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Type 2 diabetes mellitus (T2DM) and major depressive disorder (MDD) are two prevalent chronic conditions that interact bidirectionally, with their high comorbidity posing a serious global health challenge. Recent studies highlight the gut-brain axis, particularly the gut microbiota-astrocyte axis, as a key mechanism underlying this comorbidity. The review reveals a common gut dysbiosis pattern in both T2DM and MDD, marked by reduced short-chain fatty acids (SCFAs)-producing bacteria and elevated lipopolysaccharide (LPS)-associated pro-inflammatory bacteria. Nevertheless, the two diseases present opposing astrocytic states: overactivation in T2DM and inhibition in MDD. In the progression from T2DM to secondary MDD, microbiota dysbiosis induces astrocyte hyperactivation in the hippocampus and hypothalamus, which in turn reduces glutamine synthetase (GS) and brain-derived neurotrophic factor (BDNF), exacerbates neuroinflammation, promotes insulin resistance (IR) and hypothalamic-pituitary-adrenal (HPA) axis overactivation, and disrupts the glutamate-glutamine (Glu-Gln) cycle, ultimately culminating in MDD. Conversely, as MDD progresses to secondary T2DM, microbiota dysbiosis suppresses astrocyte activation in the hippocampus and prefrontal cortex, which similarly aggravates neuroinflammation, promotes IR, and disrupts the Glu-Gln cycle, thereby contributing to T2DM. Together, these results advance our knowledge of the bidirectional interplay between T2DM and MDD, while simultaneously identifying potential nodes for therapeutic modulation.