Verified email at go.tuat.ac.jp
Tokyo University of Agriculture and Technology
Eunyoung Lee, Xilin Zhang, Tomoe Noda, Junki Miyamoto, Ikuo Kimura, Tomoaki Tanaka, Kenichi Sakurai, Ryo Hatano, and Takashi Miki
International Journal of Molecular Sciences, ISSN: 16616596, eISSN: 14220067, Published: October-1 2021 MDPI AG
Background: α-cyclodextrin (α-CD) is one of the dietary fibers that may have a beneficial effect on cholesterol and/or glucose metabolism, but its efficacy and mode of action remain unclear. Methods: In the present study, we examined the anti-hyperglycemic effect of α-CD after oral loading of glucose and liquid meal in mice. Results: Administration of 2 g/kg α-CD suppressed hyperglycemia after glucose loading, which was associated with increased glucagon-like peptide 1 (GLP-1) secretion and enhanced hepatic glucose sequestration. By contrast, 1 g/kg α-CD similarly suppressed hyperglycemia, but without increasing secretions of GLP-1 and insulin. Furthermore, oral α-CD administration disrupts lipid micelle formation through its inclusion of lecithin in the gut luminal fluid. Importantly, prior inclusion of α-CD with lecithin in vitro nullified the anti-hyperglycemic effect of α-CD in vivo, which was associated with increased intestinal mRNA expressions of SREBP2-target genes (Ldlr, Hmgcr, Pcsk9, and Srebp2). Conclusions: α-CD elicits its anti-hyperglycemic effect after glucose loading by inducing lecithin inclusion in the gut lumen and activating SREBP2, which is known to induce cholecystokinin secretion to suppress hepatic glucose production via a gut/brain/liver axis.
Akari Nishida, Junki Miyamoto, Hidenori Shimizu, and Ikuo Kimura
Biochemical and Biophysical Research Communications, ISSN: 0006291X, eISSN: 10902104, Volume: 557, Pages: 48-54, Published: 11 June 2021 Elsevier BV
Olfactory receptor 78 (Olfr78), which is also known as a receptor for short-chain fatty acids (SCFAs) produced via gut microbial fermentation from indigestible polysaccharides such as dietary fibers, is expressed in the enteroendocrine cells of the colon. However, the role of Olfr78 in gut hormone secretion remains unknown. Here, we aimed to investigate the function and mechanism of action of Olfr78 in vivo and in vitro. Toward this, we assessed the expression of Olfr78 in several tissues, affinity of Olfr78 to various monocarboxylates, and the secretion of anorexigenic gut hormone peptide YY (PYY) via Olfr78 using various molecular and biochemical techniques. Olfr78 was abundantly expressed in the colon and mouse enteroendocrine cell line STC-1 and showed specific affinity to SCFAs such as acetate and propionate, but not butyrate, in a monocarboxylate ligand screening assay using a heterologous expression system. Acetate promoted PYY secretion in STC-1 cells via Olfr78-protein kinase A signaling, whereas the effects were abolished by Olfr78 RNA interference. Colonic SCFAs production via oral administration of fructo-oligosaccharide significantly increased plasma PYY levels, whereas this effect was abolished in Olfr78-deficient and germ-free mice. These results suggested that the SCFA receptor Olfr78 is important for anti-obesity and anorexigenic effects of the gut microbiota and dietary fibers.
Kiyotaka Uchiyama, Shu Wakino, Junichiro Irie, Junki Miyamoto, Ayumi Matsui, Takaya Tajima, Tomoaki Itoh, Yoichi Oshima, Ayumi Yoshifuji, Ikuo Kimura, and Hiroshi Itoh
Nephrology Dialysis Transplantation, ISSN: 09310509, eISSN: 14602385, Pages: 1501-1517, Published: 1 September 2020 Oxford University Press (OUP)
Abstract Background Chronic kidney disease (CKD) leads to insulin resistance (IR) and sarcopenia, which are associated with a high mortality risk in CKD patients; however, their pathophysiologies remain unclear. Recently, alterations in gut microbiota have been reported to be associated with CKD. We aimed to determine whether uremic dysbiosis contributes to CKD-associated IR and sarcopenia. Methods CKD was induced in specific pathogen-free mice via an adenine-containing diet; control animals were fed a normal diet. Fecal microbiota transplantation (FMT) was performed by oral gavage in healthy germ-free mice using cecal bacterial samples obtained from either control mice (control-FMT) or CKD mice (CKD-FMT). Vehicle mice were gavaged with sterile phosphate-buffered saline. Two weeks after inoculation, mice phenotypes, including IR and sarcopenia, were evaluated. Results IR and sarcopenia were evident in CKD mice compared with control mice. These features were reproduced in CKD-FMT mice compared with control-FMT and vehicle mice with attenuated insulin-induced signal transduction and mitochondrial dysfunction in skeletal muscles. Intestinal tight junction protein expression and adipocyte sizes were lower in CKD-FMT mice than in control-FMT mice. Furthermore, CKD-FMT mice showed systemic microinflammation, increased concentrations of serum uremic solutes, fecal bacterial fermentation products and elevated lipid content in skeletal muscle. The differences in gut microbiota between CKD and control mice were mostly consistent between CKD-FMT and control-FMT mice. Conclusions Uremic dysbiosis induces IR and sarcopenia, leaky gut and lipodystrophy.
Ikuo Kimura, Junki Miyamoto, Ryuji Ohue-Kitano, Keita Watanabe, Takahiro Yamada, Masayoshi Onuki, Ryo Aoki, Yosuke Isobe, Daiji Kashihara, Daisuke Inoue, Akihiko Inaba, Yuta Takamura, Satsuki Taira, Shunsuke Kumaki, Masaki Watanabe, Masato Ito, Fumiyuki Nakagawa, Junichiro Irie, Hiroki Kakuta, Masakazu Shinohara, Ken Iwatsuki, Gozoh Tsujimoto, Hiroaki Ohno, Makoto Arita, Hiroshi Itoh, and Koji Hase
Science, ISSN: 00368075, eISSN: 10959203, Volume: 367, Issue: 6481, Published: 28 February 2020 American Association for the Advancement of Science (AAAS)
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.
Junki Miyamoto, Miki Igarashi, Keita Watanabe, Shin-ichiro Karaki, Hiromi Mukouyama, Shigenobu Kishino, Xuan Li, Atsuhiko Ichimura, Junichiro Irie, Yukihiko Sugimoto, Tetsuya Mizutani, Tatsuya Sugawara, Takashi Miki, Jun Ogawa, Daniel J. Drucker, Makoto Arita, Hiroshi Itoh, and Ikuo Kimura
Nature Communications, eISSN: 20411723, Published: 1 December 2019 Springer Science and Business Media LLC
Gut microbiota mediates the effects of diet, thereby modifying host metabolism and the incidence of metabolic disorders. Increased consumption of omega-6 polyunsaturated fatty acid (PUFA) that is abundant in Western diet contributes to obesity and related diseases. Although gut-microbiota-related metabolic pathways of dietary PUFAs were recently elucidated, the effects on host physiological function remain unclear. Here, we demonstrate that gut microbiota confers host resistance to high-fat diet (HFD)-induced obesity by modulating dietary PUFAs metabolism. Supplementation of 10-hydroxy-cis-12-octadecenoic acid (HYA), an initial linoleic acid-related gut-microbial metabolite, attenuates HFD-induced obesity in mice without eliciting arachidonic acid-mediated adipose inflammation and by improving metabolic condition via free fatty acid receptors. Moreover, Lactobacillus-colonized mice show similar effects with elevated HYA levels. Our findings illustrate the interplay between gut microbiota and host energy metabolism via the metabolites of dietary omega-6-FAs thereby shedding light on the prevention and treatment of metabolic disorders by targeting gut microbial metabolites. The gut microbiome is an important regulator of metabolic health. Here the authors show that intestinal bacteria metabolize dietary linoleic acid to 10-hydroxy-cis-12-octadecenoic acid (HYA) which confers host resistance to high fat diet-induced obesity in mice.
Eunyoung Lee, Emily L. Miedzybrodzka, Xilin Zhang, Ryo Hatano, Junki Miyamoto, Ikuo Kimura, Kosuke Fujimoto, Satoshi Uematsu, Sergio Rodriguez-Cuenca, Antonio Vidal-Puig, Fiona M. Gribble, Frank Reimann, and Takashi Miki
International Journal of Molecular Sciences, ISSN: 16616596, eISSN: 14220067, Published: 2 September 2019 MDPI AG
As glucose-dependent insulinotropic polypeptide (GIP) possesses pro-adipogenic action, the suppression of the GIP hypersecretion seen in obesity might represent a novel therapeutic approach to the treatment of obesity. However, the mechanism of GIP hypersecretion remains largely unknown. In the present study, we investigated GIP secretion in two mouse models of obesity: High-fat diet-induced obese (DIO) mice and leptin-deficient Lepob/ob mice. In DIO mice, plasma GIP was increased along with an increase in GIP mRNA expression in the lower small intestine. Despite the robust alteration in the gut microbiome in DIO mice, co-administration of maltose and the α-glucosidase inhibitor (α-GI) miglitol induced the microbiome-mediated suppression of GIP secretion. The plasma GIP levels of Lepob/ob mice were also elevated and were suppressed by fat transplantation. The GIP mRNA expression in fat tissue was not increased in Lepob/ob mice, while the expression of an interleukin-1 receptor antagonist (IL-1Ra) was increased. Fat transplantation suppressed the expression of IL-1Ra. The plasma IL-1Ra levels were positively correlated with the plasma GIP levels. Accordingly, although circulating GIP levels are increased in both DIO and Lepob/ob mice, the underlying mechanisms differ, and the anti-obesity actions of α-GIs and leptin sensitizers may be mediated partly by the suppression of GIP secretion.
Ryuji Ohue-Kitano, Satsuki Taira, Keita Watanabe, Yuki Masujima, Toru Kuboshima, Junki Miyamoto, Yosuke Nishitani, Hideaki Kawakami, Hiroshige Kuwahara, and Ikuo Kimura
Nutrients, eISSN: 20726643, Published: May 2019 MDPI AG
4-Hydroxy-3-methoxycinnamic acid (HMCA), a hydroxycinnamic acid derivative, is abundant in fruits and vegetables, including oranges, carrots, rice bran, and coffee beans. Several beneficial effects of HMCA have been reported, including improvement of metabolic abnormalities in animal models and human studies. However, its mitigating effects on high-fat diet (HFD)-induced obesity, and the mechanism underlying these effects, remain to be elucidated. In this study, we demonstrated that dietary HMCA was efficacious against HFD-induced weight gain and hepatic steatosis, and that it improved insulin sensitivity. These metabolic benefits of HMCA were ascribable to 3-(4-hydroxy-3-methoxyphenyl)propionic acid (HMPA) produced by gut microbiota. Moreover, conversion of HMCA into HMPA was attributable to a wide variety of microbes belonging to the phylum Bacteroidetes. We further showed that HMPA modulated gut microbes associated with host metabolic homeostasis by increasing the abundance of organisms belonging to the phylum Bacteroidetes and reducing the abundance of the phylum Firmicutes. Collectively, these results suggest that HMPA derived from HMCA is metabolically beneficial, and regulates hepatic lipid metabolism, insulin sensitivity, and the gut microbial community. Our results provide insights for the development of functional foods and preventive medicines, based on the microbiota of the intestinal environment, for the prevention of metabolic disorders.
Junki Miyamoto, Ryuji Ohue-Kitano, Hiromi Mukouyama, Akari Nishida, Keita Watanabe, Miki Igarashi, Junichiro Irie, Gozoh Tsujimoto, Noriko Satoh-Asahara, Hiroshi Itoh, and Ikuo Kimura
Proceedings of the National Academy of Sciences of the United States of America, ISSN: 00278424, eISSN: 10916490, Volume: 116, Pages: 23813-23821, Published: 2019 Proceedings of the National Academy of Sciences
Ketone bodies, including β-hydroxybutyrate and acetoacetate, are important alternative energy sources during energy shortage. β-Hydroxybutyrate also acts as a signaling molecule via specific G protein-coupled receptors (GPCRs); however, the specific associated GPCRs and physiological functions of acetoacetate remain unknown. Here we identified acetoacetate as an endogenous agonist for short-chain fatty acid (SCFA) receptor GPR43 by ligand screening in a heterologous expression system. Under ketogenic conditions, such as starvation and low-carbohydrate diets, plasma acetoacetate levels increased markedly, whereas plasma and cecal SCFA levels decreased dramatically, along with an altered gut microbiota composition. In addition, Gpr43-deficient mice showed reduced weight loss and suppressed plasma lipoprotein lipase activity during fasting and eucaloric ketogenic diet feeding. Moreover, Gpr43-deficient mice exhibited minimal weight decrease after intermittent fasting. These observations provide insight into the role of ketone bodies in energy metabolism under shifts in nutrition and may contribute to the development of preventive medicine via diet and foods.
T. Ogita, J. Miyamoto, Y. Hirabayashi, M. Rossi, G. Mazzarella, I. Takahashi, S. Tanabe, and T. Suzuki
Beneficial Microbes, ISSN: 18762883, eISSN: 18762891, Pages: 801-810, Published: 2019 Wageningen Academic Publishers
The aim of this study was to analyse hypoxia-associated dendritic cells (DCs) in colitic mice and the effects of probiotics on interleukin (IL)-10 production in inflammatory DCs under hypoxic conditions. Extensive hypoxia was observed in the colonic mucosa of dextran sodium sulphate-induced colitic mice. Flow cytometric analysis demonstrated that hypoxia-inducible factor-1α+ DCs in colonic lamina propria (CLP) lymphocytes and mesenteric lymph nodes (MLN) were more abundant in colitic mice than those in controls. Among three subsets of DCs, i.e. plasmacytoid DCs, conventional DCs (cDCs), and monocyte-derived DCs (mDCs), cDCs and mDCs were more abundant in CLP of colitic mice. Bone marrow-derived Flt-3L-induced DCs (Flt-DCs) but not bone marrow-derived GM-CSF-induced DCs (GM-DCs), incubated with 1% O2 exhibited an inflammatory phenotype, with higher CD86, IL-6, and tumour necrosis factor-α expression, and lower IL-10 levels than those in Flt-DCs incubated with 21% O2. The hypoxia-induced decrease in IL-10 expression in Flt-DCs was restored by Bifidobacterium bifidum JCM 1255T promoted IL-10 expression through the p38 pathway under normoxic conditions. The anti-inflammatory effects of B. bifidum JCM 1255T in Flt-DCs were mediated through different cellular mechanisms under hypoxic and normoxic conditions. B. bifidum JCM 1255T could be used therapeutically for its anti-inflammatory effects.
Eun-Young Lee, Xilin Zhang, Junki Miyamoto, Ikuo Kimura, Tomoaki Taknaka, Kenichi Furusawa, Takahito Jomori, Kosuke Fujimoto, Satoshi Uematsu, and Takashi Miki
Journal of Endocrinology, ISSN: 00220795, eISSN: 14796805, Volume: 239, Pages: 267-276, Published: 1 December 2018 Bioscientifica
Mechanisms of carbohydrate-induced secretion of the two incretins namely glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are considered to be mostly similar. However, we found that mice exhibit opposite secretory responses in response to co-administration of maltose plus an α-glucosidase inhibitor miglitol (maltose/miglitol), stimulatory for GLP-1, as reported previously, but inhibitory for GIP. Gut microbiota was shown to be involved in maltose/miglitol-induced GIP suppression, as the suppression was attenuated in antibiotics (Abs)-treated mice and abolished in germ-free mice. In addition, maltose/miglitol administration increased plasma levels of short-chain fatty acids (SCFAs), carbohydrate-derived metabolites, in the portal vein. GIP suppression by maltose/miglitol was not observed in mice lacking a SCFA receptor Ffar3, but it was normally seen in Ffar2-deficient mice. Similar to maltose/miglitol administration, co-administration of glucose plus a sodium glucose transporter inhibitor phloridzin (glucose/phloridzin) induced GIP suppression, which was again cancelled by Abs treatment. In conclusion, oral administration of carbohydrates with α-glucosidase inhibitors suppresses GIP secretion through a microbiota/SCFA/FFAR3 pathway.
Keita Watanabe, Miki Igarashi, Xuan Li, Akiho Nakatani, Junki Miyamoto, Yuka Inaba, Asuka Sutou, Tsutomu Saito, Takumi Sato, Nobuhiko Tachibana, Hiroshi Inoue, and Ikuo Kimura
PLoS ONE, eISSN: 19326203, Published: August 2018 Public Library of Science (PLoS)
The consumption of soybean protein has well-known favorable metabolic effects (e.g., reduced body weight, body fat, hyperglycemia, insulin resistance, hepatic steatosis, and lipogenesis). These effects of soy protein have been linked to modulation by the gut microbiota; however, the dynamic interplay among these factors remains unclear. Accordingly, we examined the metabolic phenotype, intestinal BA pool, and the gut microbiome of male C57BL/6 mice that were randomized to receive either a regular high-fat diet (HFD) or HFD that contained soybean protein isolate (SPI) in place of dairy protein. The intake of SPI significantly reduced the HFD-induced weight gain and adipose tissue mass accumulation and attenuated hepatic steatosis. Along with an enhancement in the secretion of intestinal Glucagon-like peptide-1 (GLP-1), an enlarged cecal BA pool with an elevated secondary/primary BA ratio was observed in the mice that consumed SPI, while fecal BA excretion remained unaltered. SPI also elicited dramatic changes in the gut microbiome, characterized by an expansion of taxa that may be involved in the biotransformation of BAs. The observed effects were abolished in germ-free (GF) mice, indicating that they were dependent on the microbiota. These findings collectively indicate that the metabolic benefits of SPI under the HFD regime may arise from a microbiota-driven increase in BA transformation and increase in GLP-1 secretion.
Akiho Nakatani, Xuan Li, Junki Miyamoto, Miki Igarashi, Hitoshi Watanabe, Asuka Sutou, Keita Watanabe, Takayasu Motoyama, Nobuhiko Tachibana, Mitsutaka Kohno, Hiroshi Inoue, and Ikuo Kimura
Biochemical and Biophysical Research Communications, ISSN: 0006291X, eISSN: 10902104, Volume: 501, Pages: 955-961, Published: 2 July 2018 Elsevier BV
The 8-globulin-rich mung bean protein (MPI) suppresses hepatic lipogenesis in rodent models and reduces fasting plasma glucose and insulin levels in obese adults. However, its effects on mitigating high fat diet (HFD)-induced obesity and the mechanism underlying these effects remain to be elucidated. Herein, we examined the metabolic phenotype, intestinal bile acid (BA) pool, and gut microbiota of conventionally raised (CONV-R) male C57BL/6 mice and germ-free (GF) mice that were randomized to receive either regular HFD or HFD containing mung bean protein isolate (MPI) instead of the dairy protein present in regular HFD. MPI intake significantly reduced HFD-induced weight gain and adipose tissue accumulation, and attenuated hepatic steatosis. Enhancement in the secretion of intestinal glucagon-like peptide-1 (GLP-1) and an enlarged cecal and fecal BA pool of dramatically elevated secondary/primary BA ratio were observed in mice that had consumed MPI. These effects were abolished in GF mice, indicating that the effects were dependent upon the presence of the microbiota. As revealed by 16S rRNA gene sequence analysis, MPI intake also elicited dramatic changes in the gut microbiome, such as an expansion of taxa belonging to the phylum Bacteroidetes along with a reduced abundance of the Firmicutes.
Junki Miyamoto, Keita Watanabe, Satsuki Taira, Mayu Kasubuchi, Xuan Li, Junichiro Irie, Hiroshi Itoh, and Ikuo Kimura
PLoS ONE, eISSN: 19326203, Published: April 2018 Public Library of Science (PLoS)
Dietary intake of barley β-glucan (BG) is known to affect energy metabolism. However, its underlying mechanism remains poorly understood because studies have presented inconsistent results, with both positive and negative effects reported in terms of satiety, energy intake, weight loss, and glycemic control. The objective of this study was to clarify the physiological role underlying the metabolic benefits of barley BG using a mouse model of high fat diet (HFD)-induced obesity. Male 4-wk-old C57BL/6J mice were fed an HFD with 20% barley flour containing either high BG (HBG; 2% BG) or low BG (LBG; 0.6% BG) levels under conventional and germ-free (GF) conditions for 12 wks. In addition, mice were fed either an HFD with 5% cellulose (HFC; high fiber cellulose) or 5% barley BG (HFB; high fiber β-glucan) for 12 wks. Then, metabolic parameters, gut microbial compositions, and the production of fecal short-chain fatty acids (SCFAs) were analyzed. The weight gain and fat mass of HBG-fed mice were lower than those of control mice at 16-wk-old. Moreover, the secretion of the gut hormones PYY and GLP-1 increased in HBG-fed mice, thereby reducing food intake and improving insulin sensitivity by changing the gut microbiota and increasing SCFAs (especially, butyrate) under conventional condition. These effects in HBG-fed mice were abolished under GF conditions. Moreover, the HFB diets also increased PYY and GLP-1 secretion, and decreased food intake compared with that in HFC-fed mice. These results suggest that the beneficial metabolic effects of barley BG are primary due to the suppression of appetite and improvement of insulin sensitivity, which are induced by gut hormone secretion promoted via gut microbiota-produced SCFAs.
Hiroko Kaikiri, Junki Miyamoto, Takahiro Kawakami, Si-Bum Park, Nahoko Kitamura, Shigenobu Kishino, Yasunori Yonejima, Keiko Hisa, Jun Watanabe, Tasuku Ogita, Jun Ogawa, Soichi Tanabe, and Takuya Suzuki
International Journal of Food Sciences and Nutrition, ISSN: 09637486, eISSN: 14653478, Pages: 941-951, Published: 17 November 2017 Informa UK Limited
Abstract The present study investigated the antiallergic and anti-inflammatory effects of 10-hydroxy-cis-12-octadecenoic acid (HYA), a novel gut microbial metabolite of linoleic acid, in NC/Nga mice, a model of atopic dermatitis (AD). Feeding HYA decreased the plasma immunoglobulin E level and skin infiltration of mast cells with a concomitant decrease in dermatitis score. HYA feeding decreased TNF-α and increased claudin-1, a tight junction protein, levels in the mouse skin. Cytokine expression levels in the skin and intestinal Peyer’s patches cells suggested that HYA improved the Th1/Th2 balance in mice. Immunoglobulin A concentration in the feces of the HYA-fed mice was approximately four times higher than that in the control mice. Finally, denaturing gradient gel electrophoresis of the PCR-amplified 16 S rRNA gene of fecal microbes indicated the modification of microbiota by HYA. Taken together, the alterations in the intestinal microbiota might be, at least in part, associated with the antiallergic effect of HYA. Graphical Abstract
Akihito Nakajima, Naoko Kaga, Yumiko Nakanishi, Hiroshi Ohno, Junki Miyamoto, Ikuo Kimura, Shohei Hori, Takashi Sasaki, Keiichi Hiramatsu, Ko Okumura, Sachiko Miyake, Sonoko Habu, and Sumio Watanabe
Journal of Immunology, ISSN: 00221767, eISSN: 15506606, Volume: 199, Pages: 3516-3524, Published: 15 November 2017 The American Association of Immunologists
Short-chain fatty acids (SCFAs), the end products of dietary fiber, influence the immune system. Moreover, during pregnancy the maternal microbiome has a great impact on the development of the offspring’s immune system. However, the exact mechanisms by which maternal SCFAs during pregnancy and lactation influence the immune system of offspring are not fully understood. We investigated the molecular mechanisms underlying regulatory T cell (Treg) differentiation in offspring regulated by a maternal high fiber diet (HFD). Plasma levels of SCFAs in offspring from HFD-fed mice were higher than in those from no fiber diet–fed mice. Consequently, the offspring from HFD-fed mice had higher frequencies of thymic Treg (tTreg) and peripheral Tregs. We found that the offspring of HFD-fed mice exhibited higher autoimmune regulator (Aire) expression, a transcription factor expressed in the thymic microenvironment, suggesting SCFAs promote tTreg differentiation through increased Aire expression. Notably, the receptor for butyrate, G protein–coupled receptor 41 (GPR41), is highly expressed in the thymic microenvironment and Aire expression is not increased by stimulation with butyrate in GPR41-deficient mice. Our studies highlight the significance of SCFAs produced by a maternal HFD for Treg differentiation in the thymus of offspring. Given that Aire expression is associated with the induction of tTregs, the maternal microbiome influences Treg differentiation in the thymus of offspring through GPR41-mediated Aire expression.
Junki Miyamoto, Mayu Kasubuchi, Akira Nakajima, and Ikuo Kimura
Handbook of Experimental Pharmacology, ISSN: 01712004, eISSN: 18650325, Volume: 236, Pages: 221-231, Published: 2017 Springer International Publishing
Chronic low-grade inflammation in macrophages and adipose tissues can promote the development of obesity and type 2 diabetes. Free fatty acids (FFAs) have important roles in various tissues, acting as both essential energy sources and signaling molecules. FFA receptors (FFARs) can modulate inflammation in various types of cells and tissues; however the underlying mechanisms mediating these effects are unclear. FFARs are activated by specific FFAs; for example, GPR40 and GPR120 are activated by medium and long chain FFAs, GPR41 and GPR43 are activated by short chain FFAs, and GPR84 is activated by medium-chain FFAs. To date, a number of studies associated with the physiological functions of G protein-coupled receptors (GPCRs) have reported that these GPCRs are expressed in various tissues and involved in inflammatory and metabolic responses. Thus, the development of selective agonists or antagonists for various GPCRs may facilitate the establishment of novel therapies for the treatment of various diseases. In this review, we summarize current literature describing the potential of GPCRs as therapeutic targets for inflammatory and metabolic disorders.
Junki Miyamoto, Mayu Kasubuchi, Akira Nakajima, Junichiro Irie, Hiroshi Itoh, and Ikuo Kimura
Current Opinion in Nephrology and Hypertension, ISSN: 10624821, eISSN: 14736543, Pages: 379-383, Published: 1 September 2016 Ovid Technologies (Wolters Kluwer Health)
Purpose of reviewThe gut microbiota and its metabolites have been implicated in the regulation of host physiological functions such as inflammatory and metabolic responses. The short-chain fatty acid (SCFA) receptor is expressed in the kidney and blood vessels as well, and has been reported to function as a regulator of blood pressure (BP). This review highlights the role of SCFAs derived from gut microbial fermentation in the regulation of BP. Recent findingsOlfactory receptor 78 (Olfr78) is a member of the G-protein-coupled receptor family, and it plays a key role as a chemosensor in various tissues. Both Olfr78 and G protein-coupled receptor 41 (GPR41) are expressed in smooth muscle cells of blood vessels and they recognize SCFAs. Oral administration of SCFAs was found to change BP in vivo, an effect that was altered in Olfr78 and GPR41-deficient mice. SummaryThe regulation of BP via SCFA receptors has provided new insights into the interactions between the gut microbiota and BP control systems. We summarize these interactions and describe their contributions to a novel pathway involved in BP regulation. These recent findings could open new avenues for the development of therapeutic strategies for the treatment of cardiovascular diseases.
Junki Miyamoto, Sae Hasegawa, Mayu Kasubuchi, Atsuhiko Ichimura, Akira Nakajima, and Ikuo Kimura
International Journal of Molecular Sciences, ISSN: 16616596, eISSN: 14220067, Published: 25 March 2016 MDPI AG
Excess energy is stored primarily as triglycerides, which are mobilized when demand for energy arises. Dysfunction of energy balance by excess food intake leads to metabolic diseases, such as obesity and diabetes. Free fatty acids (FFAs) provided by dietary fat are not only important nutrients, but also contribute key physiological functions via FFA receptor (FFAR)-mediated signaling molecules, which depend on FFAs’ carbon chain length and the ligand specificity of the receptors. Functional analyses have revealed that FFARs are critical for metabolic functions, such as peptide hormone secretion and inflammation, and contribute to energy homeostasis. In particular, recent studies have shown that the administration of selective agonists of G protein-coupled receptor (GPR) 40 and GPR120 improved glucose metabolism and systemic metabolic disorders. Furthermore, the anti-inflammation and energy metabolism effects of short chain FAs have been linked to the activation of GPR41 and GPR43. In this review, we summarize recent progress in research on FFAs and their physiological roles in the regulation of energy metabolism.
Junki Miyamoto, Taichi Mizukure, Si-Bum Park, Shigenobu Kishino, Ikuo Kimura, Kanako Hirano, Paolo Bergamo, Mauro Rossi, Takuya Suzuki, Makoto Arita, Jun Ogawa, and Soichi Tanabe
Journal of Biological Chemistry, ISSN: 00219258, eISSN: 1083351X, Volume: 290, Pages: 2902-2918, Published: 30 January 2015 Elsevier BV
Background: The physiological activity of gut microbial metabolites has recently attracted much attention. Results: A gut microbial metabolite of linoleic acid, 10-hydroxy-cis-12-octadecenoic acid (HYA), ameliorates intestinal epithelial barrier impairments by regulating TNFR2 expression via the GPR40-MEK-ERK pathway. Conclusion: HYA-induced GPR40 signaling contributes to the intestinal homeostasis. Significance: Our findings indicate a novel function of GPR40 in the inflamed intestine. Gut microbial metabolites of polyunsaturated fatty acids have attracted much attention because of their various physiological properties. Dysfunction of tight junction (TJ) in the intestine contributes to the pathogenesis of many disorders such as inflammatory bowel disease. We evaluated the effects of five novel gut microbial metabolites on tumor necrosis factor (TNF)-α-induced barrier impairment in Caco-2 cells and dextran sulfate sodium-induced colitis in mice. 10-Hydroxy-cis-12-octadecenoic acid (HYA), a gut microbial metabolite of linoleic acid, suppressed TNF-α and dextran sulfate sodium-induced changes in the expression of TJ-related molecules, occludin, zonula occludens-1, and myosin light chain kinase. HYA also suppressed the expression of TNF receptor 2 (TNFR2) mRNA and protein expression in Caco-2 cells and colonic tissue. In addition, HYA suppressed the protein expression of TNFR2 in murine intestinal epithelial cells. Furthermore, HYA significantly up-regulated G protein-coupled receptor (GPR) 40 expression in Caco-2 cells. It also induced [Ca2+]i responses in HEK293 cells expressing human GPR40 with higher sensitivity than linoleic acid, its metabolic precursor. The barrier-recovering effects of HYA were abrogated by a GPR40 antagonist and MEK inhibitor in Caco-2 cells. Conversely, 10-hydroxyoctadacanoic acid, which is a gut microbial metabolite of oleic acid and lacks a carbon-carbon double bond at Δ12 position, did not show these TJ-restoring activities and down-regulated GPR40 expression. Therefore, HYA modulates TNFR2 expression, at least partially, via the GPR40-MEK-ERK pathway and may be useful in the treatment of TJ-related disorders such as inflammatory bowel disease.
Paolo Bergamo, Diomira Luongo, Junki Miyamoto, Ennio Cocca, Shigenobu Kishino, Jun Ogawa, Soichi Tanabe, and Mauro Rossi
Journal of Functional Foods, ISSN: 17564646, Pages: 192-202, Published: 2014 Elsevier BV
Various hydroxy-, oxo-, and conjugated fatty acids are generated by gut microbes throughout the metabolism of dietary PUFAs. Specifically, 10-Hydroxy-cis-12-(HYA), 10-oxo-cis12-(KetoA) and 10-oxo-cis9,trans11-octadecenoic acid (KetoC) are intermediates free fatty acids (iFFA) produced during the isomerization of dietary linoleic acid to cis9,trans11 (c9,t11) isomer of conjugated linoleic acid (CLA). Herein, immunomodulatory and antioxidant activity of selected iFFA was studied in resting (iDCs), LPS-matured DCs (mDCs) and in murine enterocyte cells (MODE-K). Phenotypic maturation of iDCs was not influenced by iFFA, but the release of pro-inflammatory molecules from mDCs was reduced following HYA pre-treatment. HYA ability to improve antioxidant/detoxifying defenses associated with decreased expression of maturation markers in mDCs and in MODE-K cells. The pro-oxidant activity, via NADPH oxidase activation, was responsible for the pro-inflammatory effect of 10-hydroxy-octadecanoic acid. Presented data suggest that the immunomodulatory ability of HYA is determined, at least in part, by its ability to improve antioxidant/detoxifying defenses.
Diomira Luongo, Junki Miyamoto, Paolo Bergamo, Filomena Nazzaro, Federico Baruzzi, Toshihiro Sashihara, Soichi Tanabe, and Mauro Rossi
BMC Microbiology, eISSN: 14712180, Published: 23 December 2013 Springer Science and Business Media LLC
BackgroundProbiotics species appear to differentially regulate the intestinal immune response. Moreover, we have shown that different immune-modulatory abilities can be found among probiotic strains belonging to the same species. In this study, we further addressed this issue while studying L. gasseri, a species that induces relevant immune activities in human patients.ResultsWe determined the ability of two strains of L. gasseri, OLL2809 and L13-Ia, to alter cell surface antigen expression, cytokine production and nuclear erythroid 2-related factor 2 (Nrf2)-mediated cytoprotection in murine bone marrow-derived dendritic cells (DCs) and MODE-K cells, which represent an enterocyte model. Differential effects of L. gasseri strains were observed on the expression of surface markers in mature DCs; nevertheless, both strains dramatically induced production of IL-12, TNF-α and IL-10. Distinctive responses to OLL2809 and L13-Ia were also shown in MODE-K cells by analyzing the expression of MHC II molecules and the secretion of IL-6; however, both L. gasseri strains raised intracellular glutathione. Treatment of immature DCs with culture medium from MODE-K monolayers improved cytoprotection and modified the process of DC maturation by down-regulating the expression of co-stimulatory markers and by altering the cytokine profile. Notably, bacteria-conditioned MODE-K cell medium suppressed the expression of the examined cytokines, whereas cytoprotective defenses were significantly enhanced only in DCs exposed to OLL2809-conditioned medium. These effects were essentially mediated by secreted bacterial metabolites.ConclusionsWe have demonstrated that L. gasseri strains possess distinctive abilities to modulate in vitro DCs and enterocytes. In particular, our results highlight the potential of metabolites secreted by L. gasseri to influence enterocyte-DC crosstalk. Regulation of cellular mechanisms of innate immunity by selected probiotic strains may contribute to the beneficial effects of these bacteria in gut homeostasis.
Eiji Miyauchi, Tasuku Ogita, Junki Miyamoto, Seiji Kawamoto, Hidetoshi Morita, Hiroshi Ohno, Takuya Suzuki, and Soichi Tanabe
PLoS ONE, eISSN: 19326203, Published: 8 November 2013 Public Library of Science (PLoS)
Although some bacterial strains show potential to prevent colitis, their mechanisms are not fully understood. Here, we investigated the anti-colitic mechanisms of Bifidobacterium longum subsp. infantis JCM 1222T, focusing on the relationship between interleukin (IL)-17A secreting CD4+ T cells and intestinal epithelial costimulatory molecules in mice. Oral administration of JCM 1222T to mice alleviated dextran sulfate sodium (DSS)-induced acute colitis. The expression of type 1 helper T (Th1)- and IL-17 producing helper T (Th17)-specific cytokines and transcriptional factors was suppressed by JCM 1222T treatment. Intestinal epithelial cells (IECs) from colitic mice induced IL-17A production from CD4+ T cells in a cell-cell contact-dependent manner, and this was suppressed by oral treatment with JCM 1222T. Using blocking antibodies for costimulatory molecules, we revealed that epithelial costimulatory molecules including CD80 and CD40, which were highly expressed in IECs from colitic mice, were involved in IEC-induced IL-17A response. Treatment of mice and intestinal epithelial cell line Colon-26 cells with JCM 1222T decreased the expression of CD80 and CD40. Collectively, these data indicate that JCM 1222T negatively regulate epithelial costimulatory molecules, and this effect might be attributed, at least in part, to suppression of IL-17A in DSS-induced colitis.
Yuuki Nagashio, Yumi Matsuura, Junki Miyamoto, Takashi Kometani, Takuya Suzuki, and Soichi Tanabe
Journal of Functional Foods, ISSN: 17564646, Pages: 1633-1641, Published: October 2013 Elsevier BV
Abstract Hesperidin (previously called vitamin P) is a predominant flavanone present in citrus fruits, and is presumed to have a role in their beneficial effect for human health because it possesses various physiological activities. In this study, we investigated the anti-allergic and anti-inflammatory effects of hesperidin and α-glucopyranosyl (αG)-hesperidin, its derivative with enhanced water-solubility, in NC/Nga mice, a human-like mouse model of atopic dermatitis. NC/Nga mice were fed a 0.1% αG-hesperidin or hesperidin diet for 8 weeks. αG-hesperidin and hesperidin feeding effectively inhibited skin lesions and immunoglobulin E (IgE) elevation. At the end of the 8-week-experimental period, the production of inflammatory cytokine interleukin (IL)-17 and interferon-gamma (IFN-γ) from splenocytes was lower in the αG-hesperidin/hesperidin-fed group than in the control group. Changes in mRNA expression in splenocytes are also examined using DNA microarray and real-time RT-PCR. It was revealed that cytotoxic T-lymphocyte antigen 4 (CTLA4), a regulatory T-cell (Treg) marker, was markedly upregulated in splenocytes, particularly by αG-hesperidin feeding. These results suggest that αG-hesperidin attenuated exacerbation of AD-like symptoms, decreased systemic immune hyper-responsiveness in part through the reduction of IgE, IL-17 and IFN-γ, and also modulated Th17/Treg balance in NC/Nga mice. Therefore, αG-hesperidin may be useful in the management of Th17-mediated allergic disorders.