{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:04:02Z","timestamp":1792065842547,"version":"4.4.0"},"reference-count":254,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Medicine and Pharmacy Carol Davila"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Modern biomedicine frequently contextualizes disease around isolated molecular or organ-specific mechanisms, but numerous chronic diseases, including Alzheimer\u2019s disease, multiple sclerosis, depression, diabetes, and sepsis, share common trajectories of systemic destabilization. An increasing body of evidence indicates that health is not a property of single organs but the emergent property of interdependent feedback networks linking the microbiome, endocannabinoidome, neuroimmune system, and metabolic regulators. We propose the Endocannabinoid\u2013Microbiota\u2013Neuroimmune Super-System (EMN-S) as an evolutionarily conserved conceptual model that describes how these fields of influence reciprocally interact through feedback control. The microbial communities constituting the EMN-S encode environmental and dietary inputs, endocannabinoid signaling serves as an integrative regulator that synchronizes neural and immune activity, and neuroimmune circuits effectuate adaptive behaviors that alter microbiotal and lipid ecosystems. This review formalizes the EMN-S, contending that it is a unitary and cohesive model of physiological resilience, as well as offering a framework for precision feedback therapeutics. We describe how three mechanisms\u2014encoder drift, integrator detuning, and executor overutilization\u2014convert stabilizing negative feedback into runaway feedback cascades that underlie chronic, recurrent, and multisystemic disease. We then specify the EMN-S signature\u2014integrated microbiome, lipidomic, and immune readouts\u2014as an early indicator of resilience collapse and prospective preclinical state. Finally, we recapitulate the potential of AI-driven digital twins to illuminate feedback collapse, predict tipping points, and direct closed-loop intervention and treatments to restore dynamic equilibrium. By anchoring complexity in concrete and measurable feedback principles, the EMN-S shifts focus to investigate pathophysiology as opposed to reductionist lesion models of systemic derangements and embraces a systemic, empirically testable theory of stability.<\/jats:p>","DOI":"10.3390\/ijms262210959","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T09:10:45Z","timestamp":1763025045000},"page":"10959","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Endocannabinoid\u2013Microbiota\u2013Neuroimmune Super-System: A Unifying Feedback Architecture for Systems Resilience, Collapse Trajectories, and Precision Feedback Medicine"],"prefix":"10.3390","volume":"26","author":[{"given":"C\u0103t\u0103lin","family":"Aliu\u0219","sequence":"first","affiliation":[{"name":"Faculty of General Medicine, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandru","family":"Breazu","sequence":"additional","affiliation":[{"name":"Faculty of General Medicine, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9043-3690","authenticated-orcid":false,"given":"Cosmin","family":"Pantu","sequence":"additional","affiliation":[{"name":"Department of Anatomy, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Puls Med Association, 051885 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corneliu","family":"Toader","sequence":"additional","affiliation":[{"name":"Puls Med Association, 051885 Bucharest, Romania"},{"name":"Department of Neurosurgery, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Department of Vascular Neurosurgery, National Institute of Neurology and Neurovascular Diseases, 077160 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matei","family":"\u0218erban","sequence":"additional","affiliation":[{"name":"Puls Med Association, 051885 Bucharest, Romania"},{"name":"Department of Neurosurgery, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Department of Vascular Neurosurgery, National Institute of Neurology and Neurovascular Diseases, 077160 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u0103zvan-Adrian","family":"Covache-Busuioc","sequence":"additional","affiliation":[{"name":"Puls Med Association, 051885 Bucharest, Romania"},{"name":"Department of Neurosurgery, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Department of Vascular Neurosurgery, National Institute of Neurology and Neurovascular Diseases, 077160 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Octavian","family":"Munteanu","sequence":"additional","affiliation":[{"name":"Department of Anatomy, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Puls Med Association, 051885 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian Vasile","family":"Dumitru","sequence":"additional","affiliation":[{"name":"Puls Med Association, 051885 Bucharest, Romania"},{"name":"Department of Pathology, Faculty of Medicine, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 030167 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ricci, G., Magosso, E., and Ursino, M. 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