{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T09:08:53Z","timestamp":1785143333721,"version":"3.55.0"},"reference-count":75,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T00:00:00Z","timestamp":1785024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Med. Sci.","Medical Sciences"],"abstract":"<jats:p>Background\/Objectives: Postbiotics are increasingly recognized as biologically active products of microorganisms with emerging potential as microbiome-inspired therapeutic interventions. While most microbiome-based strategies focus on modifying microbial composition, restoration of microbial signaling has received comparatively less attention. This review examines postbiotics through the lens of microbial signaling restoration and proposes a unified Metabolite\u2013Immune\u2013Redox (MIR) axis linking microbial-derived signals with immune regulation, redox homeostasis, endothelial integrity, and host resilience. Methods: This narrative review synthesizes current evidence on postbiotics, microbial metabolites, structural microbial components, and extracellular vesicles, with emphasis on their roles in immunometabolic regulation, redox biology, endothelial function, and host-directed interventions. Results: Current evidence suggests that short-chain fatty acids, indole derivatives, bile acid metabolites, and microbial extracellular vesicles are important mediators of host\u2013microbe communication. These signals influence interconnected pathways involving mitochondrial function, inflammasome activity, immune calibration, endothelial and glycocalyx homeostasis, and disease tolerance. The review highlights the endothelium as an underrecognized therapeutic target and discusses biomarkers, including soluble thrombomodulin, von Willebrand factor, and D-dimer, as potential tools for identifying patients most likely to benefit from host-directed interventions. Major translational challenges include product heterogeneity, incomplete mechanistic characterization, uncertain exposure\u2013response relationships, and unresolved regulatory considerations. Conclusions: The proposed MIR axis provides a hypothesis-generating framework for understanding how restoration of microbial signaling may contribute to precision host-directed therapeutic strategies. Further mechanistic and clinical studies are needed to validate this concept and define its translational potential in inflammatory, infectious, and critical illness settings.<\/jats:p>","DOI":"10.3390\/medsci14040438","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T08:15:56Z","timestamp":1785140156000},"page":"438","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Restoring Microbial Signaling: A Metabolite\u2013Immune\u2013Redox Framework for Postbiotic Host-Directed Interventions"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7958-068X","authenticated-orcid":false,"given":"Dejana","family":"Baji\u0107","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nemanja","family":"Todorovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8354-3868","authenticated-orcid":false,"given":"Mladena Lali\u0107","family":"Popovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"},{"name":"Centre for Medical and Pharmaceutical Investigations and Quality Control (CEMPhIC), Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelena","family":"Vu\u010dkovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"},{"name":"Institute for Cardiovascular Diseases of Vojvodina, Put Doktora Goldmana 4, 21204 Sremska Kamenica, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0013-364X","authenticated-orcid":false,"given":"Andrea","family":"Mihajlovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5240-5275","authenticated-orcid":false,"given":"Danijel","family":"Slavi\u0107","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8056-4989","authenticated-orcid":false,"given":"Borislav","family":"Tapavi\u010dki","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjana","family":"Stoj\u0161i\u0107","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"},{"name":"Department of Gastroenterology, Hepatology and Nutrition, Institute for Child and Youth Health Care of Vojvodina, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5286-3858","authenticated-orcid":false,"given":"Nata\u0161a","family":"Milo\u0161evi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/s41392-024-01946-6","article-title":"A systematic framework for understanding the microbiome in human health and disease: From basic principles to clinical translation","volume":"9","author":"Ma","year":"2024","journal-title":"Signal Transduct. 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