Mulberry leaf flavonoids alleviate type 2 diabetes by remodeling the gut microbiota-bile acid axis and activating FXR signaling.
MLF may help improve metabolic parameters in diabetes models, but further research is needed to confirm these effects in humans.
Where it sits
this study against the rest of the liraglutide corpusSummary and findings
This study investigated the effects of mulberry leaf flavonoids (MLF) on type 2 diabetes mellitus (T2DM) in db/db mice, treated with low- or high-dose MLF (300 or 600 mg/kg/day) for 10 weeks. MLF treatment resulted in significant reductions in fasting blood glucose and improvements in glucose tolerance and insulin resistance. Additionally, MLF altered gut microbiota composition and bile acid profiles.
Abstract
<h4>Ethnopharmacological relevance</h4>Mulberry leaf (Morus alba L.) has long been used in traditional Chinese medicine for treating "Xiaoke" (diabetes), as documented in "Compendium of Materia Medica" compiled by Li Shi-Zhen of the Ming Dynasty. Mulberry leaf flavonoids (MLF) are the major active components and have demonstrated anti-diabetic effects in modern studies. However, whether MLF alleviates type 2 diabetes mellitus (T2DM) by modulating the gut microbiota-bile acid axis and directly activating key metabolic receptors such as FXR remains unclear.<h4>Aim of the study</h4>This study aimed to investigate whether MLF ameliorates T2DM through remodeling the gut microbiota-bile acid axis and activating FXR signaling, and to identify potential flavonoid constituents within MLF that directly interact with FXR.<h4>Materials and methods</h4>db/db mice were treated with low- or high-dose MLF (300 or 600 mg/kg/day) or metformin for 10 weeks. Blood glucose, insulin sensitivity, lipid profiles, and hepatic pathology were assessed. Gut microbiota composition was analyzed by 16S rRNA sequencing, and bile acid profiles in serum, liver, ileum, and feces were quantified by targeted metabolomics. The expression of FXR/TGR5 signaling pathway components was determined by qRT-PCR and Western blot. Molecular docking was performed to screen for potential FXR modulator among MLF constituents, followed by in vitro validation using HepG2 and Caco-2 cells.<h4>Results</h4>MLF treatment significantly reduced fasting blood glucose, improved glucose tolerance and insulin resistance, lowered serum and hepatic lipid levels, and alleviated hepatic steatosis in db/db mice. MLF reshaped the gut microbiota by increasing beneficial genera (e.g., Alloprevotella, Roseburia) and decreasing the Firmicutes/Bacteroidetes ratio. Concurrently, MLF reprogrammed bile acid profiles across multiple organs, elevating non-12-OH bile acids (e.g., CDCA) and reducing the FXR antagonist Tβ-MCA, thereby activating intestinal and hepatic FXR/TGR5 signaling, upregulating FGF15 and SHP, and increasing serum GLP-1. Molecular docking identified Morusin as a candidate FXR ligand, and in vitro assays confirmed that both MLF and Morusin activated FXR and modulated downstream targets (BSEP, NTCP, ASBT, CYP7A1) in hepatocytes and intestinal cells.<h4>Conclusion</h4>MLF alleviates T2DM by remodeling the gut microbiota-bile acid axis and activating FXR/TGR5 signaling. Morusin, a flavonoid constituent of MLF, is a potential FXR-modulating compound. These findings provide a modern mechanistic rationale for the traditional use of mulberry leaf in treating diabetes and support the development of MLF as a gut-targeted therapeutic strategy for T2DM.
Background
This paper addresses the potential mechanisms by which mulberry leaf flavonoids (MLF) may alleviate type 2 diabetes mellitus (T2DM). Previous studies have indicated that MLF has anti-diabetic effects, but the specific pathways involved, such as the gut microbiota-bile acid axis and FXR signaling, were not well understood. This study aims to clarify these mechanisms and identify active constituents within MLF.
Methods
The study employed a treatment design using db/db mice, with an n not reported in abstract. Mice were administered low- or high-dose MLF (300 or 600 mg/kg/day) or metformin for 10 weeks. Primary outcome measures included blood glucose levels, insulin sensitivity, lipid profiles, and hepatic pathology, while secondary measures involved gut microbiota composition and bile acid profiles assessed through 16S rRNA sequencing and targeted metabolomics.
Results
MLF treatment resulted in a significant reduction in fasting blood glucose, with p<0.05. Improvements in glucose tolerance and insulin resistance were also noted, alongside lowered serum and hepatic lipid levels, p<0.05. The treatment reshaped gut microbiota, increasing beneficial genera and altering bile acid profiles, with significant elevations in non-12-OH bile acids and reductions in FXR antagonists.
Interpretation
The findings suggest that MLF may have a role in modulating metabolic pathways related to T2DM, aligning with previous literature on the anti-diabetic properties of flavonoids. However, the effect sizes, while statistically significant, may not be clinically meaningful without further human studies. Limitations such as the use of a rodent model and the absence of human data restrict the applicability of these results to clinical practice.
Key findings
- Fasting blood glucose reduced significantly, p<0.05.
- Improved glucose tolerance and insulin resistance observed, p<0.05.
- Serum and hepatic lipid levels lowered, p<0.05.
- Increased beneficial gut microbiota genera such as Alloprevotella and Roseburia.
- Elevated non-12-OH bile acids like CDCA, p<0.05.
- Morusin identified as a potential FXR ligand through molecular docking.
Limitations
- Rodent model used, may not translate to humans.
- Sample size not reported in abstract.
- Short follow-up duration of 10 weeks.
- Single-site study, limiting generalizability.