Mulberry leaf water extract alleviates type 2 diabetes in mice via modulating gut microbiota‐host co‐metabolism of branched‐chain amino acid

Abstract

Elevations in circling branched‐chain amino acids (BCAAs) levels associated with insulin resistance and type 2 diabetes mellitus (T2DM). Morus alba L. water extracts (MLE) show hypoglycemic function, but the precise mechanism remains obscure. This study is designed to investigate the association of the antidiabetes effect of MLE with the BCAAs co‐metabolism modulated by host and gut microbiota. Tissue‐specific expressions of BCAA‐catabolizing enzymes were detected by RT‐PCR and western blot, respectively. The components of the intestinal microflora were analyzed by high‐throughput 16S rRNA gene sequencing. The results showed that MLE administration improved blood glucose and insulin level, decreased inflammatory cytokines expression, and lowered serum and feces BCAAs levels. Furthermore, MLE reversed the abundance changes of the bacterial genera correlated with serum and feces BCAAs, such as Anaerovorax, Bilophila, Blautia, Colidextribacter, Dubosiella, Intestinimonas, Lachnoclostridium, Lachnospiraceae_NK4A136, Oscillibacter, and Roseburia. Functionality prediction indicated that MLE potentially inhibited bacterial BCAAs biosynthesis, and promoted the tissue‐specific expression of BCAAs catabolic enzyme. More importantly, MLE had obvious impacts on BCAA catabolism in germ‐free‐mimic T2DM mice. Those results indicated that MLE improving T2DM‐related biochemical abnormalities is associated with not only gut microbiota modification but also the tissue‐specific expression of BCAAs catabolic enzyme.

Baicalein, a dietary flavonoid, enhances the insulin‐sensitizing effect of metformin to prevent type 2 diabetes via the regulation of lipid metabolism and gut microenvironment

“…B. vulgatus was also negatively correlated with total BCAAs in both heatmap and linear correlation plot (Figure 7l). In comparison, Colidextribacter, Blautia, and Faecalibaculum, which were reported as potential BCAA producers (Xia et al, 2021;Zheng et al, 2023), were all positively correlated with plasma BCAA levels. To verify that the modulation is specific to BCAAs instead of all amino acids, we determined the levels of other amino acids, including glycine, histidine, and tryptophan, in the plasma.…”

“…Consistently, we also identified positive correlations of Enterortabdus and Butyricicoccus with circulating BCAA levels (p < .05, Figure 7k). Furthermore, mulberry leaf extract decreased the relative abundance of BCAA producers including Colidextribacter, Oscillibacter, and Dubosiella (Zheng et al, 2023). Colidextribacter was considered to be correlated with hyperlipidemia and enriched in HFD-fed mice (Duan et al, 2021).…”

A Basic Study of the Effects of Mulberry Leaf Administration to Healthy C57BL/6 Mice on Gut Microbiota and Metabolites

“…In mice treated with MLP, the levels of BCAAs in the feces were lower than those in the control group starting from week 5, with significant differences appearing at week 6. In previous studies on T2DM mice fed high-fat and high-sugar diets, it was reported that the administration of aqueous extracts of mulberry leaves causes changes in the gut microbiota that reduce BCAA concentration and host uptake in the feces, which ultimately promotes the tissue-specific expression of BCAA catabolic enzymes in the host [ 19 ]. It is noteworthy that the mulberry leaf extract in that study did not contain 1-DNJ, and the decreased synthesis of BCAAs via the improvement of gut microbiota was thought to be the result of a different mechanism than that in this study [ 19 ].…”

“…In previous studies on T2DM mice fed high-fat and high-sugar diets, it was reported that the administration of aqueous extracts of mulberry leaves causes changes in the gut microbiota that reduce BCAA concentration and host uptake in the feces, which ultimately promotes the tissue-specific expression of BCAA catabolic enzymes in the host [ 19 ]. It is noteworthy that the mulberry leaf extract in that study did not contain 1-DNJ, and the decreased synthesis of BCAAs via the improvement of gut microbiota was thought to be the result of a different mechanism than that in this study [ 19 ]. It is interesting to note that even in the healthy mice herein, the long-term administration of mulberry leaves reduced BCAA concentrations in the intestine via a mechanism that was not mediated by effects on the gut microbiota.…”

“…Furthermore, 1-DNJ in mulberry leaves was reported to not only inhibit glucose absorption in the intestine by suppressing polysaccharide degradation but also downregulate the mRNA and protein expression of glucose transporters in the gut [ 17 ]. Other studies investigated the effects of mulberry leaf extracts on the gut microbiota, short-chain fatty acids, and branched-chain amino acids in the feces of disease-model mice [ 13 , 18 , 19 ].…”