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Metabolic shift from oxidative phosphorylation to aerobic glycolysis links metabolism to inflammation and such a shift is commonly observed in sepsis under normoxic conditions. By shifting the metabolic state from aerobic glycolysis to oxidative phosphorylation, we hypothesized it would reverse unresolved inflammation and subsequently improve outcome. We propose a shift from aerobic glycolysis to oxidative phosphorylation as a sepsis therapy by targeting the pathways involved in the conversion of pyruvate into acetyl-CoA via pyruvate dehydrogenase (PDH). Chemical manipulation of PDH using dichloroacetic acid (DCA) will promote oxidative phosphorylation over glycolysis and decrease inflammation. We tested our hypothesis in a<jats:italic>Drosophila melanogaster<\/jats:italic>model of surviving sepsis infected with Staphylococcus aureus. Drosophila were divided into 3 groups:<jats:italic>unmanipulated<\/jats:italic>,<jats:italic>sham<\/jats:italic>and<jats:italic>sepsis survivors<\/jats:italic>, all treated with linezolid; each group was either treated or not with DCA for one week following sepsis. We followed lifespan, measured gene expression of<jats:italic>Toll<\/jats:italic>,<jats:italic>defensin<\/jats:italic>,<jats:italic>cecropin A<\/jats:italic>, and<jats:italic>drosomycin<\/jats:italic>, and levels of lactate, pyruvate, acetyl-CoA as well as TCA metabolites. In our model, metabolic effects of sepsis are modified by DCA with normalized lactate, TCA metabolites, and was associated with improved lifespan of sepsis survivors, yet had no lifespan effects on unmanipulated and sham flies. While<jats:italic>Drosomycin<\/jats:italic>and<jats:italic>cecropin A<\/jats:italic>expression increased in sepsis survivors, DCA treatment decreased both<jats:italic>and<\/jats:italic>selectively increased<jats:italic>defensin<\/jats:italic>.<\/jats:p>","DOI":"10.1371\/journal.pone.0241122","type":"journal-article","created":{"date-parts":[[2020,11,5]],"date-time":"2020-11-05T18:34:17Z","timestamp":1604601257000},"page":"e0241122","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Dichloroacetate-induced metabolic reprogramming improves lifespan in a Drosophila model of surviving sepsis"],"prefix":"10.1371","volume":"15","author":[{"given":"Veli","family":"Bakalov","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Reyes-Uribe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rahul","family":"Deshpande","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abigail L.","family":"Maloy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven D.","family":"Shapiro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Derek C.","family":"Angus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chung-Chou H.","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurence","family":"Le Moyec","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9083-6933","authenticated-orcid":true,"given":"Stacy Gelhaus","family":"Wendell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8847-0450","authenticated-orcid":true,"given":"Ata Murat","family":"Kaynar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2020,11,5]]},"reference":[{"issue":"2","key":"pone.0241122.ref001","doi-asserted-by":"crossref","first-page":"R81","DOI":"10.1186\/cc12695","article-title":"Changes in hospital mortality for United States intensive care unit admissions from 1988 to 2012.","volume":"17","author":"JE Zimmerman","year":"2013","journal-title":"Critical care"},{"issue":"10","key":"pone.0241122.ref002","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1001\/jama.1995.03530100047033","article-title":"Long-term survival following bacteremia or fungemia. 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