Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by hyperglycemia and increased insulin resistance, and is closely associated with gut microbial dysbiosis [1]. Oral antidiabetic drugs (OADs), such as metformin, sulfonylureas, alpha-glucosidase inhibitors (AGIs), and dipeptidyl-peptidase-4 (DPP-4) inhibitors are commonly prescribed for glycemic control in T2D patients, yet the effectiveness of such treatment displays considerable variations across individuals.

A number of studies have demonstrated that various OADs significantly alter the gut microbiota, which in turn have profound effects on host metabolism underlying in part the clinical benefits in individuals with T2D [2-6]. The administration of metformin significantly increased the relative abundance of Akkermansia muciniphila [5]. Acarbose, an AGI, was found to dramatically alter the gut microbial composition by elevating Bifidobacterium and depleting Bacteroides spp. [4, 7]. Our recent study demonstrated that a 12-week berberine treatment significantly reduced the abundance of Ruminococcus bromii, a secondary bile acid (SBA)-producer, and plasma levels of deoxycholic acid (DCA), associated with improved glucose homeostasis [6]. Additionally, two studies, including ours, have revealed associations between the baseline gut microbiota and therapeutic outcomes of DPP-4 inhibitors [7, 8].

However, considerable disparities persist in the reported gut microbial alterations in response to different OADs, possibly due to the variations in ethnicity, sample size, and metagenomic methodology across studies. A comprehensive evaluation using consistent pipelines is clearly warranted to understand bidirectional interactions between OADs and the gut microbiota, as well as their potential impacts on drug efficacy.