{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,9]],"date-time":"2026-11-09T22:09:16Z","timestamp":1794262156331,"version":"4.9.0"},"reference-count":137,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>The gut\u2013immune\u2013metabolic axis has emerged as a central regulator of human health, with growing evidence indicating that microbiota-derived metabolites improve gut microbial ecology, enhance intestinal barrier integrity, reduce systemic inflammation, and maintain metabolic homeostasis. This review synthesizes current mechanistic and clinical evidence on the role of postbiotics in regulating intestinal barrier integrity, immune responses, oxidative stress, and metabolic\u2013endocrine homeostasis. The literature was identified through the PubMed\/MEDLINE, Scopus, and Web of Science, integrating evidence from experimental, mechanistic, animal and clinical studies on the therapeutic potential of postbiotics to modulate the gut\u2013immune\u2013metabolic axis. Preclinical studies suggest that postbiotics may enhance epithelial barrier function by improving tight junction integrity through multiple pathways such as PI3K\/Akt signaling, stimulating mucin-2 (MUC2) production, and reducing intestinal permeability. They modulate immune responses through interactions with Toll-like receptors, nucleotide-binding oligomerization domain receptors, and G-protein-coupled receptors (GPR41\/43), influencing key signaling pathways, including NF-\u03baB and Nrf2, and altering cytokine profiles, such as IL-10, TNF-\u03b1, and IFN-\u03b3. Similarly, preclinical investigations have demonstrated that short-chain fatty acids (SCFAs) and other microbial metabolites may improve insulin sensitivity, regulate hepatic gluconeogenesis, stimulate glucagon-like peptide 1 (GLP-1) secretion, and modulate lipid metabolism through the FXR and TGR5 signaling pathways. Emerging human studies suggest potential benefits of postbiotics in regulating gut, immune, and metabolic health; nevertheless, clinical evidence remains limited and is influenced by variability in postbiotic composition, dosage, formulation, and metabolite profiles. Therefore, standardized production approaches and well-designed large-scale randomized clinical trials are required to confirm therapeutic efficacy and establish evidence-based applications of postbiotics.<\/jats:p>","DOI":"10.3390\/ph19081184","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T11:45:26Z","timestamp":1785239126000},"page":"1184","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Postbiotics as Next Generation Biotherapeutics Targeting the Gut\u2013Immune\u2013Metabolic Axis: An Integrative Review"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7154-3411","authenticated-orcid":false,"given":"Asad","family":"Abbas","sequence":"first","affiliation":[{"name":"Department of Human Nutrition, Faculty of Food Science and Nutrition, Bahauddin Zakariya University, Multan 60800, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3888-0931","authenticated-orcid":false,"given":"Ralf","family":"Weiskirchen","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Bilal","sequence":"additional","affiliation":[{"name":"Faculty of Food Science and Nutrition, Bahauddin Zakariya University, Multan 60800, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Khurram","family":"Afzal","sequence":"additional","affiliation":[{"name":"Department of Human Nutrition, Faculty of Food Science and Nutrition, Bahauddin Zakariya University, Multan 60800, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdul","family":"Malik","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhail","family":"Akhtar","sequence":"additional","affiliation":[{"name":"Department of Biomedical Education and Data Science Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masooma","family":"Khan","sequence":"additional","affiliation":[{"name":"Multan College of Nutritional Sciences, Multan Medical and Dental College, Multan 60000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izma","family":"Rashid","sequence":"additional","affiliation":[{"name":"Multan College of Nutritional Sciences, Multan Medical and Dental College, Multan 60000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"Khalid","sequence":"additional","affiliation":[{"name":"Multan College of Nutritional Sciences, Multan Medical and Dental College, Multan 60000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2378-5916","authenticated-orcid":false,"given":"Shazia","family":"Akram","sequence":"additional","affiliation":[{"name":"Department of Human Nutrition, Faculty of Food Science and Nutrition, Bahauddin Zakariya University, Multan 60800, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anza","family":"Saleem","sequence":"additional","affiliation":[{"name":"Multan College of Nutritional Sciences, Multan Medical and Dental College, Multan 60000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley Irobekhian Reuben","family":"Okoduwa","sequence":"additional","affiliation":[{"name":"Department of Research Innovation Management, Directorate of Research and Development, Nigerian Institute of Leather and Science Technology (NILEST), Zaria 810106, Nigeria"},{"name":"World Nutrition Editorial Office, World Public Health Nutrition Association, London SO16 6YD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8375","DOI":"10.1080\/10408398.2022.2056727","article-title":"Postbiotics as the New Frontier in Food and Pharmaceutical Research","volume":"63","author":"Sabahi","year":"2023","journal-title":"Crit. 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