Key Takeaways & Executive Findings
- •• Germacrone ameliorates diabetic nephropathy in mice by modulating gut microbiota composition, notably reducing pathogenic Serratia_marcescens and Lactobacillus_iners. • Untargeted fecal metabolomics reveals that Germacrone reverses metabolic dysregulation, increasing beneficial metabolites like oleic acid and lithocholic acid while decreasing stearic acid. • The study provides novel evidence linking gut microbiota and metabolites to the renoprotective effects of Germacrone, offering a potential therapeutic strategy for DN. • Integrated 16S rRNA sequencing and metabolomics approach highlights the complex interplay between gut flora and host metabolism in diabetic kidney disease.
Abstract
Diabetic nephropathy (DN) is a severe complication of diabetes and the leading cause of end-stage renal disease and death. Germacrone (Ger) possesses anti-inflammatory, antioxidant and anti-DN properties. However, it is unclear whether the improvement in kidney damage caused by Ger in DN mice is related to abnormal compositions and metabolites of the gut microbiota. This study generates a mouse model of DN to explore the potent therapeutic ability and mechanism of Ger in renal function by 16S rRNA sequencing and untargeted fecal metabolomics. Although there is no significant change in microbiota diversity, the structure of the gut microbiota in the DN group is quite different. Serratia_marcescens and Lactobacillus_iners are elevated in the model group but significantly decreased after Ger intervention (P<0.05). Under the treatment of Ger, no significant differences in the diversity and richness of the gut microbiota are observed. An imbalance in the intestinal flora leads to the dysregulation of metabolites, and non-targeted metabolomics data indicate high expression of stearic acid in the DN group, and oleic acid could serve as a potential marker of the therapeutic role of Ger in the DN model. Overall, Ger improves kidney injury in diabetic mice, in part potentially by reducing the abundance of Serratia_marcescens and Lactobacillus_iners, as well as regulating the associated increase in metabolites such as oleic acid, lithocholic acid and the decrease in stearic acid. Our research expands the understanding of the relationship between the gut microbiota and metabolites in Ger-treated DN. This contributes to the usage of natural products as a therapeutic approach for the treatment of DN via microbiota regulation.
1. Introduction
Diabetic nephropathy (DN) is characterized by microalbuminuria and is mainly associated with pathological and morphological alterations in podocytes. DN occurs in approximately 40% of people with diabetes and is the leading cause of chronic kidney disease (CKD) worldwide. DN is a common complication of type 1 and type 2 diabetes [1]. Clinical diagnosis of DN relies on measurements of the estimated glomerular filtration rate (eGFR) and albuminuria as well as clinical features such as duration of diabetes and diabetic retinopathy [2,3]. Novel drugs targeting DN have been a major focus in the development of new therapies [4]. However, to date, no effective drug has been approved for the treatment of diabetic kidney disease (DKD), and specific therapies capable of preventing the development of DN are still lacking.
Natural products are unlimited reserves of bioactive molecules that will continue to serve as important therapeutic agents. Germacrone (Ger) is a bioactive natural compound found in traditional medicinal plants of the ginger family. This multifaceted chemical entity has the potential to be used due to its numerous pharmacological properties, such as anticancer, anti-inflammatory, antiviral, antioxidant, antifungal, antiandrogenic, antibacterial, and neuroprotective [5]. DN is a serious complication of type 1 diabetes and type 2 diabetes. It has been reported that Ger works synergistically with Dexmedetomidine to attenuate symptoms of high-fat-induced T2DM, potentially through an increase in AMPKα1 expression [6]. Additionally, Ger reportedly ameliorates renal damage and inhibits podocytosis in mouse models of DN by regulating ferrosis through the targeting of the mmu_mmu_circRNA_0000309/miR-188-3p/GPX4 signaling axis [7]. In addition, Ger has been reported to reduce blood glucose levels, 24-h proteinuria, and other nephrotic symptoms in mouse models of DN type 1 by preventing mitochondrial damage [8]. These results demonstrated the therapeutic potential of Ger in DN.
The gut microbiota plays an important role in human health and disease, and its metabolites have both beneficial and harmful effects on important physiological processes. The gut microbiota may play an important role in the development and pathogenesis of diabetic neuropathy [9]. Changes in gut microbiota diversity are associated with disease progression. Certain species of the gut microbiota, including Bacteroides, Subgranular bacteria, Clostridium lactis, and rumen torque groups, may be harmful factors in DN. In addition, metabolites of the gut microbiota, such as trimethylamine N-oxide, short-chain fatty acids, and lipopolysaccharides, are important mediators of microbiome-host crosstalk [10]. For example, phenyl sulfate has been shown to contribute to albuminuria and it can be used as a disease marker and future therapeutic target for DN [11]. Sodium butyrate activates nuclear factor E2-related factor 2 (NRF2) [12].
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Yunguang Wang, Xinxin He, Mengjiao Xue, Huan Yu, Qiang He, Juan Jin (2026). Integrated 16S rRNA sequencing and metabolomic analysis reveals the potential protective mechanism of Germacrone on diabetic nephropathy in mice. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024021
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Frequently Asked Questions
What is the main finding of this study on Germacrone and diabetic nephropathy?
The study demonstrates that Germacrone improves kidney injury in diabetic mice by modulating gut microbiota composition and associated metabolites, specifically reducing pathogenic bacteria like Serratia_marcescens and Lactobacillus_iners, and regulating metabolites such as increasing oleic acid and decreasing stearic acid.
How does Germacrone affect the gut microbiota in diabetic nephropathy?
Germacrone treatment does not significantly alter overall microbial diversity but changes the structure of the gut microbiota, notably decreasing the abundance of Serratia_marcescens and Lactobacillus_iners, which are elevated in diabetic nephropathy.
What metabolomic changes are associated with Germacrone treatment?
Untargeted fecal metabolomics revealed that Germacrone treatment leads to increased levels of oleic acid and lithocholic acid, while decreasing stearic acid, suggesting a rebalancing of metabolic pathways.
What is the significance of this research for diabetic nephropathy therapy?
This research provides evidence that natural products like Germacrone can be used as a therapeutic approach for diabetic nephropathy by targeting the gut microbiota and its metabolites, offering a novel strategy for treatment.
What methods were used in this study?
The study used a mouse model of diabetic nephropathy and employed 16S rRNA sequencing for gut microbiota analysis and untargeted fecal metabolomics to assess metabolic changes.
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