, immunostaining for Paneth cell granules and mass spectrometry<i>.</i> We confirmed the stimulatory activity of the muscarinic receptor agonist carbachol and the nucleotide-binding oligomerization domain ligand muramyl dipeptide. In contrast, no release of antibacterial activity was noted after treatment with the Toll-like receptor ligands poly(I:C), lipopolysaccharide or CpG, and the cytokines interleukin (IL)-15, IL-22, IL-28 and interferon-γ. Rapid Paneth cell degranulation and antimicrobial activity release, however, was observed after stimulation with the endogenous mediators IL-4 and IL-13. This process required phosphatidylinositol 3-kinase and was associated with protein kinase B phosphorylation in Paneth cells<i>.</i> Flow cytometric analysis confirmed expression of the IL-13 receptor α1 on isolated Paneth cells. Our findings identify a novel role of IL-13 as inducer of Paneth cell degranulation and enteric antimicrobial peptide release. IL-13 may thus contribute to mucosal antimicrobial host defense and host microbial homeostasis