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Papers - Hase, Koji

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The role of gut microbiota in intestinal immune tolerance

Shiratori H., Hase K.

Drug Delivery System (Drug Delivery System) 37 ( 2 ) 159 - 167 2022

ISSN 09135006

The intestinal mucosa is constantly exposed to foreign substances and thus owns several lines of defense machinery, including epithelial barrier and secretory IgA to prevent the invasion of pathogens. Meanwhile, the intestinal immune system elicits immune tolerance to food antigens and commensal bacteria. Dysregulation of the intestinal immunity often causes severe inflammatory disorders such as inflammatory bowel disease, allergies, and autoimmune diseases. Regulatory T（Treg） cells, one of the major T cell subsets in the intestine, play a critical role in maintaining immune homeostasis. Compelling evidence has demonstrated that commensal bacteria in the intestine are essential for the expansion of Treg cells in the intestinal lamina propria. This effect is at least partly mediated by metabolites like butyrate produced by commensal bacteria. Bacterial metabolites are transported to the bloodstream to affect the immune response in local and systemic tissues, especially in the respiratory system. Thus, the regulation of immune response by gut microbiota and its pathological relevance has drawn much attention. Furthermore, the development of therapies targeting the gut microbiota by fecal transplantation and probiotic administration is underway. This article will review the latest findings on the immune regulation by commensal bacteria and discuss therapeutic intervention strategies targeting the intestinal microbiota.

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Intestinal immunity: To be, or not to be, induced? That is the question

Takahashi D., Kimura S., Hase K.

International Immunology (International Immunology) 33 ( 12 ) 755 - 759 2021.12

ISSN 09538178

The intestinal immune system maintains intestinal homeostasis in collaboration with diverse immune cell subsets residing at the epithelial layer, lamina propria and gut-associated lymphoid tissue (GALT). Bacterial components and their metabolites are essential for the establishment of the gut immune system. In addition, nutritional signals contribute to maintaining the mucosal immune response. Specialized epithelial microfold (M) cells in GALT facilitate immune surveillance on the mucosal surface by actively taking up external antigens to transport them into the lymphoid follicles. Because hyperplasia of M cells causes an excessive immune response in GALT, there is a self-regulatory mechanism to control the development of M cells appropriately. In this review, we will discuss the molecular mechanisms of mucosal immune regulation and their biological importance.

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Profiling of tumour-associated microbiota in human hepatocellular carcinoma

Komiyama S., Yamada T., Takemura N., Kokudo N., Hase K., Kawamura Y.I.

Scientific Reports (Scientific Reports) 11 ( 1 ) 2021.12

Liver cancer is the fourth leading cause of cancer-related death. Hepatocellular carcinoma (HCC) is a primary liver cancer that results from chronic hepatitis caused by multiple predisposing factors such as viral infection, alcohol consumption, and non-alcoholic fatty liver disease. Accumulating studies have indicated that dysfunction of the gut epithelial barrier and hepatic translocation of gut microbes may be implicated in the pathogenesis of HCC. However, the translocated bacteria in HCC patients remains unclear. Here, we characterised tumour-associated microbiota in patients with liver cancer and focused on HCC. We observed that the number of amplicon sequence variants in tumour-associated microbiota was significantly higher compared with that in non-tumour regions of the liver. The tumour-associated microbiota consisted of Bacteroidetes, Firmicutes, and Proteobacteria as the dominant phyla. We identified an unclassified genus that belonged to the Bacteroides, Romboutsia, uncultured bacterium of Lachnospiraceae as a signature taxon for primary liver cancer. Additionally, we identified Ruminococcus gnavus as a signature taxon for HCC patients infected with hepatitis B and/or hepatitis C viruses. This study suggests that tumour microbiota may contribute to the pathology of HCC.

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Safety and tolerability of medicinal parasite ova (Trichuris suis) in healthy Japanese volunteers: A randomized, double-blind, placebo-controlled trial

Hoshina T., Sakurai T., Ichimura H., Ishiwata K., En S., Yamada T., Kwangyole L., Shimizu A., Hase K., Kanuka H.

Parasitology International (Parasitology International) 85 2021.12

ISSN 13835769

Background: Trichuris suis ova (TSO), with the potential to modulate the human immune system, have been tested for therapeutic application in autoimmune and allergic diseases such as inflammatory bowel disease (IBD). Previous clinical studies were limited to European and American participants, whereas Asian populations have not been well documented. In this study, a clinical trial was conducted to examine the safety and tolerability of TSO administration among a healthy Japanese population. Methods: The study was a randomized, double-blind, placebo-controlled trial held at Jikei University Hospital, Tokyo. Twelve volunteers were stratified into three groups receiving different doses of TSO (TSO 1000, 2500, and 7500) and another into the control group. These cases were limited to healthy Japanese men aged over 20 years old. Single doses of medicinal TSO or placebo were given to three participants of each group. All participants were followed up to 56 days after ingestion. During the follow-up period, clinical practitioners checked each participant at the clinic at 7, 14, 28, and 56 days post-ingestion (dpi). Clinical symptoms were evaluated using questionnaire-based self-reporting, which participants filled at every visit. Blood samples were drawn at 7, 14, 28, and 56 dpi. Fecal samples were collected at 28 and 56 dpi. Results: During the study period, twelve healthy Japanese male volunteers were enrolled. All participants completed the follow-up period. No severe adverse events were observed during the study period in all groups. Three participants in the TSO 1000, 2500, and 7500 groups had mild to moderate abdominal symptoms, diarrhea, bloating, and appetite loss during the observation period. One participant in the placebo group presented with mild diarrhea. Microscopic examination identified no parasite ova in any fecal samples. Blood sample examination indicated elevated eosinophil count in several cases, especially in the groups with the higher dose of TSO. No extra-abdominal symptoms were present in all cases. Conclusions: Healthy Japanese people tolerated all doses of TSO without any severe adverse events. On the other hand, mild to moderate abdominal symptoms were observed in several participants. This study suggested that the medicinal use of TSO in Japan is relatively safe, and close follow-up is recommended for sustainable usage.

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Characterization of M Cells in Tear Duct-Associated Lymphoid Tissue of Mice: A Potential Role in Immunosurveillance on the Ocular Surface

Oya Y., Kimura S., Nakamura Y., Ishihara N., Takano S., Morita R., Endo M., Hase K.

Frontiers in Immunology (Frontiers in Immunology) 12 779709 2021.11

Research paper (scientific journal), Accepted

The ocular mucosal tissues are exposed to potentially harmful foreign antigens in the air and tear fluid. The tear duct-associated lymphoid tissue (TALT) may contribute to immune surveillance in the eye region. Follicle-associated epithelium (FAE) of TALTs is classified as stratified squamous epithelium and consists of squamous epithelial cells arranged in layers on the basement membrane. In contrast, most mucosa-associated lymphoid tissue is covered by a monolayer of epithelium containing microfold (M) cells. Therefore, antigen uptake and the presence of M cells in TALT are not fully understood. The present study found that a small population of FAE cells in the TALT expressed intestinal M-cell markers, namely Sox8, Tnfaip2, GP2, and OPG. This cell population was identified as functional M cells because of their uptake capacity of luminal nanoparticles. In addition, RANKL, which is essential for M-cell differentiation, was expressed by stroma-like cells at the subepithelial region and its receptor RANK by the FAE in the TALT. The administration of RANKL markedly increased the number of Sox8+ M cells. In contrast, deficiency in OPG, an endogenous inhibitor of RANKL, increased the number of M cells in the TALT. These data demonstrate that the RANKL-RANK axis is essential for M-cell differentiation in the TALT. Furthermore, immunization via eye drops elicited the production of antigen-specific antibodies in tears, which was enhanced by RANKL administration. Thus, TALT M cells play an important role in the immunosurveillance of the eye region.

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Identification of Novel Histone Deacetylase 6-Selective Inhibitors Bearing 3,3,3-Trifluorolactic Amide (TFLAM) Motif as a Zinc Binding Group

Kurohara T., Tanaka K., Takahashi D., Ueda S., Yamashita Y., Takada Y., Takeshima H., Yu S., Itoh Y., Hase K., Suzuki T.

ChemBioChem (ChemBioChem) 22 ( 22 ) 3158 - 3163 2021.11

ISSN 14394227

Pharmacological inhibition of histone deacetylase 6 (HDAC6) is an effective therapeutic strategy for cancer and immunological diseases. Most of the previously reported HDAC6 inhibitors have a hydroxamate group as a zinc binding group (ZBG), which coordinates to the catalytic zinc ion of HDAC6. The hydroxamate group is liable to metabolically generate mutagenetic hydroxylamine; therefore, non-hydroxamate HDAC6 inhibitors would be advantageous. In this study, to identify novel non-hydroxamate HDAC6-selective inhibitors, screening of a chemical library and the subsequent structural optimization were performed, which led to the identification of HDAC6-selective inhibitors with 3,3,3-trifluorolactic amide (TFLAM) as a novel ZBG. The identified inhibitor showed potent and selective HDAC6-inhibitory activity in cells and induced regulatory T (Treg) cell differentiation.

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Specific adsorption of a β-lactam antibiotic: In vivo by an anion-exchange resin for protection of the intestinal microbiota

Li S., Yakabe K., Zai K., Liu Y., Kishimura A., Hase K., Kim Y.G., Mori T., Katayama Y.

Biomaterials Science (Biomaterials Science) 9 ( 21 ) 7219 - 7227 2021.11

ISSN 20474830

The fraction of antibiotics that are excreted from the intestine during administration leads to disruption of commensal bacteria as well as resulting in dysbiosis and various diseases. To protect the gut microbiota during treatment with antibiotics, use of activated carbon (AC) has recently been reported as a method to adsorb antibiotics. However, the antibiotic adsorption by AC is nonspecific and may also result in the adsorption of essential biological molecules. In this work, we reported that an anion exchange resin (AER) has better specificity than AC for adsorbing the β-lactam antibiotic cefoperazone (CEF). Because CEF has a negatively charged carboxylate group and a conjugated system, the AER was used to adsorb CEF through electrostatic and π-π interactions. The AER was specific for CEF over biological molecules such as bile acids and vitamins in the intestine. The AER protected Escherichia coli from CEF in vitro. Furthermore, oral administration of the AER reduced the fecal free CEF concentration, and protected the gut microbiota from CEF-induced dysbiosis. This journal is

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Commensal microbe-derived acetate suppresses NAFLD/NASH development via hepatic FFAR2 signalling in mice

Aoki R., Onuki M., Hattori K., Ito M., Yamada T., Kamikado K., Kim Y.G., Nakamoto N., Kimura I., Clarke J.M., Kanai T., Hase K.

Microbiome (Microbiome) 9 ( 1 ) 2021.09

Research paper (scientific journal), Joint Work

Background: Non-alcoholic liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and it can progress to non-alcoholic steatohepatitis (NASH). Alterations in the gut microbiome have been implicated in the development of NAFLD/NASH, although the underlying mechanisms remain unclear. Results: We found that the consumption of the prebiotic inulin markedly ameliorated the phenotype of NAFLD/NASH, including hepatic steatosis and fibrosis, in mice. Inulin consumption resulted in global changes in the gut microbiome, including concomitant enrichment of the genera Bacteroides and Blautia, and increased concentrations of short-chain fatty acids, particularly acetate, in the gut lumen and portal blood. The consumption of acetate-releasing resistant starch protected against NAFLD development. Colonisation by Bacteroides acidifaciens and Blautia producta in germ-free mice resulted in synergetic effects on acetate production from inulin. Furthermore, the absence of free fatty acid receptor 2 (FFAR2), an acetate receptor, abolished the protective effect of inulin, as indicated by the more severe liver hypertrophy, hypercholesterolaemia and inflammation. These effects can be attributed to an exacerbation of insulin resistance in the liver, but not in muscle or adipose tissue. Conclusion: These findings demonstrated that the commensal microbiome–acetate–FFAR2 molecular circuit improves insulin sensitivity in the liver and prevents the development of NAFLD/NASH. [MediaObject not available: see fulltext.]

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A Retinoid X Receptor Agonist Directed to the Large Intestine Ameliorates T-Cell-Mediated Colitis in Mice

Matsumoto R., Takahashi D., Watanabe M., Nakatani S., Takamura Y., Kurosaki Y., Kakuta H., Hase K.

Frontiers in Pharmacology (Frontiers in Pharmacology) 12 2021.08

Retinoid X receptor (RXR) is a nuclear receptor that heterodimerizes with several nuclear receptors, integrating ligand-mediated signals across the heterodimers. Synthetic RXR agonists have been developed to cure certain inflammatory diseases, including inflammatory bowel diseases (IBDs). However, pre-existing RXR agonists, which are lipophilic and readily absorbed in the upper intestine, cause considerable adverse effects such as hepatomegaly, hyperlipidemia, and hypothyroidism. To minimize these adverse effects, we have developed an RXR agonist, NEt-3IB, which has lipophilic and thus poorly absorptive properties. In this study, we evaluated the effects of NEt-3IB in an experimental murine colitis model induced through the adoptive transfer of CD45RBhighCD4+ T cells. Pharmacokinetic studies demonstrated that the major portion of NEt-3IB was successfully delivered to the large intestine after oral administration. Notably, NEt-3IB treatment suppressed the development of T cell-mediated chronic colitis, as indicated by improvement of wasting symptoms, inflammatory infiltration, and mucosal hyperplasia. The protective effect of NEt-3IB was mediated by the suppression of IFN-γ-producing Th1 cell expansion in the colon. In conclusion, NEt-3IB, a large intestine-directed RXR agonist, is a promising drug candidate for IBDs.

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Seaweed dietary fiber sodium alginate suppresses the migration of colonic inflammatory monocytes and diet-induced metabolic syndrome via the gut microbiota

Ejima R., Akiyama M., Sato H., Tomioka S., Yakabe K., Kimizuka T., Seki N., Fujimura Y., Hirayama A., Fukuda S., Hase K., Kim Y.G.

Nutrients (Nutrients) 13 ( 8 ) 2021.08

Metabolic syndrome (MetS) is a multifactorial chronic metabolic disorder that affects ap-proximately one billion people worldwide. Recent studies have evaluated whether targeting the gut microbiota can prevent MetS. This study aimed to assess the ability of dietary fiber to control MetS by modulating gut microbiota composition. Sodium alginate (SA) is a seaweed-derived dietary fiber that suppresses high-fat diet (HFD)-induced MetS via an effect on the gut microbiota. We observed that SA supplementation significantly decreased body weight gain, cholesterol levels, and fat weight, while improving glucose tolerance in HFD-fed mice. SA changed the gut microbiota composition and significantly increased the abundance of Bacteroides. Antibiotic treatment completely abolished the suppressive effects of SA on MetS. Mechanistically, SA decreased the number of co-lonic inflammatory monocytes, which promote MetS development, in a gut microbiota-dependent manner. The abundance of Bacteroides was negatively correlated with that of inflammatory mono-cytes and positively correlated with the levels of several gut metabolites. The present study revealed a novel food function of SA in preventing HFD-induced MetS through its action on gut microbiota.

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Amino acid-based diet prevents lethal infectious diarrhea by maintaining body water balance in a murine citrobacter rodentium infection model

Kimizuka T., Seki N., Yamaguchi G., Akiyama M., Higashi S., Hase K., Kim Y.G.

Nutrients (Nutrients) 13 ( 6 ) 2021.06

Infectious diarrhea is one of the most important health problems worldwide. Although nutritional status influences the clinical manifestation of various enteric pathogen infections, the effect of diet on enteric infectious diseases remains unclear. Using a fatal infectious diarrheal model, we found that an amino acid-based diet (AD) protected susceptible mice infected with the enteric pathogen Citrobacter rodentium. While the mice fed other diets, including a regular diet, were highly susceptible to C. rodentium infection, AD-fed mice had an increased survival rate. An AD did not suppress C. rodentium colonization or intestinal damage; instead, it prevented diarrhea-induced dehydration by increasing water intake. An AD altered the plasma and fecal amino acid levels and changed the gut microbiota composition. Treatment with glutamate, whose level was increased in the plasma and feces of AD-fed mice, promoted water intake and improved the survival of C. ro-dentium-infected mice. Thus, an AD changes the systemic amino acid balance and protects against lethal infectious diarrhea by maintaining total body water content.

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Gut microbiota prevents sugar alcohol-induced diarrhea

Hattori K., Akiyama M., Seki N., Yakabe K., Hase K., Kim Y.G.

Nutrients (Nutrients) 13 ( 6 ) 2021.06

While poorly-absorbed sugar alcohols such as sorbitol are widely used as sweeteners, they may induce diarrhea in some individuals. However, the factors which determine an individual’s susceptibility to sugar alcohol-induced diarrhea remain unknown. Here, we show that specific gut bacteria are involved in the suppression of sorbitol-induced diarrhea. Based on 16S rDNA analysis, the abundance of Enterobacteriaceae bacteria increased in response to sorbitol consumption. We found that Escherichia coli of the family Enterobacteriaceae degraded sorbitol and suppressed sorbitol-induced diarrhea. Finally, we showed that the metabolism of sorbitol by the E. coli sugar phosphotransferase system helped suppress sorbitol-induced diarrhea. Therefore, gut microbiota prevented sugar alcohol-induced diarrhea by degrading sorbitol in the gut. The identification of the gut bacteria which respond to and degrade sugar alcohols in the intestine has implications for microbiome science, processed food science, and public health.

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Protective role of the M-sec-tunneling nanotube system in podocytes

Barutta F., Kimura S., Hase K., Bellini S., Corbetta B., Corbelli A., Fiordaliso F., Barreca A., Papotti M.G., Ghiggeri G.M., Salvidio G., Roccatello D., Audrito V., Deaglio S., Gambino R., Bruno S., Camussi G., Martini M., Hirsch E., Durazzo M., Ohno H., Gruden G.

Journal of the American Society of Nephrology (Journal of the American Society of Nephrology) 32 ( 5 ) 1114 - 1130 2021.05

ISSN 10466673

Background Podocyte dysfunction and loss are major determinants in the development of proteinuria. FSGS is one of the most common causes of proteinuria, but the mechanisms leading to podocyte injury or conferring protection against FSGS remain poorly understood. The cytosolic protein M-Sec has been involved in the formation of tunneling nanotubes (TNTs), membrane channels that transiently connect cells and allow intercellular organelle transfer. Whether podocytes express M-Sec is unknown and the potential relevance of the M-Sec-TNT system in FSGS has not been explored. Methods We studied the role of the M-Sec-TNT system in cultured podocytes exposed to Adriamycin and in BALB/c M-Sec knockout mice. We also assessed M-Sec expression in both kidney biopsies from patients with FSGS and in experimental FSGS (Adriamycin-induced nephropathy). Results Podocytes can form TNTs in a M-Sec-dependent manner. Consistent with the notion that the M-Sec-TNT system is cytoprotective, podocytes overexpressed M-Sec in both human and experimental FSGS. Moreover, M-Sec deletion resulted in podocyte injury, with mitochondrial abnormalities and development of progressive FSGS. In vitro, M-Sec deletion abolished TNT-mediated mitochondria transfer between podocytes and altered mitochondrial bioenergetics. Re-expression of M-Sec reestablishes TNT formation and mitochondria exchange, rescued mitochondrial function, and partially reverted podocyte injury. Conclusions These findings indicate that the M-Sec-TNT system plays an important protective role in the glomeruli by rescuing podocytes via mitochondrial horizontal transfer. M-Sec may represent a promising therapeutic target in FSGS, and evidence that podocytes can be rescued via TNT-mediated horizontal transfer may open new avenues of research.

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Partners in Leaky Gut Syndrome: Intestinal Dysbiosis and Autoimmunity

Kinashi Y., Hase K.

Frontiers in Immunology (Frontiers in Immunology) 12 2021.04

The intestinal surface is constitutively exposed to diverse antigens, such as food antigens, food-borne pathogens, and commensal microbes. Intestinal epithelial cells have developed unique barrier functions that prevent the translocation of potentially hostile antigens into the body. Disruption of the epithelial barrier increases intestinal permeability, resulting in leaky gut syndrome (LGS). Clinical reports have suggested that LGS contributes to autoimmune diseases such as type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and celiac disease. Furthermore, the gut commensal microbiota plays a critical role in regulating host immunity; abnormalities of the microbial community, known as dysbiosis, are observed in patients with autoimmune diseases. However, the pathological links among intestinal dysbiosis, LGS, and autoimmune diseases have not been fully elucidated. This review discusses the current understanding of how commensal microbiota contributes to the pathogenesis of autoimmune diseases by modifying the epithelial barrier.

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Symbiotic polyamine metabolism regulates epithelial proliferation and macrophage differentiation in the colon

Nakamura A., Kurihara S., Takahashi D., Ohashi W., Nakamura Y., Kimura S., Onuki M., Kume A., Sasazawa Y., Furusawa Y., Obata Y., Fukuda S., Saiki S., Matsumoto M., Hase K.

Nature Communications (Nature Communications) 12 ( 1 ) 2105 2021.04

Research paper (scientific journal), Joint Work, Accepted

Intestinal microbiota-derived metabolites have biological importance for the host. Polyamines, such as putrescine and spermidine, are produced by the intestinal microbiota and regulate multiple biological processes. Increased colonic luminal polyamines promote longevity in mice. However, no direct evidence has shown that microbial polyamines are incorporated into host cells to regulate cellular responses. Here, we show that microbial polyamines reinforce colonic epithelial proliferation and regulate macrophage differentiation. Colonisation by wild-type, but not polyamine biosynthesis-deficient, Escherichia coli in germ-free mice raises intracellular polyamine levels in colonocytes, accelerating epithelial renewal. Commensal bacterium-derived putrescine increases the abundance of anti-inflammatory macrophages in the colon. The bacterial polyamines ameliorate symptoms of dextran sulfate sodium-induced colitis in mice. These effects mainly result from enhanced hypusination of eukaryotic initiation translation factor. We conclude that bacterial putrescine functions as a substrate for symbiotic metabolism and is further absorbed and metabolised by the host, thus helping maintain mucosal homoeostasis in the intestine.

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Pancreatic glycoprotein 2 is a first line of defense for mucosal protection in intestinal inflammation

Kurashima Y., Kigoshi T., Murasaki S., Arai F., Shimada K., Seki N., Kim Y.G., Hase K., Ohno H., Kawano K., Ashida H., Suzuki T., Morimoto M., Saito Y., Sasou A., Goda Y., Yuki Y., Inagaki Y., Iijima H., Suda W., Hattori M., Kiyono H.

Nature Communications (Nature Communications) 12 ( 1 ) 2021.02

Research paper (scientific journal), Accepted

Increases in adhesive and invasive commensal bacteria, such as Escherichia coli, and subsequent disruption of the epithelial barrier is implicated in the pathogenesis of inflammatory bowel disease (IBD). However, the protective systems against such barrier disruption are not fully understood. Here, we show that secretion of luminal glycoprotein 2 (GP2) from pancreatic acinar cells is induced in a TNF–dependent manner in mice with chemically induced colitis. Fecal GP2 concentration is also increased in Crohn’s diease patients. Furthermore, pancreas-specific GP2-deficient colitis mice have more severe intestinal inflammation and a larger mucosal E. coli population than do intact mice, indicating that digestive-tract GP2 binds commensal E. coli, preventing epithelial attachment and penetration. Thus, the pancreas–intestinal barrier axis and pancreatic GP2 are important as a first line of defense against adhesive and invasive commensal bacteria during intestinal inflammation.

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Polyvinyl Butyrate Nanoparticles as Butyrate Donors for Colitis Treatment

Mu Y., Kinashi Y., Li J., Yoshikawa T., Kishimura A., Tanaka M., Matsui T., Mori T., Hase K., Katayama Y.

ACS Applied Bio Materials (ACS Applied Bio Materials) 4 ( 3 ) 2335 - 2341 2021.02

Research paper (scientific journal)

Butyrate has been attracting attention for the suppression of inflammatory bowel disease (IBD). However, clinical trials of butyrate for IBD treatment have resulted in controversial outcomes, likely owing to the adverse effect of butyrate on the intestinal epithelium that was observed at high butyrate concentrations. Herein, we propose polyvinyl butyrate (PVBu) nanoparticles (NPs) as butyrate donors for delivery to the lower part of the intestine for the treatment of colitis. The PVBu NPs suppressed the inflammatory activation of macrophages in vitro, although sodium butyrate inversely further activated macrophages. Oral administration of NPs did not change the luminal concentration of free butyrate; however, NPs showed a therapeutic effect on a colitis mouse model. In addition, incorporation of vitamin D3 into the NPs enhanced the therapeutic effect on colitis. Hence, PVBu NPs are a promising therapeutic for IBD treatment, not only as a butyrate donor but also as a carrier for hydrophobic drugs like vitamin D3.

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Dietary Intervention Impacts Immune Cell Functions and Dynamics by Inducing Metabolic Rewiring

Okawa T., Nagai M., Hase K.

Frontiers in Immunology (Frontiers in Immunology) 11 2021.02

Accumulating evidence has shown that nutrient metabolism is closely associated with the differentiation and functions of various immune cells. Cellular metabolism, including aerobic glycolysis, fatty acid oxidation, and oxidative phosphorylation, plays a key role in germinal center (GC) reaction, B-cell trafficking, and T-cell-fate decision. Furthermore, a quiescent metabolic status consolidates T-cell-dependent immunological memory. Therefore, dietary interventions such as calorie restriction, time-restricted feeding, and fasting potentially manipulate immune cell functions. For instance, intermittent fasting prevents the development of experimental autoimmune encephalomyelitis. Meanwhile, the fasting response diminishes the lymphocyte pool in gut-associated lymphoid tissue to minimize energy expenditure, leading to the attenuation of Immunoglobulin A (IgA) response. The nutritional status also influences the dynamics of several immune cell subsets. Here, we describe the current understanding of the significance of immunometabolism in the differentiation and functionality of lymphocytes and macrophages. The underlying molecular mechanisms also are discussed. These experimental observations could offer new therapeutic strategies for immunological disorders like autoimmunity.

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Polyamines polarized Th2/Th9 cell-fate decision by regulating GATA3 expression

Nakamura A., Takahashi D., Nakamura Y., Yamada T., Matsumoto M., Hase K.

Archives of Biochemistry and Biophysics (Archives of Biochemistry and Biophysics) 693 2020.10

ISSN 00039861

© 2020 Elsevier Inc. Polyamines produced by both prokaryotes and eukaryotes are bioactive substances with pleiotropic effects. Accumulating evidence has demonstrated that polyamines contribute to anti-inflammatory responses by suppressing the expression of proinflammatory cytokines in mononuclear cells and macrophages. However, the effects of polyamines on CD4+ T cell responses remain to be elucidated. Here, we investigated the effect of polyamines on cell fate decisions of naïve CD4+ T cells in vitro. We found that endogenously generated polyamines are essential for the development of T helper 2 (Th2) cells. Treatment with DL-2-difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, diminished GATA3 expression in CD4+ T cells under Th2-skewed conditions. Supplementation of exogenous polyamines rescued GATA3 downregulation caused by DFMO treatment in CD4+ T cells. Transcriptome analysis revealed that deprivation of endogenous polyamines resulted in upregulated Th9-related genes, such as Il9, Irf4, and Batf3, even under the Th2-skewing conditions. Depletion of intracellular polyamines reduced GATA3 expression but increased IL-9-producing CD4+ T cells under both Th2 and Th9-skewing conditions. Furthermore, oral administration of DFMO increased IL-9-producing CD4+ T cells in small intestine in mice. Thus, our data indicate that polyamines play a critical role in the regulation of the Th2/Th9 balance.

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Mucin-Derived O-Glycans act as endogenous fiber and sustain mucosal immune homeostasis via short-Chain fatty acid production in rat cecum

Hino S., Mizushima T., Kaneko K., Kawai E., Kondo T., Genda T., Yamada T., Hase K., Nishimura N., Morita T.

Journal of Nutrition (Journal of Nutrition) 150 ( 10 ) 2656 - 2665 2020.10

ISSN 00223166

Copyright © The Author(s) 2020. Background: Intestinal mucins escape digestion and enter the large bowel where they are degraded by the microbiota. To what extent and how mucins impact large-bowel physiology remain unclear. Objective: This study examined the large-bowel fermentation characteristics of mucins and mucin-derived O-glycan sugars and whether they affect gut immunity. Methods: Mucin secretion from the terminal ileum was determined from feces of ileorectostomized male Wistar rats (age 6 wk) fed an AIN76-based control diet (CD) for 15 d (experiment 1). Normal male Wistar rats (age 6 wk; 4 wk for experiment 4) were fed CD ± porcine stomach mucin (PM) at 6 or 12 g/kg diet, equivalent to 1.5 and 3 times the daily mucin secretion, for 14 d (experiment 2); CD ± N-acetylglucosamine (GlcNAc), fucose, or N-acetylneuraminic acid at 10 g/kg diet for 14 d (experiment 3); or CD ± PM (15 g/kg diet) or GlcNAc (10 g/kg diet) for 29 d (experiment 4). SCFAs, microbial composition, and cecal O-glycan content were assessed. IgA+ plasma cells and regulatory T cells and inflammatory cytokine expression in the cecum were evaluated (experiment 4). Results: Daily mucin secretion corresponded to 43.2 μmol of O-glycans. Cecal O-glycan contents were comparable between CD- and PM-fed rats. PM-fed rats harbored more mucin-degrading bacteria. Cecal concentrations of acetate (+37%) and n-butyrate (+73%) were higher in 12-g/kg PM diet–fed rats versus CD (P < 0.05). Among O-glycan sugars, only GlcNAc produced higher n-butyrate concentrations (+68%) versus CD (P < 0.05), with increased numbers of butyrate-producing bacteria. GlcNAc increased the abundance of IgA+ plasma cells (+29%) and regulatory T cells (+33%) versus CD, whereas PM increased IgA+ plasma cells (+25%) (all P < 0.05). GlcNAc and PM decreased expression of Tnfa (−30%, −40%) and Ifng (−30%, −70%) versus CD (all P < 0.05). Conclusions: Mucin-derived O-glycans act as endogenous fiber and maintain mucosal immune homeostasis via large-bowel SCFA production in rats. J Nutr 2020;150:2656–2665.

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