Cell metabolismPub Date : 2024-11-26DOI: 10.1016/j.cmet.2024.10.021
Gaia Gherardi, Anna Weiser, Flavien Bermont, Eugenia Migliavacca, Benjamin Brinon, Guillaume E. Jacot, Aurélie Hermant, Mattia Sturlese, Leonardo Nogara, Filippo Vascon, Agnese De Mario, Andrea Mattarei, Emma Garratt, Mark Burton, Karen Lillycrop, Keith M. Godfrey, Laura Cendron, Denis Barron, Stefano Moro, Bert Blaauw, Umberto De Marchi
{"title":"Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance","authors":"Gaia Gherardi, Anna Weiser, Flavien Bermont, Eugenia Migliavacca, Benjamin Brinon, Guillaume E. Jacot, Aurélie Hermant, Mattia Sturlese, Leonardo Nogara, Filippo Vascon, Agnese De Mario, Andrea Mattarei, Emma Garratt, Mark Burton, Karen Lillycrop, Keith M. Godfrey, Laura Cendron, Denis Barron, Stefano Moro, Bert Blaauw, Umberto De Marchi","doi":"10.1016/j.cmet.2024.10.021","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.021","url":null,"abstract":"Mitochondrial calcium (mtCa<sup>2+</sup>) uptake via the mitochondrial calcium uniporter (MCU) couples calcium homeostasis and energy metabolism. mtCa<sup>2+</sup> uptake via MCU is rate-limiting for mitochondrial activation during muscle contraction, but its pathophysiological role and therapeutic application remain largely uncharacterized. By profiling human muscle biopsies, patient-derived myotubes, and preclinical models, we discovered a conserved downregulation of mitochondrial calcium uniporter regulator 1 (MCUR1) during skeletal muscle aging that associates with human sarcopenia and impairs mtCa<sup>2+</sup> uptake and mitochondrial respiration. Through a screen of 5,000 bioactive molecules, we identify the natural polyphenol oleuropein as a specific MCU activator that stimulates mitochondrial respiration via mitochondrial calcium uptake 1 (MICU1) binding. Oleuropein activates mtCa<sup>2+</sup> uptake and energy metabolism to enhance endurance and reduce fatigue in young and aged mice but not in muscle-specific MCU knockout (KO) mice. Our work demonstrates that impaired mtCa<sup>2+</sup> uptake contributes to mitochondrial dysfunction during aging and establishes oleuropein as a novel food-derived molecule that specifically targets MCU to stimulate mitochondrial bioenergetics and muscle performance.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"26 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142713096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Dual impacts of serine/glycine-free diet in enhancing antitumor immunity and promoting evasion via PD-L1 lactylation","authors":"Huan Tong, Zedong Jiang, Linlin Song, Keqin Tan, Xiaomeng Yin, Chengyuan He, Juan Huang, Xiaoyue Li, Xiaofan Jing, Hong Yun, Guangqi Li, Yunuo Zhao, Qianlong Kang, Yuhao Wei, Renwei Li, Zhiwen Long, Jun Yin, Qiang Luo, Xiao Liang, Yanzhi Wan, Xuelei Ma","doi":"10.1016/j.cmet.2024.10.019","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.019","url":null,"abstract":"The effect of the serine/glycine-free diet (−SG diet) on colorectal cancer (CRC) remains unclear; meanwhile, programmed death-1 (PD-1) inhibitors are less effective for most CRC patients. Here, we demonstrate that the −SG diet inhibits CRC growth and promotes the accumulation of cytotoxic T cells to enhance antitumor immunity. Additionally, we also identified the lactylation of programmed death-ligand 1 (PD-L1) in tumor cells as a mechanism of immune evasion during cytotoxic T cell-mediated antitumor responses, and blocking the PD-1/PD-L1 signaling pathway is able to rejuvenate the function of CD8+ T cells recruited by the −SG diet, indicating the potential of combining the −SG diet with immunotherapy. We conducted a single-arm, phase I study (ChiCTR2300067929). The primary outcome suggests that the −SG diet is feasible and safe for regulating systemic immunity. Secondary outcomes include patient tolerability and potential antitumor effects. Collectively, our findings highlight the promising therapeutic potential of the −SG diet for treating solid tumors.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"18 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142679049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2024-11-21DOI: 10.1016/j.cmet.2024.10.020
Elise J. Needham, Janne R. Hingst, Johan D. Onslev, Alexis Diaz-Vegas, Magnus R. Leandersson, Hannah Huckstep, Jonas M. Kristensen, Kohei Kido, Erik A. Richter, Kurt Højlund, Benjamin L. Parker, Kristen Cooke, Guang Yang, Christian Pehmøller, Sean J. Humphrey, David E. James, Jørgen F.P. Wojtaszewski
{"title":"Personalized phosphoproteomics of skeletal muscle insulin resistance and exercise links MINDY1 to insulin action","authors":"Elise J. Needham, Janne R. Hingst, Johan D. Onslev, Alexis Diaz-Vegas, Magnus R. Leandersson, Hannah Huckstep, Jonas M. Kristensen, Kohei Kido, Erik A. Richter, Kurt Højlund, Benjamin L. Parker, Kristen Cooke, Guang Yang, Christian Pehmøller, Sean J. Humphrey, David E. James, Jørgen F.P. Wojtaszewski","doi":"10.1016/j.cmet.2024.10.020","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.020","url":null,"abstract":"Type 2 diabetes is preceded by a defective insulin response, yet our knowledge of the precise mechanisms is incomplete. Here, we investigate how insulin resistance alters skeletal muscle signaling and how exercise partially counteracts this effect. We measured parallel phenotypes and phosphoproteomes of insulin-resistant (IR) and insulin-sensitive (IS) men as they responded to exercise and insulin (<em>n</em> = 19, 114 biopsies), quantifying over 12,000 phosphopeptides in each biopsy. Insulin resistance involves selective and time-dependent alterations to signaling, including reduced insulin-stimulated mTORC1 and non-canonical signaling responses. Prior exercise promotes insulin sensitivity even in IR individuals by “priming” a portion of insulin signaling prior to insulin infusion. This includes MINDY1 S441, which we show is an AKT substrate. We found that MINDY1 knockdown enhances insulin-stimulated glucose uptake in rat myotubes. This work delineates the signaling alterations in IR skeletal muscle and identifies MINDY1 as a regulator of insulin action.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"1 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2024-11-19DOI: 10.1016/j.cmet.2024.10.018
Etienne Mouisel, Anaïs Bodon, Christophe Noll, Stéphanie Cassant-Sourdy, Marie-Adeline Marques, Remy Flores-Flores, Elodie Riant, Camille Bergoglio, Pierre Vezin, Sylvie Caspar-Bauguil, Camille Fournes-Fraresso, Geneviève Tavernier, Khalil Acheikh Ibn Oumar, Pierre Gourdy, Denis P. Blondin, Pierre-Damien Denechaud, André C. Carpentier, Dominique Langin
{"title":"Cold-induced thermogenesis requires neutral-lipase-mediated intracellular lipolysis in brown adipocytes","authors":"Etienne Mouisel, Anaïs Bodon, Christophe Noll, Stéphanie Cassant-Sourdy, Marie-Adeline Marques, Remy Flores-Flores, Elodie Riant, Camille Bergoglio, Pierre Vezin, Sylvie Caspar-Bauguil, Camille Fournes-Fraresso, Geneviève Tavernier, Khalil Acheikh Ibn Oumar, Pierre Gourdy, Denis P. Blondin, Pierre-Damien Denechaud, André C. Carpentier, Dominique Langin","doi":"10.1016/j.cmet.2024.10.018","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.018","url":null,"abstract":"Long-chain fatty acids (FAs) are the major substrates fueling brown adipose tissue (BAT) thermogenesis. Investigation of mouse models has previously called into question the contribution of brown adipocyte intracellular lipolysis to cold-induced non-shivering thermogenesis. Here, we determined the role of the lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in BAT thermogenesis. Brown fat from mice with inducible brown-adipocyte-specific deletion of ATGL and HSL (BAHKO) is hypertrophied with increased lipid droplet size and preserved mitochondria area and density. Maintenance of body temperature during cold exposure is compromised in BAHKO mice in the fasted but not in the fed state. This altered response to cold is observed in various thermal and nutritional conditions. Positron emission tomography-computed tomography using [<sup>11</sup>C]-acetate and [<sup>11</sup>C]-palmitate shows abolished cold-induced BAT oxidative activity and impaired FA metabolism in BAHKO mice. Our findings show that brown adipocyte intracellular lipolysis is required for BAT thermogenesis.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"11 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142670681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2024-11-18DOI: 10.1016/j.cmet.2024.10.015
Rongxuan Zhu, Xianglai Ye, Xiaotong Lu, Liwei Xiao, Ming Yuan, Hong Zhao, Dong Guo, Ying Meng, Hongkuan Han, Shudi Luo, Qingang Wu, Xiaoming Jiang, Jun Xu, Zhonghui Tang, Yizhi Jane Tao, Zhimin Lu
{"title":"ACSS2 acts as a lactyl-CoA synthetase and couples KAT2A to function as a lactyltransferase for histone lactylation and tumor immune evasion","authors":"Rongxuan Zhu, Xianglai Ye, Xiaotong Lu, Liwei Xiao, Ming Yuan, Hong Zhao, Dong Guo, Ying Meng, Hongkuan Han, Shudi Luo, Qingang Wu, Xiaoming Jiang, Jun Xu, Zhonghui Tang, Yizhi Jane Tao, Zhimin Lu","doi":"10.1016/j.cmet.2024.10.015","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.015","url":null,"abstract":"Lactyl-coenzyme A (CoA)-dependent histone lysine lactylation impacts gene expression and plays fundamental roles in biological processes. However, mammalian lactyl-CoA synthetases and their regulation of histone lactylation have not yet been identified. Here, we demonstrate that epidermal growth factor receptor (EGFR) activation induces extracellular signal-regulated kinase (ERK)-mediated S267 phosphorylation of acetyl-CoA synthetase 2 (ACSS2) and its subsequent nuclear translocation and complex formation with lysine acetyltransferase 2A (KAT2A). Importantly, ACSS2 functions as a bona fide lactyl-CoA synthetase and converts lactate to lactyl-CoA, which binds to KAT2A as demonstrated by a co-crystal structure analysis. Consequently, KAT2A acts as a lactyltransferase to lactylate histone H3, leading to the expression of Wnt/β-catenin, NF-κB, and PD-L1 and brain tumor growth and immune evasion. A combination treatment with an ACSS2-KAT2A interaction-blocking peptide and an anti-PD-1 antibody induces an additive tumor-inhibitory effect. These findings uncover ACSS2 and KAT2A as hitherto unidentified lactyl-CoA synthetase and lactyltransferase, respectively, and the significance of the ACSS2-KAT2A coupling in gene expression and tumor development.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"6 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2024-11-18DOI: 10.1016/j.cmet.2024.10.012
Ting Li, Yueyue Liu, Tianchi Duan, Chao Guo, Bin Liu, Xiuqiong Fu, Lu Wang, Xiaoyuan Wang, Xinyue Dong, Chennan Wang, Yalong Lu, Yu Wang, Lin Shi, Honglei Tian, Xingbin Yang
{"title":"Nondigestible stachyose binds membranous HSP90β on small intestinal epithelium to regulate the exosomal miRNAs: A new function and mechanism","authors":"Ting Li, Yueyue Liu, Tianchi Duan, Chao Guo, Bin Liu, Xiuqiong Fu, Lu Wang, Xiaoyuan Wang, Xinyue Dong, Chennan Wang, Yalong Lu, Yu Wang, Lin Shi, Honglei Tian, Xingbin Yang","doi":"10.1016/j.cmet.2024.10.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.012","url":null,"abstract":"Oligosaccharides are conventionally recognized as “passersby” in the small intestine. However, our research has reframed this understanding by uncovering a new function of oligosaccharide stachyose, which binds hydrophobic residues of membranous HSP90β on small intestinal epithelial cells, thus reprograming the exosomal miRNA profile. CRISPR-Cas9-mediated HSP90β knockout abolished the accumulation of stachyose on cell membrane and its regulatory effects on these miRNAs. Notably, stachyose’s regulation on these miRNAs is independent of its prebiotic role, as evidenced by the observation of stachyose-altered fecal miRNAs in pseudo-germ-free mice. These stachyose-altered miRNAs further shaped colonic microbiome, especially harboring <em>Lactobacillus</em> in mice. Thereinto, miR-30a-5p that was downregulated (Log<sub>2</sub>FC < −2) in both mice and human feces following stachyose treatment could specifically suppress the growth of <em>Lactobacillus reuteri</em>. These findings build a new regulatory axis of stachyose-intestinal miRNAs-gut microbiota and unveil a previously unknown mechanism underlying the direct “talk” of oligosaccharides to intestine epithelium via membranous HSP90β.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"10 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2024-11-18DOI: 10.1016/j.cmet.2024.10.007
Shen Li, Hongbo Liu, Hailong Hu, Eunji Ha, Praveena Prasad, Brenita C. Jenkins, Ujjalkumar Subhash Das, Sarmistha Mukherjee, Kyosuke Shishikura, Renming Hu, Daniel J. Rader, Liming Pei, Joseph A. Baur, Megan L. Matthews, Garret A. FitzGerald, Melanie R. McReynolds, Katalin Susztak
{"title":"Human genetics identify convergent signals in mitochondrial LACTB-mediated lipid metabolism in cardiovascular-kidney-metabolic syndrome","authors":"Shen Li, Hongbo Liu, Hailong Hu, Eunji Ha, Praveena Prasad, Brenita C. Jenkins, Ujjalkumar Subhash Das, Sarmistha Mukherjee, Kyosuke Shishikura, Renming Hu, Daniel J. Rader, Liming Pei, Joseph A. Baur, Megan L. Matthews, Garret A. FitzGerald, Melanie R. McReynolds, Katalin Susztak","doi":"10.1016/j.cmet.2024.10.007","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.007","url":null,"abstract":"The understanding of cardiovascular-kidney-metabolic syndrome remains difficult despite recently performed large scale genome-wide association studies. Here, we identified beta-lactamase (LACTB), a novel gene whose expression is targeted by genetic variations causing kidney dysfunction and hyperlipidemia. Mice with LACTB deletion developed impaired glucose tolerance, elevated lipid levels, and increased sensitivity to kidney disease, while mice with tubule-specific overexpression of LACTB were protected from kidney injury. We show that LACTB is a novel mitochondrial protease cleaving and activating phospholipase A2 group VI (PLA2G6), a kidney-metabolic risk gene itself. Genetic deletion of PLA2G6 in tubule-specific LACTB-overexpressing mice abolished the protective function of LACTB. Via mouse and human lipidomic studies, we show that LACTB and downstream PLA2G6 convert oxidized phosphatidylethanolamine to lyso-phosphatidylethanolamine and thereby regulate mitochondrial function and ferroptosis. In summary, we identify a novel gene and a core targetable pathway for kidney-metabolic disorders.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"13 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2024-11-14DOI: 10.1016/j.cmet.2024.10.016
Jivani M. Gengatharan, Michal K. Handzlik, Zoya Y. Chih, Maureen L. Ruchhoeft, Patrick Secrest, Ethan L. Ashley, Courtney R. Green, Martina Wallace, Philip L.S.M. Gordts, Christian M. Metallo
{"title":"Altered sphingolipid biosynthetic flux and lipoprotein trafficking contribute to trans-fat-induced atherosclerosis","authors":"Jivani M. Gengatharan, Michal K. Handzlik, Zoya Y. Chih, Maureen L. Ruchhoeft, Patrick Secrest, Ethan L. Ashley, Courtney R. Green, Martina Wallace, Philip L.S.M. Gordts, Christian M. Metallo","doi":"10.1016/j.cmet.2024.10.016","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.016","url":null,"abstract":"Dietary fat drives the pathogenesis of atherosclerotic cardiovascular disease (ASCVD), particularly through circulating cholesterol and triglyceride-rich lipoprotein remnants. Industrially produced <em>trans</em>-unsaturated fatty acids (TFAs) incorporated into food supplies significantly promote ASCVD. However, the molecular trafficking of TFAs responsible for this association is not well understood. Here, we demonstrate that TFAs are preferentially incorporated into sphingolipids by serine palmitoyltransferase (SPT) and secreted from cells <em>in vitro</em>. Administering high-fat diets (HFDs) enriched in TFAs to <em>Ldlr</em><sup><em>−/−</em></sup> mice accelerated hepatic very-low-density lipoprotein (VLDL) and sphingolipid secretion into circulation to promote atherogenesis compared with a <em>cis</em>-unsaturated fatty acid (CFA)-enriched HFD. SPT inhibition mitigated these phenotypes and reduced circulating atherogenic VLDL enriched in TFA-derived polyunsaturated sphingomyelin. Transcriptional analysis of human liver revealed distinct regulation of <em>SPTLC2</em> versus <em>SPTLC3</em> subunit expression, consistent with human genetic correlations in ASCVD, further establishing sphingolipid metabolism as a critical node mediating the progression of ASCVD in response to specific dietary fats.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"37 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Microbiota-derived lysophosphatidylcholine alleviates Alzheimer’s disease pathology via suppressing ferroptosis","authors":"Xu Zha, Xicheng Liu, Mengping Wei, Huanwei Huang, Jiaqi Cao, Shuo Liu, Xiaomei Bian, Yuting Zhang, Fenyan Xiao, Yuping Xie, Wei Wang, Chen Zhang","doi":"10.1016/j.cmet.2024.10.006","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.006","url":null,"abstract":"Alzheimer’s disease (AD) is a pervasive neurodegenerative disorder, and new approaches for its prevention and therapy are critically needed. Here, we elucidate a gut-microbiome-brain axis that offers actionable perspectives for achieving this objective. Using the 5xFAD mouse model, we identify increased <em>Clostridium</em> abundance and decreased <em>Bacteroides</em> abundance as key features associated with β-amyloid (Aβ) burden. Treatment with <em>Bacteroides ovatus</em>, or its associated metabolite lysophosphatidylcholine (LPC), significantly reduces Aβ load and ameliorates cognitive impairment. Mechanistically, LPC acts through the orphan receptor GPR119, inhibiting ACSL4 expression, thereby suppressing ferroptosis and ameliorating AD pathologies. Analysis of fecal and serum samples from individuals with AD also reveals diminished levels of <em>Bacteroides</em> and LPC. This study thus identifies a <em>B.</em><em>ovatus</em>-triggered pathway regulating AD pathologies and indicates that the use of single gut microbiota, metabolite, or small molecule compound may complement current prevention and treatment approaches for AD.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"13 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2024-11-05DOI: 10.1016/j.cmet.2024.10.003
Gabriel S.S. Tofani, Sarah-Jane Leigh, Cassandra E. Gheorghe, Thomaz F.S. Bastiaanssen, Lars Wilmes, Paromita Sen, Gerard Clarke, John F. Cryan
{"title":"Gut microbiota regulates stress responsivity via the circadian system","authors":"Gabriel S.S. Tofani, Sarah-Jane Leigh, Cassandra E. Gheorghe, Thomaz F.S. Bastiaanssen, Lars Wilmes, Paromita Sen, Gerard Clarke, John F. Cryan","doi":"10.1016/j.cmet.2024.10.003","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.003","url":null,"abstract":"Stress and circadian systems are interconnected through the hypothalamic-pituitary-adrenal (HPA) axis to maintain responses to external stimuli. Yet, the mechanisms of how such signals are orchestrated remain unknown. Here, we uncover the gut microbiota as a regulator of HPA-axis rhythmicity. Microbial depletion disturbs the brain transcriptome and metabolome in stress-responding pathways in the hippocampus and amygdala across the day. This is coupled with a dysregulation of the circadian pacemaker in the brain that results in perturbed glucocorticoid rhythmicity. The resulting hyper-activation of the HPA axis at the sleep/wake transition drives time-of-day-specific impairments of the stress response and stress-sensitive behaviors. Finally, microbiota transplantation confirmed that diurnal oscillations of gut microbes underlie altered glucocorticoid secretion and that <em>L. reuteri</em> is a candidate strain for such effects. Our data offer compelling evidence that the microbiota regulates stress responsiveness in a circadian manner and is necessary to respond adaptively to stressors throughout the day.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"242 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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