Rhamnogalacturonan-I enriched pectin from steamed ginseng ameliorates lipid metabolism in type 2 diabetic rats via gut microbiota and AMPK pathway

https://doi.org/10.1016/j.jep.2022.115862Get rights and content

Highlights

  • ā€¢

    A RG-I enriched pectin (GPS-1) was isolated from steamed ginseng.

  • ā€¢

    GPS-1 regulated gut microbiota structure and increased the level of metabolite SCFAs.

  • ā€¢

    SCFAs promoted GLP-1 secretion and then activated liver AMPK by ā€˜ā€˜gut-liverā€™ā€™ axis.

  • ā€¢

    GPS-1 improved lipid metabolism in T2DM rats via gut microbiota and AMPK pathway.

Abstract

Ethnopharmacological relevance

Panax ginseng C. A. Meyer (Ginseng) has traditionally been used to treat diabetes. Polysaccharide is the main active component of ginseng, and has been proved to have hypoglycaemic and hypolipidaemic effects, but its mechanism remains unclear.

Aim of the study

This study aimed to evaluate the effect and the potential mechanism of rhamnogalacturonan-I enriched pectin (GPS-1) from steamed ginseng on lipid metabolism in type 2 diabetes mellitus (T2DM) rats.

Materials and methods

GPS-1 was prepared by water extraction, ion-exchange and gel chromatography. High-glucose/high-fat diet combined with streptozotocin was used to establish T2DM rat models, and lipid levels in serum and liver were tested. 16S rRNA sequencing and gas chromatography-mass spectrometry were used to detect the changes of gut microbiota and metabolites. The protein and mRNA levels of lipid synthesis-related genes were detected by Western blot and quantitative real-time polymerase chain reaction.

Results

The polyphagia, polydipsia, weight loss, hyperglycaemia, hyperlipidaemia and hepatic lipid accumulation in T2DM rats were alleviated after GPS-1 intervention. GPS-1 modulated the gut microbiota composition of T2DM rats, increased the levels of short-chain fatty acids, and promoted the secretion of glucagon-like peptide-1 and peptide tyrosine tyrosine. Further, GPS-1 activated AMP-activated protein kinases, phosphorylated acetyl-CoA carboxylase, reduced the expression of sterol regulatory element-binding protein-1c and fatty acid synthases in T2DM rats.

Conclusions

The regulation effects of GPS-1 on lipid metabolism in T2DM rats are related to the regulation of gut microbiota and activation of AMP-activated protein kinase pathway.

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 90ā€“95% 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 gutā€“liver axis, gutā€“brain axis, gutā€“muscle 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 ā€œXiaokeā€ 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 Ć—Ā 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. 1Bā€“G).

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 ā€˜ā€˜intestinal bacteria as an environmental factor can regulate lipid metabolismā€™ā€™ 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 ā€œKey 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

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