"Targeting the TLR4 Axis with Microbiota-Oriented Interventions and Innovations in Diabetes Therapy: A Narrative Review"

Christos G. Nikolaidis^1,2*Despoina Gyriki³Elisavet Stavropoulou^4,5*ELENI KARLAFTI¹TRIANTAFYLLOS DIDANGELOS¹CHRISTINA TSIGALOU^5,6ANASTASIA THANOPOULOU²

• ¹Diabetes Center, 1st Propaedeutic Department of Internal Medicine, Medical School, 'AHEPA' University General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
• ²2nd Department of Medicine, Hippokration Hospital, National and Kapodistrian University of Athens, Athens, Greece
• ³Hepatogastroenterology Unit, Academic Department of Internal Medicine, General Oncology Hospital of Kifissia "Agioi Anargyroi", National and Kapodistrian University of Athens, Athens, Greece
• ⁴Infectious Diseases Service, Department of Medicine, Lausanne University Hospital, University of Lausanne, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
• ⁵Master Program in "Food, Nutrition and Microbiome", Laboratory of Hygiene and Environmental Protection, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
• ⁶Laboratory of Hygiene and Environmental Protection, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece

The gut microbiota–Toll-like receptor 4(TLR4)–nuclear factor kappa B(NF-κB) signaling is a key controller of low-grade chronic inflammation and insulin resistance in type 1 (T1DM) and type 2 diabetes mellitus (T2DM). While TLR4-mediated inflammation contributes to both T1DM and T2DM, the bulk of microbiota-targeted interventions have been studied in T2DM. 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-κB signaling inhibition. FMT enhanced β-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–immune 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.