Objective:

To elucidate the mechanistic pathways by which gut microbiota disruption leads to insulin resistance and low-grade inflammation in type 2 diabetes mellitus (T2DM), highlighting the significance for potential treatment strategies.

Key Findings:

• Butyrate-producing bacteria are reduced in gut dysbiosis in T2DM, while opportunistic Gram-negative pathobionts proliferate, leading to increased inflammation.
• Increased intestinal permeability facilitates lipopolysaccharide (LPS) translocation, activating inflammatory pathways that disrupt insulin signaling, contributing to insulin resistance.
• Decreased short-chain fatty acid (SCFA) synthesis impairs insulin signaling and enteroendocrine hormone release, affecting glucose metabolism.
• Dysregulated bile acid metabolism contributes to insulin resistance and chronic inflammation, highlighting the need for targeted interventions.
• Branched-chain amino acid metabolism and mTOR pathway overactivation lead to metabolic rigidity and inflammation, indicating potential therapeutic targets.

Interpretation:

The interrelated microbiota-host signaling pathways are significant contributors to the pathophysiology of T2DM and represent potential treatment targets that warrant further investigation.

Limitations:

• The review focuses primarily on mechanistic pathways without detailed descriptions of microbial taxa, which may limit understanding of specific microbial roles.
• The literature search was limited to articles published between 2015 and 2026, potentially excluding relevant earlier studies.

Conclusion:

Understanding the connections between gut microbiota and T2DM can inform microbiome-targeted treatment interventions, emphasizing the urgency for further research in this area.