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Background & Aims: Type 2 diabetes mellitus (T2DM) poses a significant global health challenge due to various lifestyle factors contributing to its prevalence and associated complications. Chronic low-grade inflammation, characterized by elevated levels of inflammatory markers such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), plays a pivotal role in the pathogenesis of T2DM. Modulation of the gut microbiota through microbiome-targeted therapy (MTT), including probiotics, prebiotics, and synbiotics, has emerged as a potential strategy to mitigate inflammation and improve metabolic outcomes in T2DM., Methods: A systematic review and meta-analysis were conducted following PRISMA guidelines to evaluate the impact of MTT on inflammatory markers in patients with T2DM. Searches were performed in PubMed, Scopus, and Web of Science databases up to June 2024, with inclusion criteria limited to English-language meta-analyses of randomized controlled trials (RCTs) assessing the effects of probiotics, prebiotics, or synbiotics on inflammatory markers in T2DM patients., Results: Ten meta-analyses met the inclusion criteria, comprising studies investigating the effects of various MTT interventions on CRP, IL-6, and TNF-α levels in T2DM patients. Meta-analysis results indicated significant reductions in CRP (SMD: -0.070; 95 % CI: -0.119 to -0.020) and TNF-α (SMD: -0.370; 95 % CI: -0.554 to -0.186) levels following MTT, while IL-6 reductions (SMD: -0.070; 95 % CI: -0.269 to 0.129) did not reach statistical significance. However, heterogeneity in study quality, intervention protocols, and participant demographics posed challenges in interpretation., Conclusions: While improvements in inflammatory markers with MTT have been observed, significant limitations-such as heterogeneity in study quality and variation in intervention protocols-highlight the need for further research to confirm its efficacy and clarify underlying mechanisms. Future studies should aim to address these limitations by exploring variations in dosage, supplement formulations, and bacterial strains, which are crucial for improving the reliability and broader applicability of MTT in the management of T2DM., Competing Interests: Declaration of competing interest None., (Copyright © 2024 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)