Increased circulating branched-chain amino acids(BCAAs)have been involved in the pathogenesis of obesity and insulin resistance.However,evidence relating berberine(BBR),gut microbiota,BCAAs,and insulin resis⁃tance is ...Increased circulating branched-chain amino acids(BCAAs)have been involved in the pathogenesis of obesity and insulin resistance.However,evidence relating berberine(BBR),gut microbiota,BCAAs,and insulin resis⁃tance is limited.Here,we showed that BBR could effectively rectify steatohepatitis and glucose intolerance in high-fat diet(HFD)-fed mice.BBR reorganized gut microbiota populations under both the normal chow diet(NCD)and HFD.Particu⁃larly,BBR noticeably decreased the relative abundance of BCAA-producing bacteria,including order Clostridiales;fami⁃lies Streptococcaceae,Clostridiaceae,and Prevotellaceae;and genera Streptococcus and Prevotella.Compared with the HFD group,predictive metagenomics indicated a reduction in the proportion of gut microbiota genes involved in BCAA biosynthesis but the enrichment genes for BCAA degradation and transport by BBR treatment.Accordingly,the elevated serum BCAAs of HFD group were significantly decreased by BBR.Furthermore,the Western blotting results implied that BBR could promote the BCAA catabolism in the liver and epididymal white adipose tissues of HFD-fed mice by acti⁃vation of the multienzyme branched-chain α-ketoacid dehydrogenase complex,whereas by inhibition of the phosphoryla⁃tion state of BCKDHA(E1α subunit)and branched-chain α-ketoacid dehydrogenase kinase.The ex vivo assay further confirmed that BBR could increase BCAA catabolism in both AML12 hepatocytes and 3T3-L1 adipocytes.Finally,data from healthy subjects and diabetics confirmed that BBR could improve glycemic control and modulate circulating BCAAs.Besides,functional microbiomics integrated high-throughput microbial genomics,metabolomics and molecular biotechnology has also been successfully applied to reveal the anti-obesity mechanism of hydroxysafflor yellow A.展开更多
Alzheimer disease(AD)is the leading cause of dementia that affects millions of elderly people worldwide.The currently available therapies have limited efficacy.Liuwei Dihuang formula(LW),a classical traditional Chines...Alzheimer disease(AD)is the leading cause of dementia that affects millions of elderly people worldwide.The currently available therapies have limited efficacy.Liuwei Dihuang formula(LW),a classical traditional Chinese medicine(TCM)prescription,has long been used to treat various diseases,including dementia.A great number of pharmacological studies have showed that LW and its active fractions had beneficial effects on AD associated cognitive impairments.Our recent study found that LW,especially its oligosaccharide fraction CA-30,could improve the gastrointestinal microbiota dysbiosis in senescence-accelerated mouse prone 8(SAMP8),an AD mouse model.Here,we sought to determine the effects of CA-30 on the composition and function of the intestinal microbiome in SAMP8 mice.Administration with CA-30 decreased the degree of senescence,increased the nest building and locomotor activity,ameliorated the impairments in object recognition,spatial learningand memory behavour,and decreased the active avoidance response in SAMP8 mice.Meanwhile,CA-30 improvedthe cytokine and hormone secretion and lymphocyte subset dysregulation in SAMP8 mice.Moreover,we found that CA-30 altered the abundance of 4 genera and 10 newborn genera.Advantageous changes in carbohydrate-active enzymes of SAMP8 mice following CA-30 treatment,especially GH85,were also noted.We further found that 7 genera were significantly correlated with the NIM network and cognitive performance.CA-30 influenced the relative abundance of these intestinal microbiomes in SAMP8 mice and restored them to SAMR1 mouse levels.CA-30 ameliorated the intestinal microbiome,rebalanced the NIM network,improved the AD-like cognitive impairments in SAMP8,and might thus be a potential therapeutic agent for AD.展开更多
OBJECTIVE To investigate the effects of LW-AFC,a new formula derived fromLiuwei Dihuang decoction,on gut microbiota and the behavior of learning and memory of SAMP8 mice,a mouse model of Alzheimer Disease(AD),and iden...OBJECTIVE To investigate the effects of LW-AFC,a new formula derived fromLiuwei Dihuang decoction,on gut microbiota and the behavior of learning and memory of SAMP8 mice,a mouse model of Alzheimer Disease(AD),and identify the specific intestinal microbiota correlating with cognitive ability.METHODS Morris-water maze test,novel object recognition test and shuttle-box test were conducted to observe the ability of learning and memory.16S rRNA amplicon sequencing(Illumina,San Diego,CA,USA)was employed to investigate gut microbiota.RESULTS The treatment of LW-AFC improved cognitive impairments of SAMP8 mice,including spatial learning and memory ability,active avoidance response,and object recognition memory capability.Our data indicated that there were significantly 8 increased and 12 decreased operational taxonomic units(OTUs)in the gut microbiota of SAMP8 mice compared with senescence accelerated mouse resistant 1(SAMR1) strains,the control of SAMP8 mice.The treatment of LW-AFC altered 22(16 increased and 6 decreased)OTUs in SAMP8 mice and among them,15 OTUs could be reversed by LW-AFC treatment resulting in a microbial composition similar to that of SAMR1 mice.We further showed that there were7(3 negative and 4 positive correlation)OTUs significantly correlated with all the three types of cognitive abilities,at the order level,including Bacteroidales,Clostridiales,Desulfovibrionales,CW040,and two unclassified orders.LW-AFC had influences on bacterial taxa correlated with the abilities of learning and memory in SAMP8 mice and restored them to SAMR1 mice.CONCLUSION The effects of LW-AFC on improving cognitive impairments of SAMP8 mice might be via modulating intestinal microbiome and LW-AFC could be used as a potential anti-AD agent.展开更多
文摘Increased circulating branched-chain amino acids(BCAAs)have been involved in the pathogenesis of obesity and insulin resistance.However,evidence relating berberine(BBR),gut microbiota,BCAAs,and insulin resis⁃tance is limited.Here,we showed that BBR could effectively rectify steatohepatitis and glucose intolerance in high-fat diet(HFD)-fed mice.BBR reorganized gut microbiota populations under both the normal chow diet(NCD)and HFD.Particu⁃larly,BBR noticeably decreased the relative abundance of BCAA-producing bacteria,including order Clostridiales;fami⁃lies Streptococcaceae,Clostridiaceae,and Prevotellaceae;and genera Streptococcus and Prevotella.Compared with the HFD group,predictive metagenomics indicated a reduction in the proportion of gut microbiota genes involved in BCAA biosynthesis but the enrichment genes for BCAA degradation and transport by BBR treatment.Accordingly,the elevated serum BCAAs of HFD group were significantly decreased by BBR.Furthermore,the Western blotting results implied that BBR could promote the BCAA catabolism in the liver and epididymal white adipose tissues of HFD-fed mice by acti⁃vation of the multienzyme branched-chain α-ketoacid dehydrogenase complex,whereas by inhibition of the phosphoryla⁃tion state of BCKDHA(E1α subunit)and branched-chain α-ketoacid dehydrogenase kinase.The ex vivo assay further confirmed that BBR could increase BCAA catabolism in both AML12 hepatocytes and 3T3-L1 adipocytes.Finally,data from healthy subjects and diabetics confirmed that BBR could improve glycemic control and modulate circulating BCAAs.Besides,functional microbiomics integrated high-throughput microbial genomics,metabolomics and molecular biotechnology has also been successfully applied to reveal the anti-obesity mechanism of hydroxysafflor yellow A.
文摘Alzheimer disease(AD)is the leading cause of dementia that affects millions of elderly people worldwide.The currently available therapies have limited efficacy.Liuwei Dihuang formula(LW),a classical traditional Chinese medicine(TCM)prescription,has long been used to treat various diseases,including dementia.A great number of pharmacological studies have showed that LW and its active fractions had beneficial effects on AD associated cognitive impairments.Our recent study found that LW,especially its oligosaccharide fraction CA-30,could improve the gastrointestinal microbiota dysbiosis in senescence-accelerated mouse prone 8(SAMP8),an AD mouse model.Here,we sought to determine the effects of CA-30 on the composition and function of the intestinal microbiome in SAMP8 mice.Administration with CA-30 decreased the degree of senescence,increased the nest building and locomotor activity,ameliorated the impairments in object recognition,spatial learningand memory behavour,and decreased the active avoidance response in SAMP8 mice.Meanwhile,CA-30 improvedthe cytokine and hormone secretion and lymphocyte subset dysregulation in SAMP8 mice.Moreover,we found that CA-30 altered the abundance of 4 genera and 10 newborn genera.Advantageous changes in carbohydrate-active enzymes of SAMP8 mice following CA-30 treatment,especially GH85,were also noted.We further found that 7 genera were significantly correlated with the NIM network and cognitive performance.CA-30 influenced the relative abundance of these intestinal microbiomes in SAMP8 mice and restored them to SAMR1 mouse levels.CA-30 ameliorated the intestinal microbiome,rebalanced the NIM network,improved the AD-like cognitive impairments in SAMP8,and might thus be a potential therapeutic agent for AD.
基金supported by National Science and Technology Major Project(2013ZX09508104,2012ZX09301003-002-001)
文摘OBJECTIVE To investigate the effects of LW-AFC,a new formula derived fromLiuwei Dihuang decoction,on gut microbiota and the behavior of learning and memory of SAMP8 mice,a mouse model of Alzheimer Disease(AD),and identify the specific intestinal microbiota correlating with cognitive ability.METHODS Morris-water maze test,novel object recognition test and shuttle-box test were conducted to observe the ability of learning and memory.16S rRNA amplicon sequencing(Illumina,San Diego,CA,USA)was employed to investigate gut microbiota.RESULTS The treatment of LW-AFC improved cognitive impairments of SAMP8 mice,including spatial learning and memory ability,active avoidance response,and object recognition memory capability.Our data indicated that there were significantly 8 increased and 12 decreased operational taxonomic units(OTUs)in the gut microbiota of SAMP8 mice compared with senescence accelerated mouse resistant 1(SAMR1) strains,the control of SAMP8 mice.The treatment of LW-AFC altered 22(16 increased and 6 decreased)OTUs in SAMP8 mice and among them,15 OTUs could be reversed by LW-AFC treatment resulting in a microbial composition similar to that of SAMR1 mice.We further showed that there were7(3 negative and 4 positive correlation)OTUs significantly correlated with all the three types of cognitive abilities,at the order level,including Bacteroidales,Clostridiales,Desulfovibrionales,CW040,and two unclassified orders.LW-AFC had influences on bacterial taxa correlated with the abilities of learning and memory in SAMP8 mice and restored them to SAMR1 mice.CONCLUSION The effects of LW-AFC on improving cognitive impairments of SAMP8 mice might be via modulating intestinal microbiome and LW-AFC could be used as a potential anti-AD agent.
