Hyperglycemia in individuals with diabetes causes cognitive impairment,called diabetic encephalopathy(DE).The pathogenesis of DE is closely related to angiopathy,and effective treatment is highly desirable.The botanic...Hyperglycemia in individuals with diabetes causes cognitive impairment,called diabetic encephalopathy(DE).The pathogenesis of DE is closely related to angiopathy,and effective treatment is highly desirable.The botanical agent berberine(BBR)effectively lowers blood glucose in diabetic patients.Here,we show for the first time that BBR significantly improved cognitive function in type 2 diabetic encephalopathy KK-Ay(2DEK)mice.High-resolution imaging via fluorescence micro-optical sectioning tomography(fMOST)revealed that the integrity of brain vessels was improved by BBR treatment.The improvements in average vessel diameter,vessel length,and total vessel volume were significant in the parietal association cortex(PtA),as well as in the CA1 and CA3 regions.A mechanistic study revealed that oral BBR inhibited δ-valerobetaine(δ-VB,a metabolite of the gut microbiota)production in the intestine.As intestinal δ-VB can enter the circulation and activate the Toll-like receptor-4(TLR-4)/myeloid differentiation factor 88(MyD88)/nuclear factor kappa B(NF-jB)inflammatory pathway in the epithelial cells of blood vessels through interacting with TLR-4,BBR might reduce the intestinal level of δ-VB to protect the cerebral blood vessels of DE mice and improve their brain function.Fecal microbiota transplantation(FMT)using the gut microbiota from BBR-treated mice confirmed the vital role of the gut microbiota.BBR showed a wide range of effects on the gut flora,also increasing short-chain fatty acid(SCFA)production and decreasing lipopolysaccharide(LPS)levels in the intestine by adjusting the abundance of SCFA-or LPS-producing bacteria.The observed therapeutic efficacy in vivo revealed a synergistic effect of BBR on the gut microbiota.Conclusively,we found an association between the gut microbiota and blood vessels,of which intestinal δ-VB might be a chemical link.Mainly through downregulating δ-VB in the intestine,BBR protected cerebral vessels and alleviated DE.展开更多
基金funded by the National Key Research and Devel-opment Program of China(2022YFA0806400)the CAMS Innova-tion Fund for Medical Sciences(CIFMS)(2023-I2M-2-006,2021-1-I2M-027,and 2021-1-I2M-028)+1 种基金the National Natural Science Foundation of China(82173888 and 81973290)the Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study(Z141102004414062).
文摘Hyperglycemia in individuals with diabetes causes cognitive impairment,called diabetic encephalopathy(DE).The pathogenesis of DE is closely related to angiopathy,and effective treatment is highly desirable.The botanical agent berberine(BBR)effectively lowers blood glucose in diabetic patients.Here,we show for the first time that BBR significantly improved cognitive function in type 2 diabetic encephalopathy KK-Ay(2DEK)mice.High-resolution imaging via fluorescence micro-optical sectioning tomography(fMOST)revealed that the integrity of brain vessels was improved by BBR treatment.The improvements in average vessel diameter,vessel length,and total vessel volume were significant in the parietal association cortex(PtA),as well as in the CA1 and CA3 regions.A mechanistic study revealed that oral BBR inhibited δ-valerobetaine(δ-VB,a metabolite of the gut microbiota)production in the intestine.As intestinal δ-VB can enter the circulation and activate the Toll-like receptor-4(TLR-4)/myeloid differentiation factor 88(MyD88)/nuclear factor kappa B(NF-jB)inflammatory pathway in the epithelial cells of blood vessels through interacting with TLR-4,BBR might reduce the intestinal level of δ-VB to protect the cerebral blood vessels of DE mice and improve their brain function.Fecal microbiota transplantation(FMT)using the gut microbiota from BBR-treated mice confirmed the vital role of the gut microbiota.BBR showed a wide range of effects on the gut flora,also increasing short-chain fatty acid(SCFA)production and decreasing lipopolysaccharide(LPS)levels in the intestine by adjusting the abundance of SCFA-or LPS-producing bacteria.The observed therapeutic efficacy in vivo revealed a synergistic effect of BBR on the gut microbiota.Conclusively,we found an association between the gut microbiota and blood vessels,of which intestinal δ-VB might be a chemical link.Mainly through downregulating δ-VB in the intestine,BBR protected cerebral vessels and alleviated DE.
