Publications by authors named "Jun Kunisawa"

132 Publications

Relationship between Nutrient Intake and Human Gut Microbiota in Monozygotic Twins.

Medicina (Kaunas) 2021 Mar 16;57(3). Epub 2021 Mar 16.

Center for Twin Research, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.

: The gut microbiota is associated with human health and dietary nutrition. Various studies have been reported in this regard, but it is difficult to clearly analyze human gut microbiota as individual differences are significant. The causes of these individual differences in intestinal microflora are genetic and/or environmental. In this study, we focused on differences between identical twins in Japan to clarify the effects of nutrients consumed on the entire gut microbiome, while excluding genetic differences. : We selected healthy Japanese monozygotic twins for the study and confirmed their zygosity by matching 15 short tandem repeat loci. Their fecal samples were subjected to 16S rRNA sequencing and bioinformatics analyses to identify and compare the fluctuations in intestinal bacteria. : We identified 12 genera sensitive to environmental factors, and found that was relatively unaffected by environmental factors. Moreover, we identified protein, fat, and some nutrient intake that can affect 12 genera, which have been identified to be more sensitive to environmental factors. Among the 12 genera, had a positive correlation with retinol equivalent intake ( = 0.38), had a significantly negative correlation with protein, sodium, iron, vitamin D, vitamin B6, and vitamin B12 intake ( = -0.38, -0.41, -0.39, -0.63, -0.42, -0.49, respectively), ND3007 group had a positive correlation with fat intake ( = 0.39), and UCG-008 group had a negative correlation with the saturated fatty acid intake ( = -0.45). : Our study is the first to focus on the relationship between human gut microbiota and nutrient intake using samples from Japanese twins to exclude the effects of genetic factors. These findings will broaden our understanding of the more intuitive relationship between nutrient intake and the gut microbiota and can be a useful basis for finding useful biomarkers that contribute to human health.
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http://dx.doi.org/10.3390/medicina57030275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002349PMC
March 2021

ω3 fatty acid metabolite, 12-hydroxyeicosapentaenoic acid, alleviates contact hypersensitivity by downregulation of CXCL1 and CXCL2 gene expression in keratinocytes via retinoid X receptor α.

FASEB J 2021 Apr;35(4):e21354

Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.

ω3 fatty acids show potent bioactivities via conversion into lipid mediators; therefore, metabolism of dietary lipids is a critical determinant in the properties of ω3 fatty acids in the control of allergic inflammatory diseases. However, metabolic progression of ω3 fatty acids in the skin and their roles in the regulation of skin inflammation remains to be clarified. In this study, we found that 12-hydroxyeicosapentaenoic acid (12-HEPE), which is a 12-lipoxygenase metabolite of eicosapentaenoic acid, was the prominent metabolite accumulated in the skin of mice fed ω3 fatty acid-rich linseed oil. Consistently, the gene expression levels of Alox12 and Alox12b, which encode proteins involved in the generation of 12-HEPE, were much higher in the skin than in the other tissues (eg, gut). We also found that the topical application of 12-HEPE inhibited the inflammation associated with contact hypersensitivity by inhibiting neutrophil infiltration into the skin. In human keratinocytes in vitro, 12-HEPE inhibited the expression of two genes encoding neutrophil chemoattractants, CXCL1 and CXCL2, via retinoid X receptor α. Together, the present results demonstrate that the metabolic progression of dietary ω3 fatty acids differs in different organs, and identify 12-HEPE as the dominant ω3 fatty acid metabolite in the skin.
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http://dx.doi.org/10.1096/fj.202001687RDOI Listing
April 2021

Enzymatically polymerised polyphenols prepared from various precursors potentiate antigen-specific immune responses in both mucosal and systemic compartments in mice.

PLoS One 2021 8;16(2):e0246422. Epub 2021 Feb 8.

Department of Drug Delivery and Molecular Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.

Despite significant modern medicine progress, having an infectious disease is a major risk factor for humans. Mucosal vaccination is now widely considered as the most promising strategy to defeat infectious diseases; however, only live-attenuated and inactivated mucosal vaccines are used in the clinical field. To date, no subunit mucosal vaccine was approved mainly because of the lack of safe and effective methodologies to either activate or initiate host mucosal immune responses. We have recently elucidated that intranasal administration of enzymatically polymerised caffeic acid potentiates antigen-specific mucosal and systemic antibody responses in mice. However, our earlier study has not confirmed whether these effects are specific to the polymer synthesised from caffeic acid. Here, we show that enzymatically polymerised polyphenols (EPPs) from various phenolic compounds possess mucosal adjuvant activities when administered nasally with an antigen to mice. Potentiation of antigen-specific immune responses by all EPPs tested in this study showed no clear difference among the precursors used. We found that intranasal administration of ovalbumin as the antigen, in combination with all enzymatically polymerised polyphenols used in this study, induced ovalbumin-specific mucosal IgA in the nasal cavity, bronchoalveolar lavage fluid, vaginal fluids, and systemic IgG, especially IgG1, in sera. Our results demonstrate that the mucosal adjuvant activities of polyphenols are not limited to polymerised caffeic acid but are broadly observable across the studied polyphenols. These properties of polyphenols may be advantageous for the development of safe and effective nasal vaccine systems to prevent and/or treat various infectious diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246422PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870002PMC
February 2021

Lipopolysaccharide from Gut-Associated Lymphoid-Tissue-Resident Alcaligenes faecalis: Complete Structure Determination and Chemical Synthesis of Its Lipid A.

Angew Chem Int Ed Engl 2021 Jan 31. Epub 2021 Jan 31.

Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan.

Alcaligenes faecalis is the predominant Gram-negative bacterium inhabiting gut-associated lymphoid tissues, Peyer's patches. We previously reported that an A. faecalis lipopolysaccharide (LPS) acted as a weak agonist for Toll-like receptor 4 (TLR4)/myeloid differentiation factor-2 (MD-2) receptor as well as a potent inducer of IgA without excessive inflammation, thus suggesting that A. faecalis LPS might be used as a safe adjuvant. In this study, we characterized the structure of both the lipooligosaccharide (LOS) and LPS from A. faecalis. We synthesized three lipid A molecules with different degrees of acylation by an efficient route involving the simultaneous introduction of 1- and 4'-phosphates. Hexaacylated A. faecalis lipid A showed moderate agonistic activity towards TLR4-mediated signaling and the ability to elicit a discrete interleukin-6 release in human cell lines and mice. It was thus found to be the active principle of the LOS/LPS and a promising vaccine adjuvant candidate.
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http://dx.doi.org/10.1002/anie.202012374DOI Listing
January 2021

Orally desensitized mast cells form a regulatory network with Treg cells for the control of food allergy.

Mucosal Immunol 2020 Dec 10. Epub 2020 Dec 10.

Department of Mucosal Immunology, The University of Tokyo Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.

Oral immunotherapy (OIT) is an effective approach to controlling food allergy. Although the detailed molecular and cellular mechanisms of OIT are unknown currently, they must be understood to advance the treatment of allergic diseases in general. To elucidate the mechanisms of OIT, especially during the immunological transition from desensitization to allergy regulation, we generated a clinical OIT murine model and used it to examine immunological events of OIT. We found that in mice that completed OIT successfully, desensitized mast cells (MCs) showed functionally beneficial alterations, such as increased induction of regulatory cytokines and enhanced expansion of regulatory T cells. Importantly, these regulatory-T-cell-mediated inhibitions of allergic responses were dramatically decreased in mice lacking OIT-induced desensitized MC. Collectively, these findings show that the desensitization process modulates the activation of MCs, leading directly to enhanced induction of regulatory-T-cell expansion and promotion of clinical allergic unresponsiveness. Our results suggest that efficiently inducing regulatory MCs is a novel strategy for the treatment of allergic disease.
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http://dx.doi.org/10.1038/s41385-020-00358-3DOI Listing
December 2020

MANTA, an integrative database and analysis platform that relates microbiome and phenotypic data.

PLoS One 2020 4;15(12):e0243609. Epub 2020 Dec 4.

Laboratory of Bioinformatics, Artificial Intelligence Center for Health and Biomedical Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.

With an ever-increasing interest in understanding the relationships between the microbiota and the host, more tools to map, analyze and interpret these relationships have been developed. Most of these tools, however, focus on taxonomic profiling and comparative analysis among groups, with very few analytical tools designed to correlate microbiota and the host phenotypic data. We have developed a software program for creating a web-based integrative database and analysis platform called MANTA (Microbiota And pheNoType correlation Analysis platform). In addition to storing the data, MANTA is equipped with an intuitive user interface that can be used to correlate the microbial composition with phenotypic parameters. Using a case study, we demonstrated that MANTA was able to quickly identify the significant correlations between microbial abundances and phenotypes that are supported by previous studies. Moreover, MANTA enabled the users to quick access locally stored data that can help interpret microbiota-phenotype relations. MANTA is available at https://mizuguchilab.org/manta/ for download and the source code can be found at https://github.com/chenyian-nibio/manta.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243609PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717536PMC
January 2021

Lymphoid Tissue-Resident Establish an Intracellular Symbiotic Environment by Creating a Unique Energy Shift in Dendritic Cells.

Front Microbiol 2020 24;11:561005. Epub 2020 Sep 24.

Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, Ibaraki, Japan.

Lymphoid-tissue-resident commensal bacteria (LRCs), including , are present in intestinal lymphoid tissue including the Peyer's patches (PPs) of mammals and modulate the host immune system. Although LRCs can colonize within dendritic cells (DCs), the mechanisms through which LRCs persist in DCs and the symbiotic relationships between LRCs and DCs remain to be investigated. Here, we show an intracellular symbiotic system in which the LRC creates a unique energy shift in DCs. Whereas DCs showed low mitochondrial respiration when they were co-cultured with , DCs carrying maintained increased mitochondrial respiration. Furthermore, induced apoptosis of DCs but did not. Regarding an underlying mechanism, -unlike -did not induce intracellular nitric oxide (NO) production in DCs due to the low activity of its lipopolysaccharide (LPS). Therefore, , an example of LRCs, may persist within intestinal lymphoid tissue because they elicit little NO production in DCs. In addition, the symbiotic DCs exhibit characteristic physiologic changes, including a low rate of apoptosis and increased mitochondrial respiration.
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http://dx.doi.org/10.3389/fmicb.2020.561005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545135PMC
September 2020

Selective expression of claudin-5 in thymic endothelial cells regulates the blood-thymus barrier and T-cell export.

Int Immunol 2021 Mar;33(3):171-182

Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

T-cell development depends on the thymic microenvironment, in which endothelial cells (ECs) play a vital role. Interestingly, vascular permeability of the thymic cortex is lower than in other organs, suggesting the existence of a blood-thymus barrier (BTB). On the other hand, blood-borne molecules and dendritic cells bearing self-antigens are accessible to the medulla, facilitating central tolerance induction, and continuous T-precursor immigration and mature thymocyte egress occur through the vessels at the cortico-medullary junction (CMJ). We found that claudin-5 (Cld5), a membrane protein of tight junctions, was expressed in essentially all ECs of the cortical vasculatures, whereas approximately half of the ECs of the medulla and CMJ lacked Cld5 expression. An intravenously (i.v.) injected biotin tracer hardly penetrated cortical Cld5+ vessels, but it leaked into the medullary parenchyma through Cld5- vessels. Cld5 expression in an EC cell line caused a remarkable increase in trans-endothelial resistance in vitro, and the biotin tracer leaked from the cortical vasculatures in Cldn5-/- mice. Furthermore, i.v.-injected sphingosine-1 phosphate distributed selectively into the medulla through the Cld5- vessels, probably ensuring the egress of CD3high mature thymocytes from Cld5- vessels at the CMJ. These results suggest that distinct Cld5 expression profiles in the cortex and medulla may control the BTB and the T-cell gateway to blood circulation, respectively.
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http://dx.doi.org/10.1093/intimm/dxaa069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936066PMC
March 2021

Impact of the intestinal environment on the immune responses to vaccination.

Vaccine 2020 10 12;38(44):6959-6965. Epub 2020 Sep 12.

Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health, and Nutrition (NIBIOHN), Japan; International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Japan; Graduate School of Medicine, Graduate School of Pharmaceutical Sciences, Graduate School of Density, Osaka University, Japan; Graduate School of Medicine, Kobe University, Japan; Research Organization for Nano & Life Innovation, Waseda University, Japan. Electronic address:

Vaccination has contributed greatly to the control of infectious diseases; however, regional and individual differences are occasionally observed in the efficacy of vaccination. As one explanation for these differences, much attention has focused on the intestinal environment constructed by the interaction of diet and the gut microbiota. The intestinal environment has several physiological effects on the host immune system, both locally and systemically, and consequently influences the efficacy of vaccination. In this review, we discuss the impact of the gut microbiota and dietary nutrients on systemic and oral vaccination as well as their applications in various strategies for immunoregulation, including use as vaccine adjuvants. This information could contribute to establishing methods of personalized vaccination that would optimize host immunity by changing the gut environment to maximize vaccine effects.
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http://dx.doi.org/10.1016/j.vaccine.2020.08.079DOI Listing
October 2020

Gut microbiota modification suppresses the development of pulmonary arterial hypertension in an SU5416/hypoxia rat model.

Pulm Circ 2020 Jul-Sep;10(3):2045894020929147. Epub 2020 Aug 27.

Department of Respirology, Graduate School of Medicine, Chiba, Japan.

The pathogenesis of pulmonary arterial hypertension is closely associated with dysregulated inflammation. Recently, abnormal alterations in gut microbiome composition and function were reported in a pulmonary arterial hypertension experimental animal model. However, it remains unclear whether these alterations are a result or the cause of pulmonary arterial hypertension. The purpose of this study was to investigate whether alterations in the gut microbiome affected the hemodynamics in SU5416/hypoxia rats. We used the SU5416/hypoxia rat model in our study. SU5416/hypoxia rats were treated with a single SU5416 injection (30 mg/kg) and a three-week hypoxia exposure (10% O). Three SU5416/hypoxia rats were treated with a combination of four antibiotics (SU5416/hypoxia + ABx group) for four weeks. Another group was exposed to hypoxia (10% O) without the SU5416 treatment, and control rats received no treatment. Fecal samples were collected from each animal, and the gut microbiota composition was analyzed by 16S rRNA sequencing. The antibiotic treatment significantly suppressed the vascular remodeling, right ventricular hypertrophy, and increase in the right ventricular systolic pressure in SU5416/hypoxia rats. 16S rRNA sequencing analysis revealed gut microbiota modification in SU5416/hypoxia + ABx group. The Firmicutes-to-Bacteroidetes ratio in SU5416/hypoxia rats was significantly higher than that in control and hypoxia rats. Compared with the control microbiota, 14 bacterial genera, including and , increased, whereas seven bacteria, including and , decreased in abundance in SU5416/hypoxia rats. Antibiotic-induced modification of the gut microbiota suppresses the development of pulmonary arterial hypertension. Dysbiosis may play a causal role in the development and progression of pulmonary arterial hypertension.
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http://dx.doi.org/10.1177/2045894020929147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457673PMC
August 2020

Vitamin B1 Supports the Differentiation of T Cells through TGF-β Superfamily Production in Thymic Stromal Cells.

iScience 2020 Jul 31;23(9):101426. Epub 2020 Jul 31.

Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Asagi Saito, Ibaraki-city, Osaka 567-0085, Japan; Department of Microbiology and Immunology, Kobe University Graduate School of Medicine, Kusunoki-cho, Chuo-ku, Kobe-city, Hyogo 650-0017, Japan; Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita-city, Osaka 565-0871, Japan; International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; Graduate School of Medicine and Graduate School of Dentistry, Osaka University, Yamadaoka, Suita-city, Osaka 565-0871, Japan. Electronic address:

Homeostatic generation of T cells, which occurs in the thymus, is controlled at least in part by endogenous cytokines and ligands. In addition, nutritional factors are other key regulators for the homeostasis of host immunity, but whether and how nutrition affects the homeostatic generation of thymocytes remains to be established. Here, we showed that vitamin B1 deficiency resulted in a bias toward the maturation of γδ thymocytes accompanied by decreased differentiation into double-positive thymocytes during thymic involution. These events were mediated through the increased production of TGF-β superfamily members due to the accumulation of branched-chain α-keto acids in thymic stromal cells. These findings revealed essential roles of vitamin B1 in the appropriate differentiation of T cells through the metabolism of thymic stromal cells.
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http://dx.doi.org/10.1016/j.isci.2020.101426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452312PMC
July 2020

Chemically Synthesized Lipid A Shows a Potent and Safe Nasal Vaccine Adjuvant Activity for the Induction of -Specific IgA and Th17 Mediated Protective Immunity.

Microorganisms 2020 Jul 23;8(8). Epub 2020 Jul 23.

Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka 567-0085, Japan.

Effective and safe vaccine adjuvants are needed to appropriately augment mucosal vaccine effects. Our previous study demonstrated that lipopolysaccharide (LPS) from Peyer's patch resident stimulated dendritic cells to promote the production of mucosal immunity-enhancing cytokines (e.g., IL-6 and BAFF), thus enhancing antigen-specific immune responses (including IgA production and Th17 responses) without excessive inflammation. Here, we chemically synthesized lipid A, the biologically active part of LPS, and examined its efficacy as a nasal vaccine adjuvant for the induction of protectively immunity against infection. Mice were nasally immunized with pneumococcal surface protein A (PspA) as a vaccine antigen for , together with lipid A. lipid A supported the generation of high levels of PspA-specific IgA and IgG responses through the augmentation of germinal center formation in the nasopharynx-associated lymphoid tissue and cervical lymph nodes (CLNs). Moreover, lipid A promoted PspA-specific CD4 Th17 responses in the CLNs and spleen. Furthermore, neutrophils were recruited to infection sites upon nasal infection and synchronized with the antigen-specific T and B cell responses, resulting in the protection against infection. Taken together, lipid A could be applied to the prospective adjuvant to enhance nasal vaccine efficacy by means of augmenting both the innate and acquired arms of mucosal immunity against respiratory bacterial infection.
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http://dx.doi.org/10.3390/microorganisms8081102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464877PMC
July 2020

Adjuvant Activity of Synthetic Lipid A of , a Gut-Associated Lymphoid Tissue-Resident Commensal Bacterium, to Augment Antigen-Specific IgG and Th17 Responses in Systemic Vaccine.

Vaccines (Basel) 2020 Jul 20;8(3). Epub 2020 Jul 20.

Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka 567-0085, Japan.

spp. are identified as commensal bacteria and have been found to inhabit Peyer's patches in the gut. We previously reported that -derived lipopolysaccharides (LPS) exerted adjuvant activity in systemic vaccination, without excessive inflammation. Lipid A is one of the components responsible for the biological effect of LPS and has previously been applied as an adjuvant. Here, we examined the adjuvant activity and safety of chemically synthesized lipid A. We found that levels of OVA-specific serum IgG antibodies increased in mice that were subcutaneously immunized with ovalbumin (OVA) plus lipid A relative to those that were immunized with OVA alone. In addition, lipid A promoted antigen-specific T helper 17 (Th17) responses in the spleen; upregulated the expression of MHC class II, CD40, CD80, and CD86 on bone marrow-derived dendritic cells (BMDCs); enhanced the production of Th17-inducing cytokines IL-6 and IL-23 from BMDCs. Stimulation with lipid A also induced the production of IL-6 and IL-1β in human peripheral blood mononuclear cells. Moreover, lipid A caused minor side effects, such as lymphopenia and thrombocytopenia. These findings suggest that lipid A is a safe and effective Th17-type adjuvant by directly stimulating dendritic cells in systemic vaccination.
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http://dx.doi.org/10.3390/vaccines8030395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565795PMC
July 2020

[CONTROL OF THE ALLERGIC DISEASES AND MUCOSAL VACCINE RESPONSES BY DIETARY LIPIDS].

Arerugi 2020;69(5):324-328

Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN).

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http://dx.doi.org/10.15036/arerugi.69.324DOI Listing
November 2020

Gut microbial composition in patients with atrial fibrillation: effects of diet and drugs.

Heart Vessels 2021 Jan 18;36(1):105-114. Epub 2020 Jul 18.

Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 6500017, Japan.

Atrial fibrillation (AF) reduces the quality of life by triggering stroke and heart failure. The association between AF onset and gut metabolites suggests a causal relationship between AF and gut microbiota dysbiosis; however, the relationship remains poorly understood. We prospectively enrolled 34 hospitalized patients with AF and 66 age-, sex-, and comorbidity-matched control subjects without a history of AF. Gut microbial compositions were evaluated by amplicon sequencing targeting the 16S ribosomal RNA gene. We assessed differences in dietary habits by using a brief-type self-administered diet history questionnaire (BDHQ). Gut microbial richness was lower in AF patients, although the diversity of gut microbiota did not differ between the two groups. At the genus level, Enterobacter was depleted, while Parabacteroides, Lachnoclostridium, Streptococcus, and Alistipes were enriched in AF patients compared to control subjects. The BDHQ revealed that the intake of n-3 polyunsaturated fatty acids and eicosadienoic acid was higher in AF patients. Our results suggested that AF patients had altered gut microbial composition in connection with dietary habits.
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http://dx.doi.org/10.1007/s00380-020-01669-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788021PMC
January 2021

Impaired mucociliary motility enhances antigen-specific nasal IgA immune responses to a cholera toxin-based nasal vaccine.

Int Immunol 2020 07;32(8):559-568

Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.

Nasal mucosal tissues are equipped with physical barriers, mucus and cilia, on their surface. The mucus layer captures inhaled materials, and the cilia remove the inhaled materials from the epithelial layer by asymmetrical beating. The effect of nasal physical barriers on the vaccine efficacy remains to be investigated. Tubulin tyrosine ligase-like family, member 1 (Ttll1) is an essential enzyme for appropriate movement of the cilia on respiratory epithelium, and its deficiency (Ttll1-KO) leads to mucus accumulation in the nasal cavity. Here, when mice were intra-nasally immunized with pneumococcal surface protein A (PspA, as vaccine antigen) together with cholera toxin (CT, as mucosal adjuvant), Ttll1-KO mice showed higher levels of PspA-specific IgA in the nasal wash and increased numbers of PspA-specific IgA-producing plasma cells in the nasal passages when compared with Ttll1 hetero (He) mice. Mucus removal by N-acetylcysteine did not affect the enhanced immune responses in Ttll1-KO mice versus Ttll1-He mice. Immunohistological and flow cytometry analyses revealed that retention time of PspA in the nasal cavity in Ttll1-KO mice was longer than that in Ttll1-He mice. Consistently, uptake of PspA by dendritic cells was higher in the nasopharynx-associated lymphoid tissue (NALT) of Ttll1-KO mice than that of Ttll1-He mice. These results indicate that the ciliary function of removing vaccine antigen from the NALT epithelial layer is a critical determinant of the efficacy of nasal vaccine.
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http://dx.doi.org/10.1093/intimm/dxaa029DOI Listing
July 2020

Diversity of energy metabolism in immune responses regulated by micro-organisms and dietary nutrition.

Int Immunol 2020 06;32(7):447-454

Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health, and Nutrition (NIBIOHN), Ibaraki City, Osaka, Japan.

Immune metabolism has been recognized as a new paradigm in the regulation of host immunity. In the environment, there are many micro-organisms including pathogenic and non-pathogenic and/or beneficial ones. Immune cells exhibit various responses against different types of microbes, which seem to be associated with changes in energy metabolism. In addition, dietary nutrition influences host metabolism and consequent responses by immune cells. In this review, we describe the complex network of immune metabolism from the perspectives of nutrition, micro-organisms and host immunity for the control of immunologic health and diseases.
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http://dx.doi.org/10.1093/intimm/dxaa020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318777PMC
June 2020

Effects of the oral adsorbent AST-120 on fecal p-cresol and indole levels and on the gut microbiota composition.

Biochem Biophys Res Commun 2020 05 5;525(3):773-779. Epub 2020 Mar 5.

Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, 980-8578, Japan; Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.

In chronic kidney disease, elevated levels of circulating uremic toxins are associated with a variety of symptoms and organ dysfunction. Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) are microbiota-derived metabolites and representative uremic toxins. We have previously shown that the oral adsorbent AST-120 profoundly reduced pCS compared to IS in adenine-induced renal failure in mice. However, the mechanisms of the different attenuation effects of AST-120 between IS and pCS are unclear. To clarify the difference of AST-120 on IS and pCS, we investigated the levels of fecal indole and p-cresol, the respective precursors of IS and pCS, and examined the influence on the gut microbiota. Although fecal indole was detected in all groups analyzed, fecal p-cresol was not detected in AST-120 treatment groups. In genus level, a total of 23 organisms were significantly changed by renal failure or AST-120 treatment. Especially, AST-120 reduced the abundance of Erysipelotrichaceae uncultured and Clostridium sensu stricto 1, which have a gene involved in p-cresol production. Our findings suggest that, in addition to the adsorption of the uremic toxin precursors, AST-120 affects the abundance of some gut microbiota in normal and renal failure conditions, thereby explaining the different attenuation effects on IS and pCS.
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http://dx.doi.org/10.1016/j.bbrc.2020.02.141DOI Listing
May 2020

17(),18()-epoxyeicosatetraenoic acid generated by cytochrome P450 BM-3 from inhibits the development of contact hypersensitivity via G-protein-coupled receptor 40-mediated neutrophil suppression.

FASEB Bioadv 2020 Jan 24;2(1):59-71. Epub 2019 Dec 24.

Laboratory of Vaccine Materials Center for Vaccine and Adjuvant Research Laboratory of Gut Environmental System National Institutes of Biomedical Innovation Health and Nutrition (NIBIOHN) Osaka Japan.

Dietary intake of ω3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid is beneficial for health control. We recently identified 17,18-epoxyeicosatetraenoic acid (17,18-EpETE) as a lipid metabolite endogenously generated from eicosapentaenoic acid that exhibits potent anti-allergic and anti-inflammatory properties. However, chemically synthesized 17,18-EpETE is enantiomeric due to its epoxy group-17(),18()-EpETE and 17(),18()-EpETE. In this study, we demonstrated stereoselective differences of 17(),18()-EpETE and 17(),18()-EpETE in amelioration of skin contact hypersensitivity and found that anti-inflammatory activity was detected in 17(),18()-EpETE, but not in 17(),18()-EpETE. In addition, we found that cytochrome P450 BM-3 derived from stereoselectively converts EPA into 17(),18()-EpETE, which effectively inhibited the development of skin contact hypersensitivity by inhibiting neutrophil migration in a G protein-coupled receptor 40-dependent manner. These results suggest the new availability of a bacterial enzyme to produce a beneficial lipid mediator, 17(),18()-EpETE, in a stereoselective manner. Our findings highlight that bacterial enzymatic conversion of fatty acid is a promising strategy for mass production of bioactive lipid metabolites.
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http://dx.doi.org/10.1096/fba.2019-00061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996328PMC
January 2020

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

Mucosal Immunol 2020 07 10;13(4):679-690. Epub 2020 Feb 10.

Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, 105-0011, Japan.

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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http://dx.doi.org/10.1038/s41385-020-0263-0DOI Listing
July 2020

Maternal ω3 docosapentaenoic acid inhibits infant allergic dermatitis through TRAIL-expressing plasmacytoid dendritic cells in mice.

Allergy 2020 08 4;75(8):1939-1955. Epub 2020 Mar 4.

Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki-city, Japan.

Background: Maternal dietary exposures are considered to influence the development of infant allergies through changes in the composition of breast milk. Cohort studies have shown that ω3 polyunsaturated fatty acids (PUFAs) in breast milk may have a beneficial effect on the preventing of allergies in infants; however, the underlying mechanisms remain to be investigated. We investigated how the maternal intake of dietary ω3 PUFAs affects fatty acid profiles in the breast milk and their pups and reduced the incidence of allergic diseases in the pups.

Methods: Contact hypersensitivity (CHS) induced by 2,4-dinitrofluorobenzene (DNFB) and fluorescein isothiocyanate was applied to the skin in pups reared by mother maintained with diets mainly containing ω3 or ω6 PUFAs. Skin inflammation, immune cell populations, and expression levels of immunomodulatory molecules in pups and/or human cell line were investigated by using flow cytometric, immunohistologic, and quantitative RT-PCR analyses. ω3 PUFA metabolites in breast milk and infant's serum were evaluated by lipidomics analysis using LC-MS/MS.

Results: We show that maternal intake of linseed oil, containing abundant ω3 α-linolenic acid, resulted in the increased levels of ω3 docosapentaenoic acid (DPA) and its 14-lipoxygenation products in the breast milk of mouse dams; these metabolites increased the expression of TNF-related apoptosis-inducing ligand (TRAIL) on plasmacytoid dendritic cells (pDCs) in their pups and thus inhibited infant CHS. Indeed, the administration of DPA-derived 14-lipoxygenation products to mouse pups ameliorated their DNFB CHS.

Conclusion: These findings suggest that an inhibitory mechanism in infant skin allergy is induced through maternal metabolism of dietary ω3 PUFAs in mice.
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http://dx.doi.org/10.1111/all.14217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496639PMC
August 2020

Essential Role of Host Double-Stranded DNA Released from Dying Cells by Cationic Liposomes for Mucosal Adjuvanticity.

Vaccines (Basel) 2019 Dec 27;8(1). Epub 2019 Dec 27.

Department of Drug Delivery and Molecular Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan.

Infectious disease remains a substantial cause of death. To overcome this issue, mucosal vaccine systems are considered to be a promising strategy. Yet, none are approved for clinical use, except for live-attenuated mucosal vaccines, mainly owing to the lack of effective and safe systems to induce antigen-specific immune responses in the mucosal compartment. We have reported that intranasal vaccination of an antigenic protein, with cationic liposomes composed of 1,2-dioleoyl-3-trimethylammonium-propane and 3β-[N-(N',N'-dimethylaminoethane)-carbamoyl], induced antigen-specific mucosal and systemic antibody responses in mice. However, precise molecular mechanism(s) underlying the mucosal adjuvant effects of cationic liposomes remain to be uncovered. Here, we show that a host double-stranded DNA (dsDNA), released at the site of cationic liposome injection, plays an essential role for the mucosal adjuvanticity of the cationic liposome. Namely, we found that nasal administration of the cationic liposomes induced localized cell death, at the site of injection, resulting in extracellular leakage of host dsDNA. Additionally, DNase I treatment markedly impaired OVA-specific mucosal and systemic antibody production exerted by cationic liposomes. Our report reveals that host dsDNA, released from local dying cells, acts as a damage-associated molecular pattern that mediates the mucosal adjuvant activity of cationic liposomes.
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http://dx.doi.org/10.3390/vaccines8010008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157664PMC
December 2019

Dietary Omega-3 Fatty Acid Dampens Allergic Rhinitis via Eosinophilic Production of the Anti-Allergic Lipid Mediator 15-Hydroxyeicosapentaenoic Acid in Mice.

Nutrients 2019 11 22;11(12). Epub 2019 Nov 22.

Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka 567-0085, Japan.

The metabolism and generation of bioactive lipid mediators are key events in the exertion of the beneficial effects of dietary omega-3 fatty acids in the regulation of allergic inflammation. Here, we found that dietary linseed oil, which contains high amounts of alpha-linolenic acid (ALA) dampened allergic rhinitis through eosinophilic production of 15-hydroxyeicosapentaenoic acid (15-HEPE), a metabolite of eicosapentaenoic acid (EPA). Lipidomic analysis revealed that 15-HEPE was particularly accumulated in the nasal passage of linseed oil-fed mice after the development of allergic rhinitis with the increasing number of eosinophils. Indeed, the conversion of EPA to 15-HEPE was mediated by the 15-lipoxygenase activity of eosinophils. Intranasal injection of 15-HEPE dampened allergic symptoms by inhibiting mast cell degranulation, which was mediated by the action of peroxisome proliferator-activated receptor gamma. These findings identify 15-HEPE as a novel EPA-derived, and eosinophil-dependent anti-allergic metabolite, and provide a preventive and therapeutic strategy against allergic rhinitis.
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http://dx.doi.org/10.3390/nu11122868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950470PMC
November 2019

Persistent colonization of non-lymphoid tissue-resident macrophages by Stenotrophomonas maltophilia.

Int Immunol 2020 02;32(2):133-141

International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Accumulating evidence has revealed that lymphoid tissue-resident commensal bacteria (e.g. Alcaligenes spp.) survive within dendritic cells. We extended our previous study by investigating microbes that persistently colonize colonic macrophages. 16S rRNA-based metagenome analysis using DNA purified from murine colonic macrophages revealed the presence of Stenotrophomonas maltophilia. The in situ intracellular colonization by S. maltophilia was recapitulated in vitro by using bone marrow-derived macrophages (BMDMs). Co-culture of BMDMs with clinically isolated S. maltophilia led to increased mitochondrial respiration and robust IL-10 production. We further identified a 25-kDa protein encoded by the gene assigned as smlt2713 (recently renamed as SMLT_RS12935) and secreted by S. maltophilia as the factor responsible for enhanced IL-10 production by BMDMs. IL-10 production is critical for maintenance of the symbiotic condition, because intracellular colonization by S. maltophilia was impaired in IL-10-deficient BMDMs, and smlt2713-deficient S. maltophilia failed to persistently colonize IL-10-competent BMDMs. These findings indicate a novel commensal network between colonic macrophages and S. maltophilia that is mediated by IL-10 and smlt2713.
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http://dx.doi.org/10.1093/intimm/dxz071DOI Listing
February 2020

Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasis.

EBioMedicine 2019 Oct 11;48:513-525. Epub 2019 Sep 11.

Division of Biochemistry, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan; International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo, Japan. Electronic address:

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 RORgtTreg 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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http://dx.doi.org/10.1016/j.ebiom.2019.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838389PMC
October 2019

Clostridium perfringens enterotoxin-based protein engineering for the vaccine design and delivery system.

Vaccine 2019 09 26;37(42):6232-6239. Epub 2019 Aug 26.

Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan; Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan; Division of Mucosal Immunology, Department of Microbiology and Immunology and International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Kobe University Graduate School of Medicine, Hyogo, Japan; Graduate School of Medicine and Graduate School of Dentistry, Osaka University, Osaka, Japan. Electronic address:

Clostridium perfringens is a major cause of food poisoning worldwide, with its enterotoxin (CPE) being the major virulence factor. The C-terminus of CPE (C-CPE) is non-toxic and is the part of the toxin that binds to epithelial cells via the claudins in tight junctions; however, C-CPE has low antigenicity. To address this issue, we have used protein engineering technology to augment the antigenicity of C-CPE and have developed a C-CPE-based vaccine against C. perfringens-mediated food poisoning. Moreover, C-CPE has properties that make it potentially useful for the development of vaccines against other bacterial toxins that cause food poisoning. For example, we hypothesized that the ability of C-CPE to bind to claudins could be harnessed to deliver vaccine antigens directly to mucosa-associated lymphoid tissues, and we successfully developed a nasally administered C-CPE-based vaccine delivery system that promotes antigen-specific mucosal and systemic immune responses. In addition, our group has revealed the roles that the nasal mucus plays in lowering the efficacy of C-CPE-based nasal vaccines. Here, we review recent advances in the development of C-CPE-based vaccines against the major bacterial toxins that cause food poisoning and discuss our C-CPE-based nasal vaccine delivery system.
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http://dx.doi.org/10.1016/j.vaccine.2019.08.032DOI Listing
September 2019

Potential for Tight Junction Protein-Directed Drug Development Using Claudin Binders and Angubindin-1.

Int J Mol Sci 2019 Aug 17;20(16). Epub 2019 Aug 17.

Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.

The tight junction (TJ) is an intercellular sealing component found in epithelial and endothelial tissues that regulates the passage of solutes across the paracellular space. Research examining the biology of TJs has revealed that they are complex biochemical structures constructed from a range of proteins including claudins, occludin, tricellulin, angulins and junctional adhesion molecules. The transient disruption of the barrier function of TJs to open the paracellular space is one means of enhancing mucosal and transdermal drug absorption and to deliver drugs across the blood-brain barrier. However, the disruption of TJs can also open the paracellular space to harmful xenobiotics and pathogens. To address this issue, the strategies targeting TJ proteins have been developed to loosen TJs in a size- or tissue-dependent manner rather than to disrupt them. As several TJ proteins are overexpressed in malignant tumors and in the inflamed intestinal tract, and are present in cells and epithelia conjoined with the mucosa-associated lymphoid immune tissue, these TJ-protein-targeted strategies may also provide platforms for the development of novel therapies and vaccines. Here, this paper reviews two TJ-protein-targeted technologies, claudin binders and an angulin binder, and their applications in drug development.
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http://dx.doi.org/10.3390/ijms20164016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719960PMC
August 2019

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

Sci Rep 2019 07 25;9(1):10842. Epub 2019 Jul 25.

Headquarters, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan.

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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http://dx.doi.org/10.1038/s41598-019-47132-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658492PMC
July 2019

BLT1 mediates commensal bacteria-dependent innate immune signals to enhance antigen-specific intestinal IgA responses.

Mucosal Immunol 2019 09 29;12(5):1082-1091. Epub 2019 May 29.

Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Asagi Saito, Ibaraki, Osaka, 567-0085, Japan.

Leukotriene B receptor 1 (BLT1) triggers the migration of granulocytes and activated T cells; however, its role in B-cell function remains unclear. Here we report that BLT1 is required to induce the production of antigen-specific IgA against oral vaccine through mediating innate immune signals from commensal bacteria. B cells acquire BLT1 expression during their differentiation to IgA B cells and plasma cells in Peyer's patches and the small intestinal lamina propria, respectively. BLT1 KO mice exhibited impaired production of antigen-specific fecal IgA to oral vaccine despite normal IgG responses to systemically immunized antigen. Expression of MyD88 was decreased in BLT1 KO gut B cells and consequently led to diminished proliferation of commensal bacteria-dependent plasma cells. These results indicate that BLT1 enhances the proliferation of commensal bacteria-dependent IgA plasma cells through the induction of MyD88 and thereby plays a key role in the production of antigen-specific intestinal IgA.
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http://dx.doi.org/10.1038/s41385-019-0175-zDOI Listing
September 2019

Fatty acid metabolism in the host and commensal bacteria for the control of intestinal immune responses and diseases.

Gut Microbes 2020 05 23;11(3):276-284. Epub 2019 May 23.

Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health, and Nutrition (NIBIOHN) , Osaka, Japan.

Intestinal tissue has a specialized immune system that exhibits an exquisite balance between active and suppressive responses important for the maintenance of health. Intestinal immunity is functionally affected by both diet and gut commensal bacteria. Here, we review the effects of fatty acids on the regulation of intestinal immunity and immunological diseases, revealing that dietary fatty acids and their metabolites play an important role in the regulation of allergy, inflammation, and immunosurveillance in the intestine. Several lines of evidence have revealed that some dietary fatty acids are converted to biologically active metabolites by enzymes not only in the host but also in the commensal bacteria. Thus, biological interaction between diet and commensal bacteria could form the basis of a new era in the control of host immunity and its associated diseases.
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http://dx.doi.org/10.1080/19490976.2019.1612662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524326PMC
May 2020