[in Japanese]

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  It has recently become apparent that obesity is associated with chronic inflammation and several common types of cancer development. Although several events were proposed to be involved in these pathologies, the precise mechanisms underlying obesity-associated inflammation and cancer largely remain unclear. Here, we show that senescence-associated secretory phenotype (SASP) plays crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of a bacterial metabolite that cause DNA damage. The enterohepatic circulation of the bacterial metabolites provokes SASP phenotype in hepatic stellate cells (HSCs), which in turn, secretes various inflammatory and tumour promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Importantly, reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer or depleted of senescent HSCs, indicating that the induction of SASP by the gut bacterial metabolite in HSCs plays key roles in obesity-associated HCC development. Interestingly, moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with nonalcoholic steatohepatitis (NASH), implying that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer.

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  The microbiota plays a fundamental role in the development and the maintenance of the host immune system. Since microbiota is important in the induction and the expansion of Th17 cells and regulatory T cells, growing evidence supports that microbiome affect the induction and the disease course of autoimmune disorders. In this review, we describe the recent studies on the involvement of microbes in animal models of autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS) using germ-free conditions, antibiotics treatment and gnotobiotic mice. Furthermore, we introduce the studies on analysis of microbiota in human autoimmune diseases including RA and MS.

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  Complex host-gut microbiota interaction is involved in the formation of a unique ecosystem in our body, the “gut ecosystem”. In order to understand the complex gut ecosystem, we propose integrated multi-omics approach, where multiple layers of unbiased cyclopedic analyses such as genomics, transcriptomics and metabolomics are combined. Applying this approach, we have revealed the mechanism that gut microbiota-derived acetate, a short-chain fatty acid, protects mice from enterohemorrhagic Escherichia coli O157-infectious death. We have also shown that butyrate produced by gut microbiota such as order Clostridiales promotes differentiation of regulatory T cells from naïve T cells in colonic lamina propria, through epigenetic modification. Epigenetic modification by butyrate also acts on colonic macrophages to confer anti-inflammatory phenotype by rendering them hyporesponsive to Toll-like receptor signaling. Short-chain fatty acids also signal via their G protein-coupled receptors. For example, it has been suggested that gut microbiota-derived short-chain fatty acids absorbed in the blood play a role in regulation of systemic inflammation by inducing apoptosis of neutrophils as well as chemotaxis of regulatory T cells.

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  Analysis of the human gut microbiome, collective genomes of over 100 trillion cells of intestinal microbes which form the complex bacterial community, has recently become more practical due to remarkable advances in next-generation sequencing technologies (NGS). Several studies using NGS-based metagenomic approaches have been conducted to comprehensively analyze genes/functions and species composition in the human gut microbiome. These NGS-based approaches have demonstrated that their ecological and biological features that have been rather difficult to pursue can now be characterized with relative ease and high-throughput. There have also been several analytical developments and improvements to accurately evaluate the microbiome data from viewpoint of biology and ecology. In addition to the impact of external factors such as diet, these NGS-based studies have strongly suggested that the human gut microbiome has profound influences on various host physiologies including disease, of which the gut microbiome exhibited ecologically and functionally aberrant structure as compared with that of healthy control. On the other hand, the detailed assessment of the effect of experimental protocols including sample storage and delivery, DNA preparation, and sequencers used on the gut microbiome structure is also necessary. I herein present the NGS-based methodology for the human gut microbiome analysis.

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  A third of world's population is invaded with Mycobacterium tuberculosis, about 9.0 million people developed tuberculosis (TB) illness and 1.3 million people died from the disease every year. Acquired immunity (cytotoxic CD8⁺ T cell, Th1 CD4⁺ helper T cell) and macrophage play important role for TB infection. Recently, natural immunity also play a very attractive role for the development TB immunity, with several cytokines, microbicidal proteins and Toll-like receptors.
  The introduction and uptake of biological disease-modifying anti-rheumatic drugs has dramatically advanced and improved the standard care and the prognosis of patients with rheumatoid arthritis (RA). However, as clinical experience with these drugs has grown, risk of granulomatous infections – especially disseminated tuberculosis in adult RA – and reactivation of hepatitis B virus (HBV) are focused. This year marks the tenth anniversary of the approvals of the first tumor necrosis factor (TNF)-alpha antagonist for the treatment of rheumatoid arthritis in Japan. Our understanding of this subject and the knowledge of basic immunology has also advanced during ten years.
  This review especially focuses on the pathologic action of the TNF blockers in the development of secondary (disseminated) tuberculosis.

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  Anticardiolipin antibodies (aCL-IgG/IgM) and anti-β₂-glycoprotein I antibodies (aβ₂GPI-IgG/IgM) are laboratory tests included in the current classification criteria for definite antiphospholipid syndrome (APS). However, not all of these assays have been commercially available in Japan. We investigated the efficacy of aCL-IgG/IgM and aβ₂GPI-IgG/IgM assays using fluorescence enzyme immunoassay (Phadia:EliA^TM) for the diagnosis of APS in Japan. This study comprised 229 sera from patients (100 with APS and 129 without APS). The diagnosis of APS was made according to Sydney revised Sapporo criteria. EliA^TMCardiolipin and EliA^TMβ₂-Glycoprotein (Phadia AB. Uppsala Sweden) were used to detect aCL IgG/M and aβ₂GPI IgG/M, respectively. Sensitivity, specificity and area under the receiver operating characteristic curve (AUC) were as follows; aCL-IgG (45%, 94%, 0.80), aCL-IgM (20%, 94%, 0.54), aβ₂GPI-IgG (33%, 98%, 0.88) and aβ₂GPI-IgM (16%, 99%, 0.64) respectively. aCL-IgM, aβ₂GPI-IgG or aβ₂GPI-IgM were detected in 10 patients (18%) with aCL-IgG negative. The use of Phadia:EliA^TMantiphospholipid antibodies assays improve the diagnostic yield of thrombotic risk in APS patients.

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