Protective mechanism of Ramulus Mori (Sangzhi) Alkaloids on T2DM combined with MASLD by hepatic lipid metabolism and gut microbiota analyses

Abstract

Background and objective Both type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) are known to be influenced by environmental and lifestyle factors. Ramulus Mori (Sangzhi) alkaloids (SZ-A) are effective hypoglycemic agents. Recent studies suggest that SZ-A may improve T2DM, MASLD, and metabolic syndrome, but the underlying mechanisms remain unclear. This study aimed to investigate whether SZ-A can modulate hepatic lipid metabolism and gut microbiota in a mouse model of T2DM combined with MASLD. Methods A combined T2DM-MASLD mouse model was established using a high-fat diet and streptozotocin injection. Liver morphology and histology were assessed using a portable small-animal ultrasound imaging system, hematoxylin and eosin (H&E) staining, and Oil Red O staining. Serum levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were measured using standard assay kits. Gut microbiota composition was analyzed by 16S rRNA sequencing, and hepatic lipid metabolites were profiled using liquid chromatographymass spectrometry (LC-MS)MS. Results SZ-A improved liver function by ameliorating morphological and structural abnormalities, reducing lipid droplet accumulation, and lowering serum levels of TG, TC, LDL, ALT, and AST. It also led to decreased hepatic ultrasound echo intensity compared to the kidney. Additionally, SZ-A helped restore gut microbiota balance, including a partial reversal of the Firmicutes/Bacteroidetes ratio. Lipidomic analysis revealed that SZ-A downregulated most TG and diglycerides (DG), while upregulating phosphatidylcholine (PC) and phosphatidylethanolamine (PE) in the model group. Conclusions SZ-A partially alleviates liver injury in T2DM-MASLD mice by modulating hepatic lipid metabolism and gut microbiota composition.

Keywords

Ramulus Mori (Sangzhi) Alkaloids / gut microbiota / lipidomics analysis

Acknowledgments

Not applicable.

Research ethics

The study was approved by the Institutional Review Board (or Ethics Committee) of the Second Affiliated Hospital of Harbin Medical University (KY2021-298). Additionally, this research followed the Animal Research: Reporting In Vivo Experiments (ARRIVE) Guidelines.

Informed consent

Not applicable.

Author contributions

Qiao H and Fu X L were responsible for research design and manuscript writing, Meng H and Wang M T performed in vivo study, Zhao J was responsible for data collection and statistical analysis.

Use of large language models, AI and machine learning tools

No large language models, AI or machine learning tool was used for any part of the present study.

Conflict of interest

The authors declare no competing financial interest.

Research funding

This research was supported by the Fund for Independent Innovation of Hypoglycemic Drugs from Basic Research to Clinical Application (070500020373).

Data availability

All relevant data are within the manuscript.

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