Rhamnogalacturonan-I enriched pectin from steamed ginseng ameliorates lipid metabolism in type 2 diabetic rats via gut microbiota and AMPK pathway
Graphical abstract
Introduction
Type 2 diabetes mellitus (T2DM) is a metabolic disease characterised by chronic hyperglycaemia and causes many complications such as heart disease, kidney failure, lower limb amputation, vision loss and increased risk of premature death (Akash et al., 2013a). With the increasing prevalence rates over the past few decades, diabetes has become a major public health problem (Akash et al., 2013b). The International Diabetes Federation Diabetes Atlas, 10th edition, showed that the global prevalence of diabetes in 2021 is about 537 million adults and is expected to rise to 783 million people by 2045, with 90ā95% of these cases being T2DM (Sun et al., 2022). Currently, the drugs used to treat T2DM are generally chemical drugs with single target, and their long-term use can lead to drug resistance and adverse reactions. Therefore, natural, multi-targeted drugs for T2DM with good efficacy and high safety should be developed. Because of the complexity of the pathogenesis of T2DM, the ideal animal model realistically reproduced human pathogenesis is required (Akash et al., 2013c). Studies have shown that SD rat model induced by high-fat diet combined with streptozotocin (STZ) is correlated well with human pathophysiology, and usually was used to evaluate the anti-diabetic effect of natural products such as polysaccharides (Engel et al., 2019).
Polysaccharides have been widely studied due to their biological activities and low toxicity. Various polysaccharides, such as Astragalus polysaccharide and Boletus polysaccharide, have been proved to have anti-T2DM effects, reducing the blood glucose and lipid levels in T2DM rats (Wei et al., 2018; Xiao et al., 2019). Recent studies found that majority of polysaccharides cannot be degraded by enzymes encoded by the body because of their complex structure; however, they can be decomposed by gut microbiota to produce functional factors such as short-chain fatty acids (SCFAs), which protect the body (Makki et al., 2018). The bacteria in the human gastrointestinal tract constitute a huge and complex ecosystem, there are about 100 times as many genes encoded by bacteria as there are human genes (Fiayyaz et al., 2021). Through long-term research on gut microbiota, Professor Gordon and his team found that gut microbiota dysbiosis is related to obesity, T2DM and other diseases (Ussar et al., 2015). Moreover, several studies have confirmed that gut microbiota affect host health in multiple ways via the gutāliver axis, gutābrain axis, gutāmuscle axis, or in situ gut (Lu et al., 2019). Gut microbiota have become a new direction for the prevention and control of various diseases such as obesity and T2DM (Ma et al., 2019).
The degradation of polysaccharides by gut microbiota is one of the main ways in which polysaccharides exert their pharmacological effects. Similarly, gut microbiota metabolise and utilise polysaccharides as carbon sources. Polysaccharides can affect gut microbiota in terms of gut structure, composition and function by improving gut integrity, regulating the gut microbiota structure and up-regulating the activities of functional enzymes (Song et al., 2021). Gut microbiota contain polysaccharide utilization loci, especially Bacteroidetes, which encode carbohydrate-active enzymes (Liang et al., 2021). These enzymes transform polysaccharides into monosaccharides or oligosaccharides through different degradation and transport systems. Then, monosaccharides and oligosaccharides enter the different metabolic pathways of bacteria to produce SCFAs and other metabolites that will be used by the body. A number of studies have shown that polysaccharides from traditional Chinese medicine have the ability to improve glucose and lipid metabolism in T2DM or other diseases by affecting gut microbiota. Polysaccharides from Holothuria leucospilota and Cyclocarya paliurus can improve the lipid metabolism disorder of T2DM by modulating gut microbiota structure and the levels of SCFAs and gut hormones (Yao et al., 2020; Zhao et al., 2020).
Panax ginseng C. A. Meyer (Ginseng) is a perennial herb belonging to the family Araliaceae and genus Panax, and is one of the most valuable and well-known traditional medicines used in Asian countries for the treatment of many diseases. Ginseng has long been used in China to treat diabetes, also named āXiaokeā disease. This was recorded in the official pharmacopoeia (Formularies of the Bureau of People's Welfare Pharmacies) as early as the Chinese Song Dynasty (1078 A.D.) (L. Chen et al., 2019). Polysaccharide is one of the major active components of ginseng, which contains starch-like polysaccharides and pectin-like polysaccharides, and ginseng pectin contains homogalacturonan (HG) and rhamnogalacturonan (RG) domains. Several studies confirmed the hypoglycaemic and hypolipidaemic effect of ginseng polysaccharides (Niu et al., 2012; Sun et al., 2014; Kwak et al., 2010). In our previous study, we also isolated RG-I enriched polysaccharide (GPS-1) with hypoglycaemic and lipid-lowering activity from steamed ginseng (Jiao et al., 2014, 2020). However, its mechanism is not clear.
Therefore, this study aimed to investigate the protective effect and mechanism of RG-I enriched GPS-1 on lipid metabolism in rats with T2DM induced by high-glucose/high-fat (HG/HF) diet combined with STZ. Our findings will provide new strategies for the prevention and treatment of T2DM, and provide new insights into the medicinal effects of steamed ginseng pectin.
Section snippets
Preparation of GPS-1
The ginseng roots were obtained from Changbai Mountain, Jinlin province, China in August 2019, which were identified by Doctor Bo Li at the College of Pharmacy, Changchun University of Chinese Medicine, and the plant name had been checked with http://www.theplantlist.org. A voucher specimen (No. 20190056) was deposited in the herbarium of Changchun University of Chinese Medicine.
Steamed ginseng and GPS-1 (molecular weight, 9.61Ā ĆĀ 105Ā Da) were prepared in accordance with our previously reported
Improvement effect of GPS-1 on body weight, food intake, water intake, blood glucose, insulin and HOMA-IR in T2DM rats
Compared with Normal group rats, T2DM rats in the Negative group showed decreased body weight, increased food intake/water intake and elevated blood glucose. Furthermore, the level of insulin was decreased in T2DM rats, while the HOMA-IR index was increased. GPS-1 treatment improved weight loss, polyphagia, polydipsia, hyperglycaemia, decreased insulin and insulin resistance of T2DM rats after administration for 4 weeks (pĀ <Ā 0.05) (Fig. 1BāG).
Improvement effect of GPS-1 on biochemical parameters and physiological changes of T2DM rats
The contents of TC, TG, FFA and LDL-C were obviously
Discussion
Diabetes is a metabolic disease that threatens human health. Lipid metabolism disorder is one of the distinguishing characteristics of diabetic patients and is also considered as the root of glucose metabolism disorders in T2DM (Kokil et al., 2015). Thus, regulating lipid metabolism disorders is an indispensable process for the treatment of T2DM.
After Professor Gordon firstly proposed that āāintestinal bacteria as an environmental factor can regulate lipid metabolismāā in 2004, several studies
Conclusion
Taken together, our results showed that GPS-1 improved the gut microbiota dysbiosis and promoted the secretion of gut metabolite SCFAs. The combination between SCFAs and GPCRs promoted the section of gut hormones GLP-1 and PYY in T2DM rats. Finally, GPS-1 inhibited the expression of downstream lipid synthesis genes SREBP-1c and FAS by activating the phosphorylation of AMPK in the liver, thereby improving lipid metabolism disorders in T2DM rats (Fig. 10).
Although RG-I enriched pectin is thought
CRediT authorship contribution statement
Ting Ren: Conceptualization, Writing ā original draft, Data curation, Investigation, Formal analysis. Furao Liu: Methodology, Investigation. Dongxue Wang: Investigation, Methodology. Bo Li: Investigation, Formal analysis. Peng Jiang: Software, Supervision. Junming Li: Formal analysis, Visualization. Hui Li: Investigation, Validation. Changbao Chen: Resources, Funding acquisition. Wei Wu: Resources, Funding acquisition. Lili Jiao: Conceptualization, Writing ā review & editing, Project
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was supported by the National Natural Science Foundation of China [grant number 31700703]; the Science and Technology Major Project āKey New Drug Creation and Manufacturing Programā of China [grant number 2019ZX09735-001]; the Science and Technology Program of Jilin [grant numbers 20190201297JC, 20200404042YY and 20200504003YY]; the National Key Research and Development Project [grant number 2019YFC1710704]; and the Administration of Traditional Chinese Medicine of Jilin Province
References (51)
- et al.
Rodent models of diet-induced type 2 diabetes mellitus: a literature review and selection guide
Diabetes Metabol. Syndr.
(2019) - et al.
Study on structure characterization of pectin from the steamed ginseng and the inhibition activity of lipid accumulation in oleic acid-induced HepG2 cells
Int. J. Biol. Macromol.
(2020) - et al.
Chemical and antihyperglycemic activity changes of ginseng pectin induced by heat processing
Carbohydr. Polym.
(2014) - et al.
From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites
Cell
(2016) - et al.
Edible fungal polysaccharides, the gut microbiota, and host health
Carbohydr. Polym.
(2021) - et al.
Urinary metabolomics analysis reveals the anti-diabetic effect of stachyose in high-fat diet/streptozotocin-induced type 2 diabetic rats
Carbohydr. Polym.
(2020) - et al.
Enhancing clinical efficacy through the gut microbiota: a new field of traditional Chinese medicine
Engineering
(2019) Pectin structure and biosynthesis
Curr. Opin. Plant Biol.
(2008)- et al.
Research progress in the relationship between type 2 diabetes mellitus and intestinal flora
Biomed. Pharmacother.
(2019) - et al.
The impact of dietary fiber on gut microbiota in host health and disease
Cell Host Microbe
(2018)
Effect of ginseng polysaccharide on the urinary excretion of type 2 diabetic rats studied by liquid chromatography-mass spectrometry
J. Chromatogr., B: Anal. Technol. Biomed. Life Sci.
Review of the relationships among polysaccharides, gut microbiota, and human health
Food Res. Int.
IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045
Diabetes Res. Clin. Pract.
Interactions between gut microbiota, host genetics and diet modulate the predisposition to obesity and metabolic syndrome
Cell Metabol.
Composite probiotics alleviate type 2 diabetes by regulating intestinal microbiota and inducing GLP-1 secretion in db/db mice
Biomed. Pharmacother.
The effect of boletus polysaccharides on diabetic hepatopathy in rats
Chem. Biol. Interact.
Cyclocarya paliurus polysaccharides alleviate type 2 diabetic symptoms by modulating gut microbiota and short-chain fatty acids
Phytomedicine
Pectin reduces environmental pollutant-induced obesity in mice through regulating gut microbiota: a case study of p,p'-DDE
Environ. Int.
Therapeutic mechanisms of traditional Chinese medicine to improve metabolic diseases via the gut microbiota
Biomed. Pharmacother.
A sea cucumber (Holothuria leucospilota) polysaccharide improves the gut microbiome to alleviate the symptoms of type 2 diabetes mellitus in Goto-Kakizaki rats
Food Chem. Toxicol.
Berberine attenuates nonalcoholic hepatic steatosis through the AMPK-SREBP-1c-SCD1 pathway
Free Radic. Biol. Med.
Microbial fermentation of flaxseed fibers modulates the transcriptome of GPR41-expressing enteroendocrine cells and protects mice against diet-induced obesity
Am. J. Physiol. Endocrinol. Metab.
Sustained delivery of IL-1Ra from PF127-gel reduces hyperglycemia in diabetic GK-rats
PLoS One
Goto-Kakizaki rats: its suitability as non-obese diabetic animal model for spontaneous type 2 diabetes mellitus
Curr. Diabetes Rev.
An overview of valuable scientific models for diabetes mellitus
Curr. Diabetes Rev.
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