Multiomics Approach to Explore the Amelioration Mechanisms of Glucomannans on the Metabolic Disorder of Type 2 Diabetic Rats

Abstract

Type 2 diabetes (T2D) is a worldwide epidemic associated with metabolic disorders and intestinal microbiota alterations. Polysaccharides have been considered to be beneficial to the prevention and alleviation of T2D. In the present study, ultra-performance liquid chromatography−triple-time-of-flight-based metabolomics and proteomics and 16S rRNA sequencing methods were employed to evaluate the effects of glucomannans from Dendrobium officinale stem, konjac, and Aloe vera leaves on host metabolism and intestinal microbiota regulation in type 2 diabetic rats and potential mechanisms. The metabolism of amino acids was significantly disturbed in the type 2 diabetic rats, especially the upregulated branched-chain amino acid (BCAA) metabolism. Host-derived BCAA metabolism was significantly decreased in type 2 diabetic rats. However, the levels of BCAAs in host circulation and gene abundance of BCAA biosynthesis in gut microbiota were significantly increased in diabetic rats, which suggested that the disturbed intestinal microbiota might be responsible for the increased circulation of BCAAs in T2D. Glucomannan treatment decreased the abundance of microbial BCAA biosynthesis-related genes and ameliorated the host BCAA metabolism. Also, glucomannan with a higher molecular weight and a lower ratio of mannose/glucose possessed better antidiabetic effects. In summary, the antidiabetic effects of glucomannans might be associated with the amelioration of BCAA metabolism by modulating intestinal microbiota.

Gut Microbiota as the Link between Elevated BCAA Serum Levels and Insulin Resistance

“…While it is difficult to adjust to a different dietary intake of individual AA in large human trials, animal studies allow for such a standardization and, therefore, for a more precise identification of microbiota-derived BCAA in the circulation. Several studies addressing the relationship between gut microbiota, circulating metabolites, and metabolic health were performed in animal models of obesity (mice fed a high-fat diet) [48,74] or diabetes (rats fed a high-fat diet and treated with streptozotocin) [75] (Table 2). In all models, serum BCAAs were significantly elevated and could be regarded as serum biomarkers of obesity-related insulin resistance.…”

“…HFD induced significant changes in the gut microbiota composition characterized by the increased Firmicutes to Bacteroidetes ratio but, at the genus level, the outcomes were quite heterogeneous. Pathway analysis based on the metabolite abundances [48,75] or PICRUSt analysis based on the gut microbiota composition [74] identified an increased BCAA biosynthesis pathway in the HFD groups. The BCAA degradation pathway was decreased in HFD-fed mice only in the study of Zeng et al [48] but not in the others.…”

“…BCAA composition as well as to the glucose metabolism-related parameters. To our knowledge, this effect was described after a treatment with citrus polymethoxyflavones (PMFE) [48], Luffa cylindrical (luffa) [74], berberine [77], glucomannans [75], and inulin [78]. The chemical nature of these compounds is quite heterogeneous.…”

Plant Extracts in Obesity: A Role of Gut Microbiota

“…In turn, the amendatory gut microbiota could accelerate the fermentation of dietary KF to improve the SCFAs' concentration in the intestinal contents, thus ameliorating obesity and its-related complications ( 161 , 163 ). On the other hand, it is well known that increased circulating BCAA concentrations can deteriorate host glucose and lipid metabolism, and subsequently prognosticate future risk of developing insulin resistance and diabetes ( 169 ). Interestingly, a recent study has demonstrated that KGM treatment (160 mg kg −1 ) of type 2 diabetic rats for 4 weeks reduced the abundance of BCAA-producing bacteria and improved BCAA metabolism, further ameliorating host lipid metabolism and diabetes ( 169 ).…”

“…On the other hand, it is well known that increased circulating BCAA concentrations can deteriorate host glucose and lipid metabolism, and subsequently prognosticate future risk of developing insulin resistance and diabetes ( 169 ). Interestingly, a recent study has demonstrated that KGM treatment (160 mg kg −1 ) of type 2 diabetic rats for 4 weeks reduced the abundance of BCAA-producing bacteria and improved BCAA metabolism, further ameliorating host lipid metabolism and diabetes ( 169 ). In summary, KF might be a promising agent to prevent and to treat obesity, and the potential mechanism was associated with reprogramming gut microbiota and metabolism, especially decreasing BCAA-producing bacteria abundance ( Figure 6 ).…”