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Papers - Hase, Koji

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Effect of polyvinyl butyrate nanoparticles incorporated with immune suppressing vitamins on alteration of population of intestinal immune cells

Mu Y., Kinashi Y., Kishimura A., Mori T., Hase K., Katayama Y.

Progress in Natural Science: Materials International (Progress in Natural Science: Materials International) 30 ( 5 ) 707 - 710 2020.10

ISSN 10020071

© 2020 Chinese Materials Research Society The nanoparticles (NPs) from polyvinyl butyrate (PVBu) which can work as an orally applicable donor of butyrate for intestine were prepared. Immunotolerance inducing molecules such as vitamin D3 and all-trans retinoic acid (ATRA) were incorporated into PVBu NPs. The alteration in populations and numbers of DC103+ dendritic cells (DC) and regulatory T (Treg) cells in intestinal immune tissues were examined after oral administration of NPs. It was found that NPs reduced the population of CD103+ DC and Treg cells in Peyer's patched in lower part of the intestine and inversely increased the population of CD103+ DC in mesenteric lymph node (MLN), while the population of Treg cells in MLN was unchanged. These observations indicate that NPs may enhance the immunotolerance at MLN and lamina propria toward luminal antigens, indicating the promising features of PVBu NPs as therapeutics of allergy and autoimmune diseases.

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Microbiota-derived butyrate limits the autoimmune response by promoting the differentiation of follicular regulatory T cells

Takahashi D, Hoshina N, Kabumoto Y, Maeda Y, Suzuki A, Tanabe H, Isobe J, Yamada T, Muroi K, Yanagisawa Y, Nakamura A, Fujimura Y, Saeki A, Ueda M, Matsumoto R, Asaoka H, Clarke JM, Harada Y, Umemoto E, Komatsu N, Okada T, Takayanagi H, Takeda K, Tomura M, Hase K.

EBioMedicine (EBioMedicine) 58 102913 2020.08

Research paper (scientific journal), Joint Work, Accepted

© 2020 The Author(s) Background: Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder with a high prevalence, especially in industrialized countries. Dysbiosis of the intestinal microbiota has been observed in RA patients. For instance, new-onset untreated RA (NORA) is associated with the underrepresentation of the Clostridium cluster XIVa, including Lachnospiraceae, which are major butyrate producers, although the pathological relevance has remained obscure. Follicular regulatory T (TFR) cells play critical regulatory roles in the pathogenesis of autoimmune diseases, including RA. Reduced number of circulating TFR cells has been associated with the elevation of autoantibodies and disease severity in RA. However, the contribution of commensal microbe-derived butyrate in controlling TFR cell differentiation remains unknown. Methods: We examined the contribution of microbe-derived butyrate in controlling autoimmune arthritis using collagen-induced arthritis (CIA) and SKG arthritis models. We phenotyped autoimmune responses in the gut-associated lymphoid tissues (GALT) in the colon and joint-draining lymph nodes in the CIA model. We developed an in vitro CXCR5+Bcl-6+Foxp3+ TFR (iTFR) cell culture system and examined whether butyrate promotes the differentiation of iTFR cells. Findings: Microbe-derived butyrate suppressed the development of autoimmune arthritis. The immunization of type II collagen (CII) caused hypertrophy of the GALT in the colon by amplifying the GC reaction prior to the onset of the CIA. Butyrate mitigated these pathological events by promoting TFR cell differentiation. Butyrate directly induced the differentiation of functional TFR cells in vitro by enhancing histone acetylation in TFR cell marker genes. This effect was attributed to histone deacetylase (HDAC) inhibition by butyrate, leading to histone hyperacetylation in the promoter region of the TFR-cell marker genes. The adoptive transfer of the butyrate-treated iTFR cells reduced CII-specific autoantibody production and thus ameliorated the symptoms of arthritis. Interpretation: Accordingly, microbiota-derived butyrate serves as an environmental cue to enhance TFR cells, which suppress autoantibody production in the systemic lymphoid tissue, eventually ameliorating RA. Our findings provide mechanistic insights into the link between the gut environment and RA risk. Funding: This work was supported by AMED-Crest (16gm1010004h0101, 17gm1010004h0102, 18gm1010004h0103, and 19gm1010004s0104 to KH), the Japan Society for the Promotion of Science (JP17KT0055, JP16H01369, and JP18H04680 to KH; JP17K15734 to DT), Keio University Special Grant-in-Aid for Innovative Collaborative Research Projects (KH), Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research (DT), the SECOM Science and Technology Foundation (KH), the Cell Science Research Foundation (KH), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (DT), the Suzuken Memorial Foundation (KH and DT), the Takeda Science Foundation (KH and DT), The Science Research Promotion Fund, and The Promotion and Mutual Aid Corporation for Private Schools of Japan (KH).

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Protection of gut microbiome from antibiotics: Development of a vancomycin-specific adsorbent with high adsorption capacity

Yuzuriha K., Yakabe K., Nagai H., Li S., Zendo T., Zai K., Kishimura A., Hase K., Kim Y.G., Mori T., Katayama Y.

Bioscience of Microbiota, Food and Health (Bioscience of Microbiota, Food and Health) 39 ( 3 ) 128 - 136 2020.02

Research paper (scientific journal), Joint Work, ISSN 21866953

The fraction of administered antibiotics that reach the cecum and colon causes dysbiosis of the gut microbiome, resulting in various diseases. Protection of the gut microbiome from antibiotics using antibiotic adsorbents in the cecum and colon is a promising method to overcome this issue. Previously, activated charcoal (AC) has been reported to protect the gut microbiome of host animals. AC is an adsorbent that is widely used to capture toxic compounds and overdosed drugs in the gastrointestinal tract. The specificity of adsorbents for antibiotics is critical to avoid the risk of unexpected side effects caused by nonspecific adsorption of biological compounds in the intestinal fluid, such as bile acids and essential micronutrients. Here, we have developed specific adsorbents for vancomycin (VCM), which is known to cause gut dysbiosis. The adsorbents were composed of polyethyleneglycolbased microparticles (MPs) in which a specific ligand for VCM, D-Ala-D-Ala-OH, was attached via dendrons of D-lysine to raise the content of the ligand in the MPs. The MPs successfully protected Staphylococcus lentus from VCM in vitro because of the adsorption of VCM in the culture media. Pre-administration of MPs to mice reduced the amount of free VCM in the feces to an undetectable level. This treatment minimized the effect of VCM on gut microbiota and provided protection against Clostridioides difficile infection after oral challenge with spores.

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Maternal gut microbiota in pregnancy influences offspring metabolic phenotype

*Kimura I, Miyamoto J, Ohue-Kitano R, Watanabe K, Yamada T, Onuki M, Aoki R, Isobe Y, Kashihara D, Inoue D, Inaba A, Takamura Y, Taira S, Kumaki S, Watanabe M, Ito M, Nakagawa F, Irie J, Kakuta H, Shinohara M, Iwatsuki K, Tsujimoto G, Ohno H, Arita M, Itoh H, and *Hase K

Science (Science) 367 ( 6481 ) eaaw8429 2020.02

Research paper (scientific journal), Accepted, ISSN 00368075

Antibiotics and dietary habits can affect the gut microbial community, thus influencing disease susceptibility. Although the effect of microbiota on the postnatal environment has been well documented, much less is known regarding the impact of gut microbiota at the embryonic stage. Here we show that maternal microbiota shapes the metabolic system of offspring in mice. During pregnancy, short-chain fatty acids produced by the maternal microbiota dictate the differentiation of neural, intestinal, and pancreatic cells through embryonic GPR41 and GPR43. This developmental process helps maintain postnatal energy homeostasis, as evidenced by the fact that offspring from germ-free mothers are highly susceptible to metabolic syndrome, even when reared under conventional conditions. Thus, our findings elaborate on a link between the maternal gut environment and the developmental origin of metabolic syndrome.

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Microfold cell-dependent antigen transport alleviates infectious colitis by inducing antigen-specific cellular immunity

Nakamura Y., Mimuro H., Kunisawa J., Furusawa Y., Takahashi D., Fujimura Y., Kaisho T., Kiyono H., Hase K.

Mucosal Immunology (Mucosal Immunology) 13 ( 4 ) 679 - 690 2020.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 19330219

Infectious colitis is one of the most common health issues worldwide. Microfold (M) cells actively transport luminal antigens to gut-associated lymphoid tissue to induce IgA responses; however, it remains unknown whether M cells contribute to the induction of cellular immune responses. Here we report that M cell-dependent antigen transport plays a critical role in the induction of Th1, Th17, and Th22 responses against gut commensals in the steady state. The establishment of commensal-specific cellular immunity was a prerequisite for preventing bacterial dissemination during enteropathogenic Citrobacter rodentium infection. Therefore, M cell-null mice developed severe colitis with increased bacterial dissemination. This abnormality was associated with mucosal barrier dysfunction. These observations suggest that antigen transport by M cells may help maintain gut immune homeostasis by eliciting antigen-specific cellular immune responses.

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Osteoprotegerin-dependent M-cell self-regulation balances gut infection and immunity.

1 Kimura S*, Nakamura Y, Kobayashi N, Shiroguchi N, Kawakami E, Mutoh M, Takahashi-Iwanaga H, Yamada T, Hisamoto M, Nakamura M, Udagawa N, Sato S, Kaisho T, Iwanaga T, and Hase K

Nature Commun. (Nature Communications) in press ( 1 ) 2020.01

Research paper (scientific journal), Joint Work, Accepted

© 2020, The Author(s). Microfold cells (M cells) are responsible for antigen uptake to initiate immune responses in the gut-associated lymphoid tissue (GALT). Receptor activator of nuclear factor-κB ligand (RANKL) is essential for M cell differentiation. Follicle-associated epithelium (FAE) covers the GALT and is continuously exposed to RANKL from stromal cells underneath the FAE, yet only a subset of FAE cells undergoes differentiation into M cells. Here, we show that M cells express osteoprotegerin (OPG), a soluble inhibitor of RANKL, which suppresses the differentiation of adjacent FAE cells into M cells. Notably, OPG deficiency increases M cell number in the GALT and enhances commensal bacterium-specific immunoglobulin production, resulting in the amelioration of disease symptoms in mice with experimental colitis. By contrast, OPG-deficient mice are highly susceptible to Salmonella infection. Thus, OPG-dependent self-regulation of M cell differentiation is essential for the balance between the infectious risk and the ability to perform immunosurveillance at the mucosal surface.

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Commensal-bacteria-derived butyrate promotes the T cell-independent IgA response in the colon.

4 Isobe J, Maeda S, Obata Y, Iizuka K, Nakamura Y, Fujimura Y, Kimizuka T, Hattori K, Kim YG, Morita T, Kimura I, Offermanns S, Adachi T, Nakao A, Kiyono H, *Takahashi D, *Hase K.

Int. Immunol (International Immunology) 32 ( 4 ) 243 - 258 2019.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 09538178

© 2020 Oxford University Press. All rights reserved. Secretory immunoglobulin A (SIgA), the most abundant antibody isotype in the body, maintains a mutual relationship with commensal bacteria and acts as a primary barrier at the mucosal surface. Colonization by commensal bacteria induces an IgA response, at least partly through a T-cell-independent process. However, the mechanism underlying the commensal-bacteria-induced T-cell-independent IgA response has yet to be fully clarified. Here, we show that commensalbacteria-derived butyrate promotes T-cell-independent IgA class switching recombination (CSR) in the mouse colon. Notably, the butyrate concentration in human stools correlated positively with the amount of IgA. Butyrate up-regulated the production of transforming growth factor β1 and all-trans retinoic acid by CD103+CD11b+ dendritic cells, both of which are critical for T-cell-independent IgA CSR. This effect was mediated by G-protein-coupled receptor 41 (GPR41/FFA3) and GPR109a/HCA2, and the inhibition of histone deacetylase. The butyrate-induced IgA response reinforced the colonic barrier function, preventing systemic bacterial dissemination under inflammatory conditions. These observations demonstrate that commensal-bacteria-derived butyrate contributes to the maintenance of the gut immune homeostasis by facilitating the T-cell-independent IgA response in the colon.

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Immunological Consequences of Antigen Sampling at Mucosal Surfaces

Mabbott NA and Hase K

Front. Immuol. 10 2773 2019.11

Research paper (scientific journal), Joint Work

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The Roles of Peyer's Patches and Microfold Cells in the Gut Immune System: Relevance to Autoimmune Diseases

Kobayashi N., Takahashi D., Takano S., Kimura S., Hase K.

Frontiers in Immunology (Frontiers in Immunology) 10 2345 2019.10

Research paper (scientific journal), Joint Work, Accepted

Microfold (M) cells are located in the epithelium covering mucosa-associated lymphoid tissues, such as the Peyer's patches (PPs) of the small intestine. M cells actively transport luminal antigens to the underlying lymphoid follicles to initiate an immune response. The molecular machinery of M-cell differentiation and function has been vigorously investigated over the last decade. Studies have shed light on the role of M cells in the mucosal immune system and have revealed that antigen uptake by M cells contributes to not only mucosal but also systemic immune responses. However, M-cell studies usually focus on infectious diseases; the contribution of M cells to autoimmune diseases has remained largely unexplored. Accumulating evidence suggests that dysbiosis of the intestinal microbiota is implicated in multiple systemic diseases, including autoimmune diseases. This implies that the uptake of microorganisms by M cells in PPs may play a role in the pathogenesis of autoimmune diseases. We provide an outline of the current understanding of M-cell biology and subsequently discuss the potential contribution of M cells and PPs to the induction of systemic autoimmunity, beyond the mucosal immune response.

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Fasting-Refeeding Impacts Immune Cell Dynamics and Mucosal Immune Responses

Nagai M., Noguchi R., Takahashi D., Morikawa T., Koshida K., Komiyama S., Ishihara N., Yamada T., Kawamura Y., Muroi K., Hattori K., Kobayashi N., Fujimura Y., Hirota M., Matsumoto R., Aoki R., Tamura-Nakano M., Sugiyama M., Katakai T., Sato S., Takubo K., Dohi T., Hase K.

Cell (Cell) 178 ( 5 ) 1072 - 1087.e14 2019.08

ISSN 00928674

© 2019 Elsevier Inc. Nutritional status potentially influences immune responses; however, how nutritional signals regulate cellular dynamics and functionality remains obscure. Herein, we report that temporary fasting drastically reduces the number of lymphocytes by ∼50% in Peyer's patches (PPs), the inductive site of the gut immune response. Subsequent refeeding seemingly restored the number of lymphocytes, but whose cellular composition was conspicuously altered. A large portion of germinal center and IgA+ B cells were lost via apoptosis during fasting. Meanwhile, naive B cells migrated from PPs to the bone marrow during fasting and then back to PPs during refeeding when stromal cells sensed nutritional signals and upregulated CXCL13 expression to recruit naive B cells. Furthermore, temporal fasting before oral immunization with ovalbumin abolished the induction of antigen-specific IgA, failed to induce oral tolerance, and eventually exacerbated food antigen-induced diarrhea. Thus, nutritional signals are critical in maintaining gut immune homeostasis. Temporary fasting drastically reduces the levels of B cells in Peyer's patches, with germinal center B cells undergoing apoptosis and naive cells migrating to the bone marrow and only egressing upon refeeding.

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Mast cells play role in wound healing through the ZnT2/GPR39/IL-6 axis

Nishida K., Hasegawa A., Yamasaki S., Uchida R., Ohashi W., Kurashima Y., Kunisawa J., Kimura S., Iwanaga T., Watarai H., Hase K., Ogura H., Nakayama M., Kashiwakura J., Okayama Y., Kubo M., Ohara O., Kiyono H., Koseki H., Murakami M., Hirano T.

Sci. Rep. (Scientific Reports) 9 ( 1 ) 10842 2019.07

Research paper (scientific journal), Joint Work, Accepted

The Author(s). Zinc (Zn) is an essential nutrient and its deficiency causes immunodeficiency and skin disorders. Various cells including mast cells release Zn-containing granules when activated; however, the biological role of the released Zn is currently unclear. Here we report our findings that Zn transporter ZnT2 is required for the release of Zn from mast cells. In addition, we found that Zn and mast cells induce IL-6 production from inflammatory cells such as skin fibroblasts and promote wound healing, a process that involves inflammation. Zn induces the production of a variety of pro-inflammatory cytokines including IL-6 through signaling pathways mediated by the Zn receptor GPR39. Consistent with these findings, wound healing was impaired in mice lacking IL-6 or GPR39. Thus, our results show that Zn and mast cells play a critical role in wound healing through activation of the GPR39/IL-6 signaling axis.

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Sox8 is essential for M-cell maturation to accelerate IgA response at the early stage after weaning in mice

Kimura S, Kobayashi N, Nakamura Y, Kanaya T, Takahashi D, Fujiki R, Mutoh M, Obata Y, Iwanaga T, Nakagawa T, Kato N, Sato S, Kaisho T, Ohno H, and *HASE Koji

J. Exp. Med. 216 ( 4 ) 831 - 846 2019.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 00221007

Microfold (M) cells residing in the follicle-associated epithelium (FAE) of the gut-associated lymphoid tissue are specialized for antigen uptake to initiate mucosal immune responses. The molecular machinery and biological significance of M cell differentiation, however, remain to be fully elucidated. Here, we demonstrate that Sox8, a member of the SRY-related HMG box transcription factor family, is specifically expressed by M cells in the intestinal epithelium. The expression of Sox8 requires activation of RANKL-RelB signaling. Chromatin immunoprecipitation and luciferase assays revealed that Sox8 directly binds the promoter region of Gp2 to increase Gp2 expression, which is the hallmark of functionally mature M cells.Furthermore, genetic deletion of Sox8 causes a marked decrease in the number of mature M cells, resulting in reduced antigen uptake in Peyer's patches. Consequently, juvenile Sox8-deficient mice showed attenuated germinal center reactions and antigen-specific IgA responses. These findings indicate that Sox8 plays an essential role in the development of M cells to establish mucosal immune responses.

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MZB1 promotes the secretion of J-chain–containing dimeric IgA and is critical for the suppression of gut inflammation

Xiong E., Li Y., Min Q., Cui C., Liu J., Hong R., Lai N., Wang Y., Sun J., Matsumoto R., Takahashi D., Hase K., Shinkura R., Tsubata T., Wang J.

Proceedings of the National Academy of Sciences of the United States of America (Proceedings of the National Academy of Sciences of the United States of America) 116 ( 27 ) 13480 - 13489 2019

ISSN 00278424

© 2019 National Academy of Sciences. All rights reserved. IgA is the most abundantly produced antibody in the body and plays a crucial role in gut homeostasis and mucosal immunity. IgA forms a dimer that covalently associates with the joining (J) chain, which is essential for IgA transport into the mucosa. Here, we demonstrate that the marginal zone B and B-1 cell-specific protein (MZB1) interacts with IgA through the α-heavy-chain tailpiece dependent on the penultimate cysteine residue and prevents the intracellular degradation of α-light-chain complexes. Moreover, MZB1 promotes J-chain binding to IgA and the secretion of dimeric IgA. MZB1-deficient mice are impaired in secreting large amounts of IgA into the gut in response to acute inflammation and develop severe colitis. Oral administration of a monoclonal IgA significantly ameliorated the colitis, accompanied by normalization of the gut microbiota composition. The present study identifies a molecular chaperone that promotes J-chain binding to IgA and reveals an important mechanism that controls the quantity, quality, and function of IgA.

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Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasis

Yamada T., Hino S., Iijima H., Genda T., Aoki R., Nagata R., Han K., Hirota M., Kinashi Y., Oguchi H., Suda W., Furusawa Y., Fujimura Y., Kunisawa J., Hattori M., Fukushima M., Morita T., Hase K.

EBioMedicine (EBioMedicine) 48 513 - 525 2019

© 2019 Background: The dysbiosis of gut microbiota has been implicated in the pathogenesis of inflammatory bowel diseases; however, the underlying mechanisms have not yet been elucidated. Heavily glycosylated mucin establishes a first-line barrier against pathogens and serves as a niche for microbial growth. Methods: To elucidate relationships among dysbiosis, abnormal mucin utilisation, and microbial metabolic dysfunction, we analysed short-chain fatty acids (SCFAs) and mucin components in stool samples of 40 healthy subjects, 49 ulcerative colitis (UC) patients, and 44 Crohn's disease (CD) patients from Japan. Findings: Levels of n-butyrate were significantly lower in stools of both CD and UC patients than in stools of healthy subjects. Correlation analysis identified seven bacterial species positively correlated with n-butyrate levels; the major n-butyrate producer, Faecalibacterium prausnitzii, was particularly underrepresented in CD patients, but not in UC patients. In UC patients, there were inverse correlations between mucin O-glycan levels and the production of SCFAs, such as n-butyrate, suggesting that mucin O-glycans serve as an endogenous fermentation substrate for n-butyrate production. Indeed, mucin-fed rodents exhibited enhanced n-butyrate production, leading to the expansion of RORgt+Treg cells and IgA-producing cells in colonic lamina propria. Microbial utilisation of mucin-associated O-glycans was significantly reduced in n-butyrate-deficient UC patients. Interpretation: Mucin O-glycans facilitate symbiosynthesis of n-butyrate by gut microbiota. Abnormal mucin utilisation may lead to reduced n-butyrate production in UC patients. Fund: Japan Society for the Promotion of Science, Health Labour Sciences Research Grant, AMED-Crest, AMED, Yakult Foundation, Keio Gijuku Academic Development Funds, The Aashi Grass Foundation, and The Canon Foundation.

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Maintenance of Intestinal Epithelial Homeostasis by Zinc Transporters

Ohashi W., Hara T., Takagishi T., Hase K., Fukada T.

Digestive Diseases and Sciences (Digestive Diseases and Sciences) 64 ( 9 ) 2404 - 2415 2019

ISSN 01632116

© 2019, Springer Science+Business Media, LLC, part of Springer Nature. Zinc is an essential micronutrient for normal organ function, and dysregulation of zinc metabolism has been implicated in a wide range of diseases. Emerging evidence has revealed that zinc transporters play diverse roles in cellular homeostasis and function by regulating zinc trafficking via organelles or the plasma membrane. In the gastrointestinal tract, zinc deficiency leads to diarrhea and dysfunction of intestinal epithelial cells. Studies also showed that zinc transporters are very important in intestinal epithelial homeostasis. In this review, we describe the physiological roles of zinc transporters in intestinal epithelial functions and relevance of zinc transporters in gastrointestinal diseases.

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Airway M Cells arise in the lower airway due to RANKL signaling and reside in the bronchiolar epithelium associated with iBALT in murine models of respiratory disease

Kimura S., Mutoh M., Hisamoto M., Saito H., Takahashi S., Asakura T., Ishii M., Nakamura Y., Iida J., Hase K., Iwanaga T.

Frontiers in Immunology (Frontiers in Immunology) 10 ( JUN ) 2019

© 2019 Kimura, Mutoh, Hisamoto, Saito, Takahashi, Asakura, Ishii, Nakamura, Iida, Hase and Iwanaga. Microfold (M) cells residing in the follicle-associated epithelium of mucosa-associated lymphoid tissues are specialized for sampling luminal antigens to initiate mucosal immune responses. In the past decade, glycoprotein 2 (GP2) and Tnfaip2 were identified as reliable markers for M cells in the Peyer's patches of the intestine. Furthermore, RANKL-RANK signaling, as well as the canonical and non-canonical NFκB pathways downstream, is essential for M-cell differentiation from the intestinal stem cells. However, the molecular characterization and differentiation mechanisms of M cells in the lower respiratory tract, where organized lymphoid tissues exist rarely, remain to be fully elucidated. Therefore, this study aimed to explore M cells in the lower respiratory tract in terms of their specific molecular markers, differentiation mechanism, and functions. Immunofluorescence analysis revealed a small number of M cells expressing GP2, Tnfaip2, and RANK is present in the lower respiratory tract of healthy mice. The intraperitoneal administration of RANKL in mice effectively induced M cells, which have a high capacity to take up luminal substrates, in the lower respiratory epithelium. The airway M cells associated with lymphoid follicles were frequently detected in the pathologically induced bronchus-associated lymphoid tissue (iBALT) in the murine models of autoimmune disease as well as pulmonary emphysema. These findings demonstrate that RANKL is a common inducer of M cells in the airway and digestive tracts and that M cells are associated with the respiratory disease. We also established a two-dimensional culture method for airway M cells from the tracheal epithelium in the presence of RANKL successfully. This model may be useful for functional studies of M cells in the sampling of antigens at airway mucosal surfaces.

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A partial agonist for retinoid X receptor mitigates experimental colitis.

Onuki M, Watanabe M, Ishihara N, Suzuki K, Takizawa K, Hirota M, Yamada T, Egawa A, Shibahara O, Nishii M, Fujihara M, Makishima M, Takahashi D, Furusawa Y, Kakuta H, HASE K

Int. Immunol. (International Immunology) [Epub ahead of print] ( 4 ) 251 - 262 2018.12

Joint Work, Accepted, ISSN 09538178

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is an intractable disease of the gastrointestinal tract. Multiple environmental factors, including food ingredients, have been implicated in the development of these diseases. For example, animal fat-rich diets are predisposing factors for ulcerative colitis, whereas n-3 unsaturated fatty acids such as docosahexaenoic acid (DHA) show protective effects in experimental colitis and are negatively correlated with the incidence of ulcerative colitis and Crohn's disease. Given that DHA exhibits agonistic activity on retinoid X receptor (RXR), activation of RXR could be a therapeutic strategy for IBD. However, conventional full RXR agonists are known to show considerable adverse effects. We therefore took advantage of a partial RXR agonist, CBt-PMN, to minimize the adverse effects, and evaluated its efficacy in dextran sodium sulfate-induced colitis. Administration of CBt-PMN efficiently ameliorated the symptoms of colitis. This effect was attributed to the down-regulation of pro-inflammatory cytokines such as TNF and Il6 in colon-infiltrating monocytes. Down-regulation of pro-inflammatory cytokines by CBt-PMN was also evident in lipopolysaccharide-stimulated bone marrow-derived macrophages (BMDMs). Among many RXR-associated nuclear receptors, activation of peroxisome proliferator-activated receptor δ(PPARd) and nuclear hormone receptor 77 (Nur77) suppressed cytokine production by BMDMs. These observations suggest that the activation of PPARδ/RXR and Nur77/RXR heterodimers by CBt-PMN through the permissive mechanism is responsible for diminishing the monocyte-mediated inflammatory response in the gut. Our data highlight the importance of RXR activation in the regulation of colitis.

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Oral Administration of Porphyromonas gingivalis Alters the Gut Microbiome and Serum Metabolome

Kato T, Yamazaki K, Nakajima M, Date Y, Kikuchi J, HASE K, Ohno H, Yamazaki K.

mSphere (mSphere) 3 ( 5 ) e00460-18 2018.10

Research paper (scientific journal), Joint Work, Accepted

© 2018 Kato et al. Periodontal disease induced by periodontopathic bacteria like Porphyromonas gingivalis is demonstrated to increase the risk of metabolic, inflammatory, and autoimmune disorders. Although precise mechanisms for this connection have not been elucidated, we have proposed mechanisms by which orally administered periodontopathic bacteria might induce changes in gut microbiota composition, barrier function, and immune system, resulting in an increased risk of diseases characterized by low-grade systemic inflammation. Accumulating evidence suggests a profound effect of altered gut metabolite profiles on overall host health. Therefore, it is possible that P. gingivalis can affect these metabolites. To test this, C57BL/6 mice were administered with P. gingivalis W83 orally twice a week for 5 weeks and compared with sham-inoculated mice. The gut microbial communities were analyzed by pyrosequencing the 16S rRNA genes. Inferred metagenomic analysis was used to determine the relative abundance of KEGG pathways encoded in the gut microbiota. Serum metabolites were analyzed using nuclear magnetic resonance (NMR)-based metabolomics coupled with multivariate statistical analyses. Oral administration of P. gingivalis induced a change in gut microbiota composition. The distributions of metabolic pathways differed between the two groups, including those related to amino acid metabolism and, in particular, the genes for phenylalanine, tyrosine, and tryptophan biosynthesis. Also, alanine, glutamine, histidine, tyrosine, and phenylalanine were significantly increased in the serum of P. gingivalis-administered mice. In addition to altering immune modulation and gut barrier function, oral administration of P. gingivalis affects the host's metabolic profile. This supports our hypothesis regarding a gut-mediated systemic pathology resulting from periodontal disease.

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Therapeutic effect of vitamin D(3)-containing nanostructured lipid carriers on inflammatory bowel disease.

Zai K, Hirota M, Yamada T, Ishihara N, Mori T, Kishimura A, Suzuki K, *HASE K, *Katayama Y

J Control Release. 286 94 - 102 2018.09

Research paper (scientific journal), Joint Work, Accepted

Therapeutic effect of vitamin D<inf>3</inf>-containing nanostructured lipid carriers on inflammatory bowel disease

Zai K., Hirota M., Yamada T., Ishihara N., Mori T., Kishimura A., Suzuki K., Hase K., Katayama Y.

Journal of Controlled Release (Journal of Controlled Release) 286 94 - 102 2018.09

ISSN 01683659

© 2018 Elsevier B.V. The active form of vitamin D3, 1,25(OH)2D3 has been found to exert multiple effects on the suppression of progression of inflammatory bowel disease (IBD). Vitamin D3 has been gathering attention as a therapy for IBD. However, the clinical trials conducted to date revealed that a relatively high dosage of vitamin D3 was required to see a significant therapeutic effect. Thus, effective formulation and delivery of vitamin D3 to colonic inflammatory lesions will be required. Herein we describe the preparation of a nanostructured lipid carrier (NLC) for the encapsulation of 1,25(OH)2D3 for colonic delivery via oral administration. The optimized fabrication procedure enabled the incorporation of 1,25(OH)2D3 in the NLC by minimizing the destruction of chemically unstable 1,25(OH)2D3. The obtained NLCs orally delivered 1,25(OH)2D3 to the colon in mice and maintained a high concentration of 1,25(OH)2D3 in the colonic tissue for at least 12 h. The NLC showed multiple effects on the suppression of symptoms of colitis induced by dextran sodium sulfate, namely maintaining crypt structure, reducing the tissue concentration of inflammatory cytokines, suppressing the infiltration of polymorphonuclear leukocytes, and augmenting anti-inflammatory CX3CR1high macrophages. Our NLCs containing 1,25(OH)2D3 may be an alternative treatment for IBD therapy.

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