{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T21:08:33Z","timestamp":1791839313449,"version":"4.3.4"},"reference-count":100,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Sepsis remains the leading cause of death in intensive care, yet decades of trials targeting individual inflammatory mediators have failed to reduce mortality. This failure may reflect a fundamental misunderstanding: sepsis may not be a disease of immune dysregulation but a centrally governed metabolic program, an evolved conservation response functionally analogous to bacterial sporulation. We bring together three lines of work. Two are established: the Selfish Brain Theory of hierarchical energy allocation and the Metabolic Shutdown Hypothesis of adaptive organ hibernation. The third is developed here from a preprint by one of the authors: the proposal that cortisol is a candidate driver of the septic state rather than an anti-inflammatory brake, and that, as a consequence, the systemic immune response can be read as an active-inference process governed by the central nervous system (CNS). These describe one phenomenon from different vantage points. The convergence yields what we call a sporulation-like conservation program: we propose that, when the CNS detects an existential threat, it activates a coordinated program of peripheral shutdown, resource centralization, and innate-dominant immune reconfiguration, mediated primarily through the hypothalamic-pituitary-adrenal axis. This response is adaptive when self-limiting but becomes pathological when the organism cannot terminate the program, a state we recognize as sepsis \u2014 specifically, the high-cortisol, catabolic, insulin-resistant sepsis phenotype to which this framework is limited. Drawing on the Free Energy Principle as an interpretive lens, we describe this governance as a pathological attractor state: the sporulation-like policy generates its own confirmatory sensory input, creating an immunometabolic echo chamber that leaves the CNS no reason to revise its model. Breaking this lock-in requires a signal the model cannot predict: a genuine metabolic surprise. We propose that insulin can serve as this termination signal, acting not through glucose control but as a CNS-directed anabolic signal that conveys metabolic safety. This reframing reinterprets the existing insulin trial literature and yields testable predictions, which we set out in full. This framework would shift the therapeutic objective from suppressing inflammation to providing the metabolic evidence the CNS needs to terminate its own emergency program, from fighting the response to persuading the controller.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1842915","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:16:08Z","timestamp":1787199368000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Sepsis as CNS-governed metabolic triage"],"prefix":"10.3389","volume":"17","author":[{"given":"Bar\u0131\u015f","family":"Yurtsever","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Istanbul Faculty of Medicine, Istanbul University","place":["Istanbul, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Demet","family":"Demirkol","sequence":"additional","affiliation":[{"name":"Division of Pediatric Intensive Care, Department of Pediatrics, Istanbul Faculty of Medicine, Istanbul University","place":["Istanbul, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","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":"B2","doi-asserted-by":"publisher","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":"B3","doi-asserted-by":"publisher","first-page":"66","DOI":"10.4161\/viru.26907","article-title":"The role of mitochondrial dysfunction in sepsis-induced multi-organ failure","volume":"5","author":"Singer","year":"2014","journal-title":"Virulence"},{"key":"B4","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1111\/j.1399-6576.1997.tb05514.x","article-title":"Cytopathic hypoxia in sepsis","volume":"41","author":"Fink","year":"1997","journal-title":"Acta Anaesthesiol Scand"},{"key":"B5","doi-asserted-by":"publisher","first-page":"16045","DOI":"10.1038\/nrdp.2016.45","article-title":"Sepsis and septic shock","volume":"2","author":"Hotchkiss","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"B6","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1016\/S1473-3099(15)70112-X","article-title":"Sepsis: a roadmap for future research","volume":"15","author":"Cohen","year":"2015","journal-title":"Lancet Infect Dis"},{"key":"B7","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.molmed.2014.01.007","article-title":"Why have clinical trials in sepsis failed","volume":"20","author":"Marshall","year":"2014","journal-title":"Trends Mol Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.910516","article-title":"Chasing the ghost: Hyperinflammation does not cause sepsis","volume":"13","author":"Shapiro","year":"2022","journal-title":"Front Pharmacol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2004.03.002","article-title":"The selfish brain: competition for energy resources","volume":"28","author":"Peters","year":"2004","journal-title":"Neurosci Biobehav Rev"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-019-05813-9","article-title":"Do critical care patients hibernate? 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