Gut modulation based anti-diabetic effects of carboxymethylated wheat bran dietary fiber in high-fat diet/streptozotocin-induced diabetic mice and their potential mechanisms

https://doi.org/10.1016/j.fct.2021.112235Get rights and content

Highlights

  • Effects of carboxymethylated wheat bran dietary fibers (DFs) on type 2 diabetic mice were explored.

  • DFs intake elevated the insulin, GLP-1, PYY, and SCFAs, and improved the liver and pancreas histopathology.

  • DFs up-regulated the expression levels of G6Pase and Prkce, and down regulated the expression levels of Glut2 and InsR.

  • DFs improved the relative abundance of Akkermansia muciniphila, and reduced the ratio of Firmicutes to Bacteroidetes.

Abstract

We explored the effect of carboxymethylated wheat bran dietary fibers (DFs) on mice with type 2 diabetes (T2D) (induced by HFD combined with STZ) and their possible hypoglycemic mechanism. After feeding the diabetic mice with modified DFs for four weeks, the DFs had lipid lowering and anti-hyperglycemic effect, via increasing the levels of insulin, GLP-1, PYY, and SCFAs in diabetic mice, and improving the histopathology of liver and pancreas. qRT-PCR results showed that the intake of DFs up-regulated the expression levels of G6Pase and Prkce, and down regulated the expression levels of Glut2 and InsR in the liver of diabetic mice. It is suggested that DFs may play a role by inhibiting 1,2-DAG-PKCε pathway, improving insulin receptor activity and insulin signal transduction. 16 S rDNA high-throughput sequencing results showed that the DFs significantly improved the relative abundance of Akkermansia muciniphila, increased the diversity of gut microbiota and reduced the ratio of Firmicutes to Bacteroidetes, thus promoting the hypoglycemic and hypolipidemic effect on diabetic mice. Our study can foster the further understanding of the gut modulatory biomarkers and related metabolites, and may extend the basis for DFs as a potential dietary intervention to prevent or treat the T2D.

Introduction

Diabetes mellitus (DM) remains as the most challenging metabolic abnormality, accounting for 11.3% of deaths globally and economic burden in the 21st century (Saeedi et al., 2020). With the ever-increasing prevalence of diabetes, it can be estimated that the number of diabetic patients globally will rise to 700 million in 2045 (Saeedi et al., 2019). Particularly in China, with the changing lifestyle and dietary factors (high fat and calories), the incidence of type 2 diabetes (T2D) has increased associated with rising obesity level. Insulin resistance and pancreatic islet β-cell dysfunction are considered to be the main cause of the development of T2D (Wang et al., 2020). In the recent years, studies have emerged emphasizing the relation of etiology or development of DM with the intestinal microbiota dysbiosis which ultimately led to changes in gut barrier function, thereby inducing the various metabolic disorders such as insulin resistance, impaired glucose tolerance, obesity, and diabetes (Ghorbani et al., 2021).

Until today, various classic hypoglycemic agents (metformin and acarbose) have been reported to play a regulatory role in gut modulation closely linked to the diabetes and the occurrence and development of insulin resistance (Pedersen et al., 2016; Xu et al., 2020), obesity (Vieira-Silva et al., 2020), and T2D (Pedersen et al., 2016). Though many oral hypoglycemic drugs have been commercialized after the clinical verification for DM therapy; however, the high cost accompanied by the complications are the major concerns for the diabetic patients to realize the full potential of existing T2D treatment methods. All these challenges and limitation lead to a huge demand for effective, economical, and natural drugs to develop novel treatments for T2D. Compared with drug therapy, the minimal side effects and long-term safety of dietary intervention from natural food plant have been widely researched (Samson et al., 2020; Tannock, 2021) to regulate the composition and abundance of gut microbiota (Cao et al., 2019; Yu et al., 2020). Among the natural compounds, dietary fibers (DFs) are reported with promising hypoglycemic properties lowering the post-prandial serum glucose levels and retarding the diffusion of glucose, adsorbing glucose, inhibiting the activities of carbohydrate digestive enzymes, and promoting the production of short chain fatty acids (SCFAs) by gut microbiota fermentation (Li et al., 2020; Schwab et al., 2021; Weickert and Pfeiffer, 2018; Zheng et al., 2019). SCFAs can provide energy matrix for colon cells, promote the growth of beneficial bacteria, inhibit the growth of pathogenic bacteria, reduce inflammation, and protect intestinal function (Forslund et al., 2015; Koh et al., 2016; Makki et al., 2018; Zhao et al., 2018). In clinical trials, increasing the intake of non-digestible but fermentable carbohydrates such as DFs reduced the disease phenotype of T2D (Silva et al., 2015; Zhao et al., 2018).

Wheat (Triticum aestivum L.) bran, as the main by-product of wheat flour processing is rich in insoluble DFs (Messia et al., 2016; Sun et al., 2019) yet remains underutilized. If DFs in wheat bran can be reasonably processed and utilized, such as modification, the added value of wheat bran can be greatly used to promote the proliferation of probiotics, and create a healthy intestinal ecology (Dhingra et al., 2012; Makki et al., 2018; Zhang et al., 2019). Studies showed that carboxymethyl chitosan had strong antioxidant activities, antitumor effect in vivo and in vitro, not cytotoxic to mice, and is widely used in wound healing, drug/enzyme delivery, and cosmetics (Shariatinia, 2018). Carboxymethylated Lachnum polysaccharide had great anti-fatigue activity in vivo (Surhio et al., 2017). In our previous work, we prepared carboxymethylated wheat bran DFs, which is formed by etherification of wheat bran DFs extracted from wheat bran via enzymatic hydrolysis with monochloroacetic acid in alkaline solution. It was found that carboxymethylated wheat bran DFs effectively improved the water retention, water swelling, the oil retention, and glucose adsorption capacities on wheat bran DFs (Zhang et al., 2019), that related to its ability to reduce blood glucose level (Song et al., 2018). Although several studies are conducted on the hypoglycemic roles of DFs but there is scanty information available on the effect of chemical modification of DFs and their resulting physiological effects in vivo. Therefore, we explored the hypoglycemic effects of wheat bran DFs after carboxymethylated modification in high fat diet (HFD) combined with streptozotocin (STZ) induced diabetes mice and their underlying mechanisms. We evaluated the effects of modified DFs on growth performance, oral glucose tolerance, and other biochemical parameters such as the serum lipids and hormones, liver, and pancreas histopathology, SCFAs production, and mRNA expression of genes related to 1,2-Diacylglycerol (DAG) - protein kinase C epsilon (PKCε) pathway. This study further investigated whether the modified DFs could modulate the gut microbiota community in HFD/STZ induced diabetic mice.

Section snippets

Materials

Wheat (Triticum aestivum L.) bran was obtained from Weifang city, Shandong province, China. According to our previous study (Zhang et al., 2019), carboxymethylated modified wheat bran dietary fibers were used in the current study. Streptozotocin (STZ) and metformin hydrochloride were purchased from Beijing Solarbio Science & Technology Co., Ltd (Beijing, China). The high fat diet (HFD) (60% kcal fat; D12492) was purchased from Jiangsu Xietong Pharmacological Bio-engineering Co., Ltd (Nanjing,

Effect of modified wheat bran dietary fiber on the growth performance of mice

As shown in Fig. 2 A, in the first three weeks of feeding with HFD, the weight gain of model group mice was higher than that of control group, and the difference of weight was significant (p < 0.05). After STZ injection, the reduction in model group mice body weight and the significant increase in daily water intake (p < 0.001) and blood glucose (p < 0.001) were observed (Fig. 2 B, C). During the last four weeks of administration with HFD accompanied by modified wheat bran DFs intervention, the

Discussion

The prevalence of diabetes in China has increased dramatically in the past 40 years (Wang et al., 2020). Hyperglycemia, hyperlipidemia, abnormal lipid metabolism, and insulin secretion disorder are the characteristics manifestation of T2D (Skovso, 2014). More and more studies have shown the imbalance of gut microbiota in patients with T2D (Larsen et al., 2010; Zhao et al., 2018). Studies have demonstrated that DFs intake can alleviate the symptoms of T2D (Ma and Mu, 2016; Zhao et al., 2018). In

Conclusions

To summarize, modified wheat bran DFs had the effect of lowering blood lipid and blood glucose, and the possible mechanism may be (1) inhibition of 1,2-DAG-PKCε pathway, improvement of insulin receptor activity and insulin signal transduction; (2) promoting the synthesis of SCFAs to drive the regulation of gastrointestinal hormones and insulin on blood glucose to reduce the blood glucose level in diabetic mice; (3) improving gut microbiota diversity in diabetic mice. Altogether, intake of

CRediT authorship contribution statement

Xiao-Xiao Li: Conceptualization, Methodology, Software, Writing – original draft. Xiu-Xiu Zhang: Methodology, Software. Rui Zhang: Methodology, Software. Zhi-Jing Ni: Data curation, Validation. Elnur Elam: Methodology, Investigation. Kiran Thakur: Data curation, Investigation, Writing – review & editing. Carlos L. Cespedes-Acuña: Supervision, Writing – review & editing. Jian-Guo Zhang: Supervision, Investigation, Funding acquisition. Zhao-Jun Wei: Funding acquisition, Supervision, Writing –

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.

Acknowledgments

This work was supported by the Major Projects of Science and Technology in Anhui Province (201903a06020021, 202004a06020042, 202004a06020052, 201904a06020008), the National Natural Science Foundation of China (31850410476).

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