Sucrose-preferring gut microbes prevent host obesity by producing exopolysaccharides Hidenori Shimizu, Junki Miyamoto, Keiko Hisa, Ryuji Ohue-Kitano, Hiromi Takada, Mayu Yamano, Akari Nishida, Daiki Sasahara, Yuki Masujima, Keita Watanabe, Shota Nishikawa, Sakura Takahashi, Takako Ikeda, Yuya Nakajima, Naofumi Yoshida, Chiaki Matsuzaki, Takuya Kageyama, Ibuki Hayashi, Akari Matsuki, Ryo Akashi, Seiichi Kitahama, Masako Ueyama, Takumi Murakami, Shinsuke Inuki, Junichiro Irie, Noriko Satoh-Asahara, Hirokazu Toju, Hiroshi Mori, Shinji Nakaoka, Tomoya Yamashita, Atsushi Toyoda, Kenji Yamamoto, Hiroaki Ohno, Takane Katayama, Hiroshi Itoh, Ikuo Kimura Nature Communications, 2025 Commensal bacteria affect host health by producing various metabolites from dietary carbohydrates via bacterial glycometabolism; however, the underlying mechanism of action remains unclear. Here, we identified Streptococcus salivarius as a unique anti-obesity commensal bacterium. We found that S. salivarius may prevent host obesity caused by excess sucrose intake via the exopolysaccharide (EPS) –short-chain fatty acid (SCFA) –carbohydrate metabolic axis in male mice. Healthy human donor-derived S. salivarius produced high EPS levels from sucrose but not from other sugars. S. salivarius abundance was significantly decreased in human donors with obesity compared with that in healthy donors, and the EPS–SCFA bacterial carbohydrate metabolic process was attenuated. Our findings reveal an important mechanism by which host–commensal interactions in glycometabolism affect energy regulation, suggesting an approach for preventing lifestyle-related diseases via prebiotics and probiotics by targeting bacteria and EPS metabolites. While diet is essential for daily nutrient acquisition, excessive intake of sugar-rich foods drives obesity and related health issues like diabetes. Here, the authors show that commensal bacterium S. salivarius curbs obesity by transforming dietary sugars into beneficial compounds.
High-Fat Diet–Wheat Gluten Interactions in HLA-DQ8 Transgenic Mice Yuri Haneishi, Lucia Treppiccione, Vera Rotondi Aufiero, Francesco Maurano, Saya Watanabe, Diomira Luongo, Giuseppe Mazzarella, Junki Miyamoto, Mauro Rossi Molecular Nutrition and Food Research, 2025 Unbalanced lipid metabolism contributes to inflammation in several conditions. Gluten, that triggers celiac disease, may also play a role in diseases associated with a high‐fat diet (HFD). Our aim was to investigate the interplay between gluten and HFD in HLA‐DQ8 (DQ8) transgenic mice, a model of gluten sensitivity. DQ8 mice were fed the gluten‐free diet, the HFD, or the HFD containing 8% gluten (HFD + G) for 12 or 23 weeks. Clinical parameters, liver and intestinal histology, immune parameters were assessed. Twelve weeks of HFD increased body and white adipose tissue weight and reduced glucose tolerance in male DQ8 mice. Gluten increased hyperinsulinemia and lipid accumulation in liver; interferon gamma (IFN‐γ) and interleukin‐10 (IL‐10) transcripts were higher in liver of HFD + G‐fed mice. IL‐1β, tumor necrosis factor‐α (TNF‐α), IFN‐γ, and IL‐10 mRNAs increased in the small intestine of HFD + G‐fed mice. However, gliadin‐specific immunity and alterations of the intestinal architecture were not induced. Feeding HFD + G for 23 weeks attenuated the gluten effect. A synergic effect between gluten and HFD after 12 weeks was found, which was instrumental to alter specific metabolic and immune functions in DQ8 mice. These findings provide new insights useful to dissect the association between obesity and gluten sensitivity.
Data-Independent Acquisition Coupled with Electron-Activated Dissociation for In-Depth Structure Elucidation of the Fatty Acid Ester of Hydroxy Fatty Acids Yuto Kurizaki, Yuki Matsuzawa, Mikiko Takahashi, Hiroaki Takeda, Mayu Hasegawa, Makoto Arita, Junki Miyamoto, Hiroshi Tsugawa Analytical Chemistry, 2025 Fatty acid esters of hydroxy fatty acid (FAHFAs) are a biologically important class of lipids known for their anti-inflammatory and antidiabetic effects in animals. The physiological activity of FAHFAs varies depending on the length of the carbon chain, number and position of double bonds (DBs), and position of the hydroxyl (OH) group. Moreover, gut bacteria produce FAHFAs with more diverse structures than those produced by the host, which necessitates a FAHFA-lipidomics approach grasping their diverse structures to fully understand the physiological and metabolic significance of FAHFAs. In this study, we developed a methodology for the in-depth structural elucidation of FAHFAs. First, FAHFAs were enriched by using a solid-phase extraction (SPE) system coated with titanium and zirconium dioxide, which separated these analytes from neutral lipids and phospholipids. The fractionated metabolites were then derivatized using N,N-dimethylethylenediamine (DMED) to facilitate FAHFA detection in the positive ion mode of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) system. A data-independent acquisition technique known as sequential window acquisition of all theoretical mass spectra (SWATH-DIA) was used to collect sequential MS/MS spectra of the DMED-derivatized fatty acid metabolites. Structural elucidation was based on fragment ions generated by electron-activated dissociation (EAD). DMED-FAHFAs were annotated using the newly updated MS-DIAL program, and FAHFA isomers were quantified using the MRMPROBS program, which quantifies lipids based on SWATH-MS/MS chromatograms. This procedure was applied to profile the FAHFAs present in mouse fecal samples, characterizing seven structures at the molecular species level, 63 structures at the OH-position-resolved level, and 15 structures at both the DB- and OH-position-resolved levels, using the MS-DIAL program. In the MRMPROBS analysis, 2OH and 3OH hydroxy fatty acids with more than 20 carbon atoms were predominantly expressed, while 5OH-13OH hydroxy fatty acids with 16 or 18 carbon atoms were the major components, abundant at positions 5, 7, 9, and 10. Furthermore, age-related changes in FAHFA isomers were also observed, where FAHFA 4:0/2O(FA 26:0) and FAHFA 16:0/10O(FA 16:0) significantly increased with age. In conclusion, our study offers a novel LC-SWATH-EAD-MS/MS technique with the update of computational MS to facilitate in-depth structural lipidomics of FAHFAs.
Impact of smoking on gut microbiota and short-chain fatty acids in human and mice: Implications for COPD Shiro Otake, Shotaro Chubachi, Junki Miyamoto, Yuri Haneishi, Tetsuya Arai, Hideto Iizuka, Takashi Shimada, Kaori Sakurai, Shinichi Okuzumi, Hiroki Kabata, Takanori Asakura, Jun Miyata, Junichiro Irie, Koichiro Asano, Hidetoshi Nakamura, Ikuo Kimura, Koichi Fukunaga Mucosal Immunology, 2025 We aimed to elucidate the dynamic changes in short-chain fatty acids (SCFA) produced by the gut microbiota following smoking exposure and their role in chronic obstructive pulmonary disease (COPD) pathogenesis. SCFA concentrations were measured in human plasma, comparing non-smokers (n = 6) and smokers (n = 12). Using a mouse COPD model induced by cigarette smoke exposure or elastase-induced emphysema, we modulated SCFA levels through dietary interventions and antibiotics to evaluate their effects on inflammation and alveolar destruction. Human smokers showed lower plasma SCFA concentrations than non-smokers, with plasma propionic acid positively correlating with forced expiratory volume in 1 s/forced vital capacity. Three-month smoking-exposed mice demonstrated altered gut microbiota and significantly reduced fecal SCFA concentrations compared to air-exposed controls. In these mice, a high-fiber diet increased fecal SCFAs and mitigated inflammation and alveolar destruction, while antibiotics decreased fecal SCFAs and exacerbated disease features. However, in the elastase-induced model, fecal SCFA concentration remained unchanged, and high-fiber diet or antibiotic interventions had no significant effect. These findings suggest that smoking exposure alters gut microbiota and SCFA production through its systemic effects. The anti-inflammatory properties of SCFAs may play a role in COPD pathogenesis, highlighting their potential as therapeutic targets.
Maternal progesterone and adipose mPRε in pregnancy regulate the embryonic nutritional state Keita Watanabe, Mayu Yamano, Junki Miyamoto, Ryuji Ohue-Kitano, Yuki Masujima, Daiki Sasahara, Yuki Mouri, Nozomu Kono, Shunsuke Inuki, Fumitaka Osakada, Kentaro Nagaoka, Junken Aoki, Yuki Sugiura, Hiroaki Ohno, Eiji Kondoh, Ikuo Kimura Cell Reports, 2025 Sex steroid hormones such as progesterone play a pivotal role in reproductive functions and maintaining pregnancy; however, the impact of progesterone on the interaction between mother and embryo is unclear. Here, we demonstrate that the relationship between maternal progesterone and membrane progesterone receptor epsilon (mPRε) in adipose tissue regulates embryonic nutritional environment and growth after birth in mice. The activation of adipose mPRε by increased progesterone during pregnancy enhances maternal insulin resistance via prostaglandin production, efficiently providing glucose to embryos. Correspondingly, the offspring of mPRε-deficient mothers exhibited metabolic dysfunction, whereas mPRε-deficient mothers with high-fat diet-induced obesity exhibited improved insulin sensitivity. These findings establish the importance of progesterone as a nutritional regulator between mother and embryo. Additionally, mPRε may represent a modulator for treating pregnant glycemic control disorders such as gestational diabetes mellitus, as well as metabolic syndrome in offspring.
Acidipropionibacterium acidipropionici, a propionate-producing bacterium, contributes to GPR41 signaling and metabolic regulation in high-fat diet-induced obesity in mice Junki Miyamoto, Yuna Ando, Mayu Yamano, Akari Nishida, Kota Murakami, Ikuo Kimura Frontiers in Nutrition, 2025 Obesity is a major healthcare problem worldwide and is induced by excess energy intake, resulting in gut microbial composition and microbial diversity changes. Through fermentation of dietary fibers, short-chain fatty acids (SCFAs) act as host energy sources and signaling molecules via G protein-coupled receptors such as GPR41. Acidipropionibacterium acidipropionici is widely used in many applications; however, in vivo studies on the beneficial effect of A. acidipropionici via propionate production and host energy homeostasis are unclear. Therefore, this study aimed to investigate the beneficial metabolic effects of A. acidipropionici by focusing on GPR41 signaling in a high-fat diet (HFD)-induced obesity mouse model. Here, we demonstrated that A. acidipropionici OB7439 improved host metabolism in HFD-induced obesity in mice. The intake of A. acidipropionici OB7439 improved metabolism in HFD-induced obese mice by increasing propionate production, regulating glucose tolerance, and inhibiting hepatic inflammation via GPR41 signaling. Our findings shed light on the potential of using A. acidipropionici OB7439 as an SCFA producer for the prevention and treatment of metabolic disorders. Based on these results, we suggest that A. acidipropionici may be a potential therapeutic bacterium that inhibits obesity and modulates the gut microbial community.
MS-DIAL 5 multimodal mass spectrometry data mining unveils lipidome complexities Hiroaki Takeda, Yuki Matsuzawa, Manami Takeuchi, Mikiko Takahashi, Kozo Nishida, Takeshi Harayama, Yoshimasa Todoroki, Kuniyoshi Shimizu, Nami Sakamoto, Takaki Oka, Masashi Maekawa, Mi Hwa Chung, Yuto Kurizaki, Saki Kiuchi, Kanako Tokiyoshi, Bujinlkham Buyantogtokh, Misaki Kurata, Aleš Kvasnička, Ushio Takeda, Haruki Uchino, Mayu Hasegawa, Junki Miyamoto, Kana Tanabe, Shigenori Takeda, Tetsuya Mori, Ryota Kumakubo, Tsuyoshi Tanaka, Tomoko Yoshino, Mami Okamoto, Hidenori Takahashi, Makoto Arita, Hiroshi Tsugawa Nature Communications, 2024 Lipidomics and metabolomics communities comprise various informatics tools; however, software programs handling multimodal mass spectrometry (MS) data with structural annotations guided by the Lipidomics Standards Initiative are limited. Here, we provide MS-DIAL 5 for in-depth lipidome structural elucidation through electron-activated dissociation (EAD)-based tandem MS and determining their molecular localization through MS imaging (MSI) data using a species/tissue-specific lipidome database containing the predicted collision-cross section values. With the optimized EAD settings using 14 eV kinetic energy, the program correctly delineated lipid structures for 96.4% of authentic standards, among which 78.0% had the sn-, OH-, and/or C = C positions correctly assigned at concentrations exceeding 1 μM. We showcased our workflow by annotating the sn- and double-bond positions of eye-specific phosphatidylcholines containing very-long-chain polyunsaturated fatty acids (VLC-PUFAs), characterized as PC n-3-VLC-PUFA/FA. Using MSI data from the eye and n-3-VLC-PUFA-supplemented HeLa cells, we identified glycerol 3-phosphate acyltransferase as an enzyme candidate responsible for incorporating n-3 VLC-PUFAs into the sn1 position of phospholipids in mammalian cells, which was confirmed using EAD-MS/MS and recombinant proteins in a cell-free system. Therefore, the MS-DIAL 5 environment, combined with optimized MS data acquisition methods, facilitates a better understanding of lipid structures and their localization, offering insights into lipid biology.
A Procedure for Solid-Phase Extractions Using Metal-Oxide-Coated Silica Column in Lipidomics Hiroaki Takeda, Manami Takeuchi, Mayu Hasegawa, Junki Miyamoto, Hiroshi Tsugawa Analytical Chemistry, 2024 Lipid enrichment is indispensable for enhancing the coverage of targeted molecules in mass spectrometry (MS)-based lipidomics studies. In this study, we developed a simple stepwise fractionation method using a titanium- and zirconium-dioxide-coated solid-phase extraction (SPE) silica column that separates neutral lipids, phospholipids, and other lipids, including fatty acids (FAs) and glycolipids. Chloroform was used to dissolve the lipids, and neutral lipids, including steryl esters, diacylglycerols, and triacylglycerols, were collected in the loading fraction. Second, methanol with formic acid (99:1, v/v) was used to retrieve FAs, ceramides, and glycolipids, including glycosylated ceramides and glycosylated diacylglycerols, by competing for affinity with the Lewis acid sites on the metal oxide surface. Finally, phospholipids strongly retained via chemoaffinity interactions were eluted using a solution containing 5% ammonia and high water content (45:50 v/v, 2-propanol:water), which canceled the electrostatic and chelating interactions with the SPE column. High average reproducibility of <10% and coverage of ∼100% compared to those of the non-SPE samples were demonstrated by untargeted lipidomics of human plasma and mouse brain, testis, and feces. The advantage of our procedure was showcased by characterizing minor lipid subclasses, including dihexosylceramides containing very long-chain polyunsaturated FA in the testis, monogalactosyl and digalactosyl monoacylglycerols in feces, and acetylated and glycolylated derivatives of gangliosides in the brain that were not detected using conventional solvent extraction methods. Likewise, the value of our method in biology is maximized during glycolipidome profiling in the absence of neutral lipids and phospholipids that cover more than 80% of the chromatographic peaks.
High Fat Diet–Wheat Gliadin Interaction and its Implication for Obesity and Celiac Disease Onset: In Vivo Studies Yuri Haneishi, Lucia Treppiccione, Francesco Maurano, Diomira Luongo, Junki Miyamoto, Mauro Rossi Molecular Nutrition and Food Research, 2024 The intestinal immune system plays a crucial role in obesity and insulin resistance. An altered intestinal immunity is associated with changes to the gut microbiota, barrier function, and tolerance to luminal antigens. Lipid metabolism and its unbalance can also contribute to acute and chronic inflammation in different conditions. In celiac disease (CD), the serum phospholipid profile in infants who developed CD is dramatically different when compared to that of infants at risk of CD not developing the disease. In a mouse model of gluten sensitivity, oral wheat gliadin challenge in connection with inhibition of the metabolism of arachidonic acid, an omega‐6 polyunsaturated fatty acid, specifically induces the enteropathy. Recent evidence suggests that gluten may play a role also for development of life‐style related diseases in populations on a high fat diet (HFD). However, the mechanisms behind these effects are not yet understood. Exploratory studies in mice feed HFD show that wheat gliadin consumption affects glucose and lipid metabolic homeostasis, alters the gut microbiota, and the immune cell profile in liver.
Impact of the lipase inhibitor orlistat on the human gut microbiota Yudai Uehira, Hiroaki Ueno, Junki Miyamoto, Ikuo Kimura, Yohei Ishizawa, Hiroshi Iijima, Shota Muroga, Toru Fujita, Soichi Sakai, Yoshishige Samukawa, Yuri Tanaka, Shinya Murayama, Hideyuki Sakoda, Masamitsu Nakazato Obesity Research and Clinical Practice, 2023
Inflammatory Bowel Diseases and Gut Microbiota Yuri Haneishi, Yuma Furuya, Mayu Hasegawa, Antonio Picarelli, Mauro Rossi, Junki Miyamoto International Journal of Molecular Sciences, 2023
Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions Junki Miyamoto, Ryuji Ohue-Kitano, Hiromi Mukouyama, Akari Nishida, Keita Watanabe, Miki Igarashi, Junichiro Irie, Gozoh Tsujimoto, Noriko Satoh-Asahara, Hiroshi Itoh, Ikuo Kimura Proceedings of the National Academy of Sciences of the United States of America, 2019
