Empagliflozin Modify gut microbiota in db/db Mice Correlating with the Improvement of Glucose and Lipid Metabolism
Authors: Dai Jin , Hao Junli , Chen Yuhang , Guo Yuru , Chen Liangwei , Chao Sujuan , Zhou Lihua , Ye Deping , Zhu Haiyang , Dai Xiaozhen , Wang Dan 
Published: June 2023

Background
Empagliflozin (EMPA) is a widely used medication in the treatment of Type 2 diabetes Mellitus (T2DM). It functions by inhibiting glucose reabsorption by the kidneys, which helps lower blood glucose levels. Studies have shown that there is a bidirectional relationship between oral medications and the gut microbiota. The gut microbiota is one of the most complex and diverse microbial communities in the body, with dysbiosis being closely associated with various metabolic diseases, such as diabetes, obesity, and cardiovascular diseases. Therefore, the aim of this study was to investigate the effects of EMPA on the gut microbiota of T2DM mice, in order to further elucidate its potential roles in blood glucose control and cardiovascular protection.
Methods and Results
We intervened with db/db mice for 20 weeks, measuring blood glucose during the intervention and blood lipids after the intervention. We collected fecal samples from the mice before and after the intervention, ensuring that the samples were uncontaminated by collecting them from the anus. Through bioinformatics analysis using 16S rRNA sequencing, we identified changes in key genus of gut microbiota in these mice. In addition to the conventional abilities of reducing blood glucose and blood lipids, we found that the impact of EMPA on gut microbiota could not be ignored. EMPA significantly changed the diversity and richness index of gut microbiota in db/db mice, such as the sobs and simpsons index. EMPA changed the β-diversity of gut microbiota, altering the complexity between different bacterial genus to be similar to that of healthy mice. EMPA also increased the abundance of species such as Clostridium_innocuum_group, Rikenellaceae, Alistipes, Prevotellaceae_UCG-001, Eubacterium_siraeum_group, Anaeroplasma, and Odoribacter, while decreasing the abundance of species such as Eubacterium_ventriosum_group, Fusobacterium, Hydrogenoanaerobacterium, Tyzzerella, Prevotellaceae_NK3B31_group, Aerococcaceae, and Aerococcus. Spearman correlation networks analysis showed that Alistipes, Odoribacter, and Anaeroplasma were significantly negatively correlated with blood glucose levels, while Aerococcus was significantly positively correlated with Total cholesterol (TC) and Total triglycerides (TG). EMPA also reduced the functional abundance of gut microbiota related to "Membrane transport," "Xenobiotics biodegradation and metabolism," and "Immune disease." EMPA may achieve its partial blood glucose-lowering and cardiovascular disease-improving effects by impacting these key species and functional abundance of gut microbiota.
Conclusion
In conclusion, our 20-week intervention on db/db mice showed that EMPA not only had a significant impact on blood glucose and lipids but also on the diversity and richness of gut microbiota. EMPA altered the abundance and ratio of Firmicutes and Bacteroidota, increased beneficial species, and decreased harmful ones. Spearman network analysis revealed the correlation between specific gut microbes and blood glucose and lipid levels. EMPA also decreased the functional abundance of "Membrane transport," "Xenobiotics biodegradation and metabolism," and "Immune disease" pathways. Our findings suggest that EMPA's therapeutic effects may partly arise from its modulation of gut microbiota.