“Barriology” is newly emerging research field initially defined by The Late Prof. Shoichiro Tsukita as the science of barriers in multicellular organisms. The mucosal surface of the gastrointestinal tract is continuously exposed to a wide variety of foreign antigens. The intestinal mucosa is covered by a single layer of intestinal epithelial cells (IECs), which establish the first line of defense against these diverse microorganisms on the luminal surface. Compromised integrity of the IEC layer leads to the development of intestinal inflammation and systemic diseases. Recent studies have demonstrated the active contribution of commensal bacteria and their metabolites in the enhancement of epithelial barrier functions. In this review, we discuss the mechanisms by which the function of the barrier is being regulated and physiological significance of epithelial barriers in the gastrointestinal tract.

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Intestinal tissues establish homeostatic immune networks to prevent excessive inflammatory responses. The development and regulation of intestinal immune system are mediated at least partly by immunologic crosstalk with gut environmental factors including commensal bacteria and nutrients. Accumulating evidence has demonstrated that the inadequate immune regulation by environmental factors leads to the development of intestinal inflammation. Recent findings have revealed the specific function of vitamins in the development of intestinal inflammation. In addition, nucleotides are currently recognized as a participant in the control of inflammatory responses. In this review, we focus on the immunological functions of vitamin B9 and extracellular adenosine triphosphate (ATP) in the development of intestinal inflammation.

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Research on intestinal epithelial stem cells has flourished in the last few years since their specific markers were identified. However, to exploit the potentials of those adult stem cells as a source for regenerative medicine, validation of the tissue regeneration capability of intestinal stem cells would be essential. We have recently shown that, by employing murine models of transplantation, cultured intestinal epithelial cells from the adult colon, fetal small intestine (SI), and adult SI are able to regenerate epithelia in vivo, preserving their stem cell properties. These data provide the evidence that multiple types of intestinal cells could be the source for the stem cell therapy for intestinal diseases in humans.

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Langerhans cells (LC) are the outermost immunological sentinels of mammalian organisms and represent the unique dendritic cell subset in epidermis. LC have been the focus of vigorous research, but their physiological roles are just beginning to be elucidated. While LC are clearly potent antigen presenting cells in vitro, demonstration of in vivo functions had been challenging. This short review will summarize a series of some recent work that has uncovered the ability of LC to induce humoral responses after antigen capture via tight junctions, a process that confers systemic immunity against antigens that have not yet breached epidermal barriers. This process, which we refer to as “preemptive” immunity, might also be relevant for percutaneous sensitization in allergic skin diseases.

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The mammalian gastrointestinal tract, the site of nutrient digestion and absorption, harbors a dense microbial community. The intestinal immune system can distinguish between symbiotic bacteria and pathogens, and activates pro-inflammatory responses against pathogenic bacteria for host defense while remaining unresponsive to the beneficial microbes and dietary antigens. Abnormal activity of innate immunity, which directs the development of adaptive immunity, causes the onset and/or progression of several inflammatory diseases. Thus, activity of innate immunity is finely regulated in the gut. Inflammatory bowel disease is a chronic inflammatory disorder caused by alteration of several factors, such as host genetics, commensal bacteria and diet-derived compounds and metabolites. In intestinal mucosa, multiple innate immune cells have been identified and some populations play a crucial role in the maintenance of gut homeostasis by preventing inadequate adaptive immune responses while others are implicated in the pathogenesis of inflammatory bowel disease by driving Th1 and Th17 responses. In addition, recent studies demonstrated that dietary components and their metabolites produced by commensal bacteria contribute to the generation of a unique intestinal environment and further regulation of a variety of immune responses. Accordingly, alterations of intestinal microbial composition and perturbation of metabolites can trigger intestinal inflammation by inducing inadequate innate/adaptive immune responses.

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The naked mole-rat (NMR) is the world's longest-living rodent, with a maximum lifespan of longer than 31 years without any evidence of neoplastic disease. Recently, the NMR has come to be regarded as a useful animal model for the study of longevity and cancer resistance. Sequencing analysis of the NMR genome revealed the existence of species-specific changes in the predicted sequence of the INK4a and ARF tumor suppressors, suggesting the possibility that these two genes might have important roles in NMR's unique longevity and cancer resistance. Here, we report the molecular cloning and characterization of the INK4a and ARF genes in vitro. To investigate the expression and function of the INK4a and ARF genes in NMR, we generated several research tools, including antibodies, real-time PCR primer sets, and overexpression and knockdown vectors. Our results showed that endogenous expression of INK4a and ARF was upregulated in NMR fibroblasts treated with DNA-damaging agents or after serial passaging. In addition, overexpression of INK4a or ARF caused cell cycle arrest in both NMR fibroblasts and mouse NIH-3T3 cells. These results suggest INK4a and ARF execute a conserved function as cell cycle inhibitors in NMR. The research tools developed in the present study will be useful for exploring the specific function of INK4a and ARF genes in the unique longevity and cancer-resistant phenotype of NMRs.

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