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The focus of the current review is on T2DM, with relevant parallels in T1DM noted where appropriate. Modulation of this pathway by dietary natural bioactive molecules, fecal microbiota transplantation (FMT), and technological innovations hold therapeutic promise for the reconstitution of metabolic and immune homeostasis. Agents like celastrol, berberine, paeoniflorin, and licorice extract exhibit anti-inflammatory and antidiabetic effects by TLR4\/Myeloid differentiation primary response 88(MyD88)\/NF-\u03baB signaling inhibition. FMT enhanced \u03b2-cell function and insulin sensitivity with evidence of immune-metabolic modulation. New technologies, like ingestible biosensors and gut-on-chip platforms, allow real-time monitoring and precision modulating of the microbiota. Gastric bypass-induced microbial remodeling is linked to long-term glycemic benefit. Pharmacological, surgical, and technological manipulation of gut microbiota\u2013immune interactions is a potential complementary strategy to diabetes. The future encompasses personalized microbiota-matching, controlled FMT regimens, and incorporation of digital therapeutics into microbiome-based precision medicine.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1701504","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T05:19:35Z","timestamp":1765430375000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Targeting the TLR4 axis with microbiota-oriented interventions and innovations in diabetes therapy: a narrative review"],"prefix":"10.3389","volume":"16","author":[{"given":"Christos G.","family":"Nikolaidis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Despoina","family":"Gyriki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisavet","family":"Stavropoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Karlafti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Triantafyllos","family":"Didangelos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Tsigalou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Thanopoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2021.154737","article-title":"Diabetes mellitus: 100 years since the discovery of insulin","volume":"118","author":"Polyzos","year":"2021","journal-title":"Metabolism"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2337\/dc14-S081","article-title":"Diagnosis and classification of diabetes mellitus","volume":"37","year":"2013","journal-title":"Diabetes Care"},{"key":"B3","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1007\/s40200-025-01674-w","article-title":"Type 5 diabetes as a growing malnutrition driven health crisis in low and middle income countries","volume":"24","author":"Prajitno","year":"2025","journal-title":"J Diabetes Metab Disord"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.115734","article-title":"Diabetes mellitus: Classification, mediators, and complications; A gate to identify potential targets for the development of new effective treatments","volume":"168","author":"Antar","year":"2023","journal-title":"Biomed Pharmacother"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/5110276","article-title":"Gut microbiota and type 2 diabetes mellitus: association, mechanism, and translational applications","volume":"2021","author":"Zhang","year":"2021","journal-title":"Mediators Inflammation"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-019-0254-y","article-title":"The heterogeneous pathogenesis of type 1 diabetes mellitus","volume":"15","author":"Ilonen","year":"2019","journal-title":"Nat Rev Endocrinol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"98","DOI":"10.34172\/hpp.2020.18","article-title":"Prevalence and incidence of type 1 diabetes in the world: a systematic review and meta-analysis","volume":"10","author":"Mobasseri","year":"2020","journal-title":"Health Promot Perspect"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202100275","article-title":"Emerging targets in type 2 diabetes and diabetic complications","volume":"8","author":"Demir","year":"2021","journal-title":"Advanced Sci"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nrdp.2017.16","article-title":"Type 1 diabetes mellitus","volume":"3","author":"Katsarou","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecl.2021.05.013","article-title":"An update on the epidemiology of type 2 diabetes","volume":"50","author":"Tinajero","year":"2021","journal-title":"Endocrinol Metab Clinics North America"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.2337\/dci22-0034","article-title":"Management of hyperglycemia in type 2 diabetes, 2022. 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