{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T04:44:46Z","timestamp":1788583486946,"version":"build-2803163510"},"reference-count":64,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T00:00:00Z","timestamp":1670284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Swiss National Science Foundation","award":["310030_207418"],"award-info":[{"award-number":["310030_207418"]}]},{"name":"Swiss National Science Foundation","award":["676129"],"award-info":[{"award-number":["676129"]}]},{"name":"Fondation Carigest\/Promex Stiftung f\u00fcr die Forschung (Gen\u00e8ve, Switzerland)","award":["310030_207418"],"award-info":[{"award-number":["310030_207418"]}]},{"name":"Fondation Carigest\/Promex Stiftung f\u00fcr die Forschung (Gen\u00e8ve, Switzerland)","award":["676129"],"award-info":[{"award-number":["676129"]}]},{"name":"European Sepsis Academy Horizon 2020 Marie Sk\u0142odowska-Curie Action: Innovative Training Network","award":["310030_207418"],"award-info":[{"award-number":["310030_207418"]}]},{"name":"European Sepsis Academy Horizon 2020 Marie Sk\u0142odowska-Curie Action: Innovative Training Network","award":["676129"],"award-info":[{"award-number":["676129"]}]},{"name":"University College London Hospital (UCLH) Biomedical Research Centre (BRC), UK National Institute of Health Research (NIHR) European Society of Intensive Care Medicine (ESICM) NEXT start up Award","award":["310030_207418"],"award-info":[{"award-number":["310030_207418"]}]},{"name":"University College London Hospital (UCLH) Biomedical Research Centre (BRC), UK National Institute of Health Research (NIHR) European Society of Intensive Care Medicine (ESICM) NEXT start up Award","award":["676129"],"award-info":[{"award-number":["676129"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Mitochondrial dysfunction and immune cell dysfunction are commonplace in sepsis and are associated with increased mortality risk. The short chain fatty acid, butyrate, is known to have anti-inflammatory effects and promote mitochondrial biogenesis. We therefore explored the immunometabolic effects of butyrate in an animal model of sepsis. Isolated healthy human volunteer peripheral mononuclear cells were stimulated with LPS in the presence of absence of butyrate, and released cytokines measured. Male Wistar rats housed in metabolic cages received either intravenous butyrate infusion or placebo commencing 6 h following faecal peritonitis induction. At 24 h, splenocytes were isolated for high-resolution respirometry, and measurement of mitochondrial membrane potential (MMP), reactive oxygen species (mtROS), and intracellular cytokines (TNF alpha, IL-10) using flow cytometry. Isolated splenocytes from septic and septic butyrate treated rats were stimulated with LPS for 18 h and the effects of butyrate on cytokine release assessed. Ex vivo, butyrate (1.8 mM) reduced LPS-induced TNF alpha (p = 0.019) and IL-10 (p = 0.001) release by human PBMCs. In septic animals butyrate infusion reduced the respiratory exchange ratio (p &lt; 0.001), consistent with increased fat metabolism. This was associated with a reduction in cardiac output (p = 0.001), and increased lactate (p = 0.031) compared to placebo-treated septic animals (p &lt; 0.05). Butyrate treatment was associated with a reduction in splenocyte basal respiration (p = 0.077), proton leak (p = 0.022), and non-mitochondrial respiration (p = 0.055), and an increase in MMP (p = 0.007) and mtROS (p = 0.027) compared to untreated septic animals. Splenocyte intracellular cytokines were unaffected by butyrate, although LPS-induced IL-10 release was impaired (p = 0.039). In summary, butyrate supplementation exacerbates myocardial and immune cell mitochondrial dysfunction in a rat model of faecal peritonitis.<\/jats:p>","DOI":"10.3390\/life12122034","type":"journal-article","created":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T02:23:42Z","timestamp":1670293422000},"page":"2034","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Butyrate Supplementation Exacerbates Myocardial and Immune Cell Mitochondrial Dysfunction in a Rat Model of Faecal Peritonitis"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1067-7392","authenticated-orcid":false,"given":"Vera B. M.","family":"Peters","sequence":"first","affiliation":[{"name":"Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nishkantha","family":"Arulkumaran","sequence":"additional","affiliation":[{"name":"Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3913-4597","authenticated-orcid":false,"given":"Miranda J.","family":"Melis","sequence":"additional","affiliation":[{"name":"Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Gaupp","sequence":"additional","affiliation":[{"name":"Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9358-0109","authenticated-orcid":false,"given":"Thierry","family":"Roger","sequence":"additional","affiliation":[{"name":"Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, CH-1066 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5338-2538","authenticated-orcid":false,"given":"Manu","family":"Shankar-Hari","sequence":"additional","affiliation":[{"name":"Centre for Inflammation Research, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh EH16 4TJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mervyn","family":"Singer","sequence":"additional","affiliation":[{"name":"Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990\u20132017: Analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1164\/ajrccm.163.2.2007102","article-title":"Normal responses to injury prevent systemic inflammation and can be immunosuppressive","volume":"163","author":"Munford","year":"2001","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/nri.2017.36","article-title":"The immunopathology of sepsis and potential therapeutic targets","volume":"17","author":"Scicluna","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1097\/00003246-199112000-00011","article-title":"Severity of illness correlates with alterations in energy metabolism in the pediatric intensive care unit","volume":"19","author":"Steinhorn","year":"1991","journal-title":"Crit. Care Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1097\/00003246-200004000-00042","article-title":"Energy expenditure in critically ill children","volume":"28","author":"Briassoulis","year":"2000","journal-title":"Crit. Care Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1097\/00003246-200007000-00021","article-title":"Energy expenditure in 100 ventilated, critically ill children: Improving the accuracy of predictive equations","volume":"28","author":"White","year":"2000","journal-title":"Crit. Care Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1097\/00003246-199211000-00012","article-title":"Oxygen consumption, energy expenditure, and substrate utilization after cardiac surgery in children","volume":"20","author":"Gebara","year":"1992","journal-title":"Crit. Care Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S441","DOI":"10.1097\/01.CCM.0000278049.48333.78","article-title":"Mitochondrial function in sepsis: Acute phase versus multiple organ failure","volume":"35","author":"Singer","year":"2007","journal-title":"Crit. Care Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/2197-425X-1-6","article-title":"The metabolic phenotype of rodent sepsis: Cause for concern?","volume":"1","author":"Zolfaghari","year":"2013","journal-title":"Intensive Care Med. Exp."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1097\/00003246-199307000-00015","article-title":"Oxygen consumption and resting metabolic rate in sepsis, sepsis syndrome, and septic shock","volume":"21","author":"Kreymann","year":"1993","journal-title":"Crit. Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0022-4804(03)00141-0","article-title":"Increased tissue oxygen extraction and acidosis with progressive severity of sepsis","volume":"112","author":"Hart","year":"2003","journal-title":"J. Surg. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1164\/ajrccm.164.3.2009088","article-title":"Mitochondrial membrane potential and apoptosis peripheral blood monocytes in severe human sepsis","volume":"164","author":"Adrie","year":"2001","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1097\/CCM.0b013e31820eda5c","article-title":"Bioenergetic failure of human peripheral blood monocytes in patients with septic shock is mediated by reduced F1Fo adenosine-5\u2032-triphosphate synthase activity","volume":"39","author":"Japiassu","year":"2011","journal-title":"Crit. Care Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1093\/infdis\/jir764","article-title":"The effects of sepsis on mitochondria","volume":"205","author":"Garrabou","year":"2012","journal-title":"J. Infect. Dis."},{"key":"ref_16","first-page":"97","article-title":"The role of the gut microbiome in the healthy adult status","volume":"451 Pt A","author":"Salvatore","year":"2015","journal-title":"Clin. Chim. Acta"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.tim.2017.11.002","article-title":"Human Gut Microbiome: Function Matters","volume":"26","author":"Wilmes","year":"2018","journal-title":"Trends Microbiol."},{"key":"ref_18","first-page":"185","article-title":"Intestinal Short Chain Fatty Acids and their Link with Diet and Human Health","volume":"7","author":"Margolles","year":"2016","journal-title":"Front. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"225","DOI":"10.3920\/BM2018.0066","article-title":"Mechanisms and immunomodulatory properties of pre- and probiotics","volume":"10","author":"Peters","year":"2019","journal-title":"Benef. Microbes"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e73","DOI":"10.1038\/cti.2016.17","article-title":"Regulation of immune cell function by short-chain fatty acids","volume":"5","author":"Fachi","year":"2016","journal-title":"Clin. Transl. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.cmet.2011.02.018","article-title":"The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon","volume":"13","author":"Donohoe","year":"2011","journal-title":"Cell Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.2337\/db08-1637","article-title":"Butyrate improves insulin sensitivity and increases energy expenditure in mice","volume":"58","author":"Gao","year":"2009","journal-title":"Diabetes"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2398","DOI":"10.2337\/db14-1213","article-title":"Short-Chain Fatty Acids Protect Against High-Fat Diet-Induced Obesity via a PPARgamma-Dependent Switch From Lipogenesis to Fat Oxidation","volume":"64","author":"Bleeker","year":"2015","journal-title":"Diabetes"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gallis, J.L., Tissier, P., Gin, H., and Beauvieux, M.-C. (2007). Decrease in oxidative phosphorylation yield in presence of butyrate in perfused liver isolated from fed rats. BMC Physiol., 7.","DOI":"10.1186\/1472-6793-7-8"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1136\/gut.28.10.1221","article-title":"Short chain fatty acids in human large intestine, portal, hepatic and venous blood","volume":"28","author":"Cummings","year":"1987","journal-title":"Gut"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1007\/s00134-011-2227-z","article-title":"Temporal changes in tissue cardiorespiratory function during faecal peritonitis","volume":"37","author":"Dyson","year":"2011","journal-title":"Intensive Care Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"R491","DOI":"10.1152\/ajpregu.00432.2003","article-title":"Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure","volume":"286","author":"Brealey","year":"2004","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s002800050922","article-title":"Plasma pharmacokinetics of butyrate after intravenous administration of sodium butyrate or oral administration of tributyrin or sodium butyrate to mice and rats","volume":"43","author":"Egorin","year":"1999","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/B978-0-12-801415-8.00016-3","article-title":"Analysis and Interpretation of Microplate-Based Oxygen Consumption and pH Data","volume":"547","author":"Divakaruni","year":"2014","journal-title":"Methods Enzymol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1097\/SHK.0b013e31802e3f4c","article-title":"Sodium butyrate prevents lethality of severe sepsis in rats","volume":"27","author":"Zhang","year":"2007","journal-title":"Shock"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0022-3468(99)90191-4","article-title":"Intravenous glutamine or short-chain fatty acids reduce central venous catheter infection in a model of total parenteral nutrition","volume":"34","author":"McAndrew","year":"1999","journal-title":"J. Pediatr. Surg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"37944","DOI":"10.1038\/srep37944","article-title":"Impact of the microbial derived short chain fatty acid propionate on host susceptibility to bacterial and fungal infections in vivo","volume":"6","author":"Ciarlo","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1111\/sji.12515","article-title":"The Inflammation Induced by Lipopolysaccharide can be Mitigated by Short-chain Fatty Acid, Butyrate, through Upregulation of IL-10 in Septic Shock","volume":"85","author":"Wang","year":"2017","journal-title":"Scand. J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1097\/00000658-198001000-00008","article-title":"Influence of Total Parenteral Nutrition on Fuel Utilization in Injury and Sepsis","volume":"191","author":"Askanazi","year":"1980","journal-title":"Ann. Surg."},{"key":"ref_35","first-page":"E756","article-title":"Influence of beta-hydroxybutyrate infusion on glucose and free fatty acid metabolism in dogs","volume":"247","author":"Shaw","year":"1984","journal-title":"Am. J. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1164\/rccm.201211-1983OC","article-title":"Mechanisms of Cardiac and Renal Dysfunction in Patients Dying of Sepsis","volume":"187","author":"Takasu","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.ajem.2016.11.022","article-title":"Butyrate pretreatment attenuates heart depression in a mice model of endotoxin-induced sepsis via anti-inflammation and anti-oxidation","volume":"35","author":"Wang","year":"2017","journal-title":"Am. J. Emerg. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1152\/ajplegacy.1917.42.3.460","article-title":"Lactic acid production in the blood following the injection of alkaline solutions and dextrose or of alkaline solutions alone","volume":"42","author":"MacLeod","year":"1917","journal-title":"Am. J. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/ki.1972.46","article-title":"Metabolic consequences of acid-base disorders","volume":"1","author":"Relman","year":"1972","journal-title":"Kidney Int."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3940","DOI":"10.1016\/S0021-9258(18)92034-X","article-title":"The effect of hydrogen ions on the control of mitochondrial respiration","volume":"243","author":"Lowenstein","year":"1968","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1194\/jlr.R067629","article-title":"Short- and medium-chain fatty acids in energy metabolism: The cellular perspective","volume":"57","author":"Schonfeld","year":"2016","journal-title":"J. Lipid. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.freeradbiomed.2008.04.029","article-title":"Fatty acids as modulators of the cellular production of reactive oxygen species","volume":"45","author":"Schonfeld","year":"2008","journal-title":"Free Radic. Biol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1038\/s41398-017-0089-z","article-title":"Butyrate enhances mitochondrial function during oxidative stress in cell lines from boys with autism","volume":"8","author":"Rose","year":"2018","journal-title":"Transl. Psychiatry"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"C404","DOI":"10.1152\/ajpcell.00214.2018","article-title":"A physiological drop in pH decreases mitochondrial respiration, and HDAC and Akt signaling, in L6 myocytes","volume":"316","author":"Genders","year":"2019","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_45","first-page":"6014631","article-title":"Diabetes Mellitus and Increased Tuberculosis Susceptibility: The Role of Short-Chain Fatty Acids","volume":"2016","author":"Lachmandas","year":"2015","journal-title":"J. Diabetes Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1007\/s10753-012-9484-z","article-title":"Short-Chain Fatty Acids Suppress Lipopolysaccharide-Induced Production of Nitric Oxide and Proinflammatory Cytokines Through Inhibition of NF-kappa B Pathway in RAW264.7","volume":"35","author":"Liu","year":"2012","journal-title":"Cells Inflamm."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.intimp.2006.08.015","article-title":"Anti-inflammatory effects of short chain fatty acids in IFN-gamma-stimulated RAW 264.7 murine macrophage cells: Involvement of NF-kappa B and ERK signaling pathways","volume":"7","author":"Park","year":"2007","journal-title":"Int. Immunopharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.1096\/fj.00-0359fje","article-title":"Anti-inflammatory effects of sodium butyrate on human monocytes: Potent inhibition of IL-12 and up-regulation of IL-10 production","volume":"14","author":"Saemann","year":"2000","journal-title":"FASEB J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1136\/gut.47.3.397","article-title":"Butyrate inhibits inflammatory responses through NF kappa B inhibition: Implications for Crohn\u2019s disease","volume":"47","author":"Segain","year":"2000","journal-title":"Gut"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1136\/annrheumdis-2014-206258","article-title":"Suppression of monosodium urate crystal-induced cytokine production by butyrate is mediated by the inhibition of class I histone deacetylases","volume":"75","author":"Cleophas","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/j.jnutbio.2010.07.009","article-title":"Suppressive effect of short-chain fatty acids on production of proinflammatory mediators by neutrophils","volume":"22","author":"Vinolo","year":"2011","journal-title":"J. Nutr. Biochem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/nri2711","article-title":"The regulation of IL-10 production by immune cells","volume":"10","author":"Saraiva","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"11312","DOI":"10.1074\/jbc.M211609200","article-title":"The Orphan G Protein-coupled Receptors GPR41 and GPR43 Are Activated by Propionate and Other Short Chain Carboxylic Acids","volume":"278","author":"Brown","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"25481","DOI":"10.1074\/jbc.M301403200","article-title":"Functional Characterization of Human Receptors for Short Chain Fatty Acids and Their Role in Polymorphonuclear Cell Activation","volume":"278","author":"Loison","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.immuni.2013.12.007","article-title":"Activation of Gpr109a, Receptor for Niacin and the Commensal Metabolite Butyrate, Suppresses Colonic Inflammation and Carcinogenesis","volume":"40","author":"Singh","year":"2014","journal-title":"Immunity"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"6766","DOI":"10.4049\/jimmunol.0904054","article-title":"Sepsis-Induced Apoptosis Leads to Active Suppression of Delayed-Type Hypersensitivity by CD8+ Regulatory T Cells through a TRAIL-Dependent Mechanism","volume":"184","author":"Unsinger","year":"2010","journal-title":"J. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1189\/jlb.1008615","article-title":"Sepsis-induced human lymphocyte apoptosis and cytokine production in \u201chumanized\u201d mice","volume":"86","author":"Unsinger","year":"2009","journal-title":"J. Leukoc. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"R112","DOI":"10.1186\/cc11404","article-title":"A prospective analysis of lymphocyte phenotype and function over the course of acute sepsis","volume":"16","author":"Boomer","year":"2012","journal-title":"Crit. Care"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2594","DOI":"10.1001\/jama.2011.1829","article-title":"Immunosuppression in Patients Who Die of Sepsis and Multiple Organ Failure","volume":"306","author":"Boomer","year":"2011","journal-title":"JAMA"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1097\/00003246-199907000-00002","article-title":"Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction","volume":"27","author":"Hotchkiss","year":"1999","journal-title":"Crit. Care Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"6952","DOI":"10.4049\/jimmunol.166.11.6952","article-title":"Sepsis-Induced Apoptosis Causes Progressive Profound Depletion of B and CD4+T Lymphocytes in Humans","volume":"166","author":"Hotchkiss","year":"2001","journal-title":"J. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/nri727","article-title":"The B7-CD28 superfamily","volume":"2","author":"Sharpe","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"45","DOI":"10.4161\/viru.26516","article-title":"The changing immune system in sepsis Is individualized immuno-modulatory therapy the answer?","volume":"5","author":"Boomer","year":"2014","journal-title":"Virulence"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1016\/j.febslet.2010.03.014","article-title":"Uncoupling protein UCP2: When mitochondrial activity meets immunity","volume":"584","author":"Emre","year":"2010","journal-title":"FEBS Lett."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/12\/12\/2034\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:34:44Z","timestamp":1760146484000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/12\/12\/2034"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,6]]},"references-count":64,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["life12122034"],"URL":"https:\/\/doi.org\/10.3390\/life12122034","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,6]]}}}