BackgroundMurine models are a crucial component of gut microbiome research. Unfortunately, a multitude of genetic backgrounds and experimental setups, together with inter-individual variation, complicates cross-study comparisons and a global understanding of the mouse microbiota landscape. Here, we investigate the variability of the healthy mouse microbiota of five common lab mouse strains using 16S rDNA pyrosequencing.ResultsWe find initial evidence for richness-driven, strain-independent murine enterotypes that show a striking resemblance to those in human, and which associate with calprotectin levels, a marker for intestinal inflammation. After enterotype stratification, we find that genetic, caging and inter-individual variation contribute on average 19%, 31.7% and 45.5%, respectively, to the variance in the murine gut microbiota composition. Genetic distance correlates positively to microbiota distance, so that genetically similar strains have more similar microbiota than genetically distant ones. Specific mouse strains are enriched for specific operational taxonomic units and taxonomic groups, while the 'cage effect' can occur across mouse strain boundaries and is mainly driven by Helicobacter infections.ConclusionsThe detection of enterotypes suggests a common ecological cause, possibly low-grade inflammation that might drive differences among gut microbiota composition in mammals. Furthermore, the observed environmental and genetic effects have important consequences for experimental design in mouse microbiome research.

Matrix metalloproteinases (MMPs), originally discovered to function in the breakdown of extracellular matrix proteins, have gained the status of regulatory proteases in signaling events by liganding and processing hormones, cytokines, chemokines, adhesion molecules and other membrane receptors. However, MMPs also cleave intracellular substrates and have been demonstrated within cells in nuclear, mitochondrial, various vesicular and cytoplasmic compartments, including the cytoskeletal intracellular matrix. Unbiased high-throughput degradomics approaches have demonstrated that many intracellular proteins are cleaved by MMPs, including apoptotic regulators, signal transducers, molecular chaperones, cytoskeletal proteins, systemic autoantigens, enzymes in carbohydrate metabolism and protein biosynthesis, transcriptional and translational regulators, and proteins in charge of protein clearance such as lysosomal and ubiquitination enzymes. Besides proteolysis inside cells, intracellular proteins may also be modulated by MMPs in the extracellular milieu. Indeed, many intracellular proteins exit cells by non-classical secretion mechanisms or by various conditions of cell death by apoptosis, necrosis and NETosis, and become accessible to extracellular proteases. Intracellular substrate proteolysis by MMPs is involved in innate immune defense and apoptosis, and affects oncogenesis and pathology of cardiac, neurological, protein conformational and autoimmune diseases, including ischemia-reperfusion injury, cardiomyopathy, Parkinson's disease, cataract, multiple sclerosis and systemic lupus erythematosus. Since the same MMP may affect physiology and pathology in different and even opposite ways, depending on its extracellular or subcellular localization, an additional layer of complexity is added to therapeutic MMP inhibition. Hence, further elucidation of intracellular MMP localizations and intracellular substrate proteolysis is a new challenge in MMP research.

Matrix metalloproteinases (MMPs) constitute a family of more than 20 endopeptidases. Identification of specific matrix and non-matrix components as MMP substrates showed that, aside from their initial role as extracellular matrix modifiers, MMPs play significant roles in highly complex processes such as the regulation of cell behavior, cell-cell communication, and tumor progression. Thanks to the comprehensive examination of the expanded MMP action radius, the initial view of proteases acting in the soluble phase has evolved into a kaleidoscope of proteolytic reactions connected to the cell surface. Important classes of cell surface molecules include adhesion molecules, mediators of apoptosis, receptors, chemokines, cytokines, growth factors, proteases, intercellular junction proteins, and structural molecules. Proteolysis of cell surface proteins by MMPs may have extremely diverse biological implications, ranging from maturation and activation, to inactivation or degradation of substrates. In this way, modification of membrane-associated proteins by MMPs is crucial for communication between cells and the extracellular milieu, and determines cell fate and the integrity of tissues. Hence, insights into the processing of cell surface proteins by MMPs and the concomitant effects on physiological processes as well as on disease onset and evolution, leads the way to innovative therapeutic approaches for cancer, as well as degenerative and inflammatory diseases.

Foxp3+ regulatory T (Treg) cells are a crucial immunosuppressive population of CD4+ T cells, yet the homeostatic processes and survival programs that maintain the Treg cell pool are poorly understood. Here we report that peripheral Treg cells markedly alter their proliferative and apoptotic rates to rapidly restore numerical deficit through an interleukin 2–dependent and costimulation-dependent process. By contrast, excess Treg cells are removed by attrition, dependent on the Bim-initiated Bak- and Bax-dependent intrinsic apoptotic pathway. The antiapoptotic proteins Bcl-xL and Bcl-2 were dispensable for survival of Treg cells, whereas Mcl-1 was critical for survival of Treg cells, and the loss of this antiapoptotic protein caused fatal autoimmunity. Together, these data define the active processes by which Treg cells maintain homeostasis via critical survival pathways.