Zheng-Wei Zhang; Wei-Ping Wang; Jia-Chun Hu; Jin-Yue Lu; Ru Feng; Shao-Feng Xu; Ling Wang; Jie Fu; Hang Yu; Hui Xu; Hao-Jian Zhang; Xin-Yu Yang; Zhao Zhai; Jing-Yue Wang; Meng-Liang Ye; Heng-Tong Zuo; Jian-Ye Song; Yi Zhao; Xiang Hui; Xiao-Liang Wang

doi:10.1016/j.eng.2025.04.018

工程（英文） ›› 2025 DOI: 10.1016/j.eng.2025.04.018

Zheng-Wei Zhang ^a ,
Wei-Ping Wang ^a ,
Jia-Chun Hu ^a ,
Jin-Yue Lu ^a ,
Ru Feng ^a ,
Shao-Feng Xu ^a ,
Ling Wang ^a ,
Jie Fu ^a ,
Hang Yu ^a ,
Hui Xu ^a ,
Hao-Jian Zhang ^a ,
Xin-Yu Yang ^a ,
Zhao Zhai ^a ,
Jing-Yue Wang ^a ,
Meng-Liang Ye ^a ,
Heng-Tong Zuo ^a ,
Jian-Ye Song ^a ,
Yi Zhao ^a ,
Xiang Hui ^a ,
Xiao-Liang Wang ^a^,^b^,^*

作者信息 +

Berberine Protects Cerebral Vessels and Alleviates Diabetic Encephalopathy by Inhibiting the Production of δ-Valerobetaine in the Gut Microbiota

Zheng-Wei Zhang ^a^,^# ,
Wei-Ping Wang ^a^,^# ,
Jia-Chun Hu ^a^,^# ,
Jin-Yue Lu ^a^,^# ,
Ru Feng ^a ,
Shao-Feng Xu ^a ,
Ling Wang ^a ,
Jie Fu ^a ,
Hang Yu ^a ,
Hui Xu ^a ,
Hao-Jian Zhang ^a ,
Xin-Yu Yang ^a ,
Zhao Zhai ^a ,
Jing-Yue Wang ^a ,
Meng-Liang Ye ^a ,
Heng-Tong Zuo ^a ,
Jian-Ye Song ^a ,
Yi Zhao ^a ,
Xiang Hui ^a ,
Xiao-Liang Wang ^a^,^b^,^*

Author information +

History +

Abstract

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-κB) 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.

Keywords

Berberine / Gut microbiota / Inflammation / δ-Valerobetaine / Diabetic encephalopathy

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Zheng-Wei Zhang, Wei-Ping Wang, Jia-Chun Hu. . Engineering. 2025 https://doi.org/10.1016/j.eng.2025.04.018

参考文献

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[1]	Gudala K, Bansal D, Schifano F, Bhansali A.Diabetes mellitus and risk of dementia: a meta-analysis of prospective observational studies.J Diabetes Investig 2013; 4:640-650.
[2]	Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P.Risk of dementia in diabetes mellitus: a systematic review.Lancet Neurol 2006; 5:64-74.
[3]	Cukierman-Yaffe T, Gerstein HC, Williamson JD, Lazar RM, Lovato L, Miller ME, et al.for the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) Investigators. Relationship between baseline glycemic control and cognitive function in individuals with type 2 diabetes and other cardiovascular risk factors.Diabetes Care 2009; 32:221-226.
[4]	De FG Felice, Lourenco MV, Ferreira ST.How does brain insulin resistance develop in Alzheimer’s disease?.Alzheimers Dement 2014; 10:S26-S32.
[5]	Nishikawa H, Suzuki H.Possible role of inflammation and galectin-3 in brain injury after subarachnoid hemorrhage.Brain Sci 2018; 8:30.
[6]	Soares LC, Al-Dalahmah O, Hillis J, Young CC, Asbed I, Sakaguchi M, et al.Novel galectin-3 roles in neurogenesis, inflammation and neurological diseases.Cells 2021; 10:3047.
[7]	W Mątroba, Grabowska AD, Szukiewicz D.Effects of diabetes mellitus-related dysglycemia on the functions of blood–brain barrier and the risk of dementia.Int J Mol Sci 2023; 24:10069.
[8]	Reis F.Soares, Nunes, Pereira, Diabetic encephalopathy: the role of oxidative stress and inflammation in type 2 diabetes.IJICMR 2012; 2012:75-85.
[9]	Mazumdar D, Singh S.Diabetic encephalopathy: role of oxidative and nitrosative factors in type 2 diabetes.Indian J Clin Biochem 2024; 39:3-17.
[10]	Zhou H, Zhang X, Lu J.Progress on diabetic cerebrovascular diseases.Bosn J Basic Med Sci 2014; 14:185.
[11]	Naufel MF, Truzzi GDM, Ferreira CM, Coelho FMS.The brain–gut–microbiota axis in the treatment of neurologic and psychiatric disorders.Arq Neuropsiquiatr 2023; 81:670-684.
[12]	Zhang ZW, Gao CS, Zhang H, Yang J, Wang YP, Pan LB, et al.Morinda officinalis oligosaccharides increase serotonin in the brain and ameliorate depression via promoting 5-hydroxytryptophan production in the gut microbiota.Acta Pharm Sin B 2022; 12:3298-3312.
[13]	Zhao ZX, Fu J, Ma SR, Peng R, Yu JB, Cong L, et al.Gut–brain axis metabolic pathway regulates antidepressant efficacy of albiflorin.Theranostics 2018; 8:5945-5959.
[14]	Yu JB, Zhao ZX, Peng R, Pan LB, Fu J, Ma SR, et al.Gut microbiota-based pharmacokinetics and the antidepressant mechanism of paeoniflorin.Front Pharmacol 2019; 10:268.
[15]	Zhang ZW, Han P, Fu J, Yu H, Xu H, Hu JC, et al.Gut microbiota-based metabolites of Xiaoyao Pills (a typical traditional Chinese medicine) ameliorate depression by inhibiting fatty acid amide hydrolase levels in brain.J Ethnopharmacol 2023; 313:116555.
[16]	Mossad O, Nent E, Woltemate S, Folschweiller S, Buescher JM, Schnepf D, et al.Microbiota-dependent increase in δ-valerobetaine alters neuronal function and is responsible for age-related cognitive decline.Nat Aging 2021; 1:1127-1136.
[17]	Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, et al.Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins.Nat Med 2004; 10:1344-1351.
[18]	Yin J, Xing H, Ye J.Efficacy of berberine in patients with type 2 diabetes.Metabolism 2008; 57:712-717.
[19]	Zhang X, Zhao Y, Zhang M, Pang X, Xu J, Kang C, et al.Structural changes of gut microbiota during berberine-mediated prevention of obesity and insulin resistance in high-fat diet-fed rats.PLoS One 2012; 7:e42529.
[20]	Feng R, Shou JW, Zhao ZX, He CY, Ma C, Huang M, et al.Transforming berberine into its intestine-absorbable form by the gut microbiota.Sci Rep 2015; 5:12155.
[21]	Wang Y, Tong Q, Shou JW, Zhao ZX, Li XY, Zhang XF, et al.Gut microbiota-mediated personalized treatment of hyperlipidemia using berberine.Theranostics 2017; 7:2443-2451.
[22]	Wang Y, Shou JW, Li XY, Zhao ZX, Fu J, He CY, et al.Berberine-induced bioactive metabolites of the gut microbiota improve energy metabolism.Metabolism 2017; 70:72-84.
[23]	Wang Y, Tong Q, Ma SR, Zhao ZX, Pan LB, Cong L, et al.Oral berberine improves brain dopa/dopamine levels to ameliorate Parkinson’s disease by regulating gut microbiota.Signal Transduct Target Ther 2021; 6:77.
[24]	Ma SR, Tong Q, Lin Y, Pan LB, Fu J, Peng R, et al.Berberine treats atherosclerosis via a vitamine-like effect down-regulating choline–TMA–TMAO production pathway in gut microbiota.Signal Transduct Target Ther 2022; 7:207.
[25]	Pan L, Yu H, Fu J, Hu J, Xu H, Zhang Z, et al.Berberine ameliorates chronic kidney disease through inhibiting the production of gut-derived uremic toxins in the gut microbiota.Acta Pharm Sin B 2023; 13:1537-1553.
[26]	Leger M, Quiedeville A, Bouet V, Haelewyn B, Boulouard M, Schumann-Bard P, et al.Object recognition test in mice.Nat Protoc 2013; 8:2531-2537.
[27]	Shen Y, Hua L, Yeh CK, Shen L, Ying M, Zhang Z, et al.Ultrasound with microbubbles improves memory, ameliorates pathology and modulates hippocampal proteomic changes in a triple transgenic mouse model of Alzheimer’s disease.Theranostics 2020; 10:11794-11819.
[28]	Li A, Gong H, Zhang B, Wang Q, Yan C, Wu J, et al.Micro-Optical sectioning tomography to obtain a high-resolution atlas of the mouse brain.Science 2010; 330:1404-1408.
[29]	Nunez J.Morris water maze experiment.J Vis Exp 2008; 19:897.
[30]	Nakai K, Imai H, Kamei I, Itakura T, Komari N, Kimura H, et al.Microangioarchitecture of rat parietal cortex with special reference to vascular “sphincters”. Scanning electron microscopic and dark field microscopic study.Stroke 1981; 12:653-659.
[31]	Corem N, Anzi S, Gelb S, Ben-Zvi A.Leptin receptor deficiency induces early, transient and hyperglycaemia-independent blood–brain barrier dysfunction.Sci Rep 2019; 9:2884.
[32]	Li X, Cai Y, Zhang Z, Zhou J.Glial and vascular cell regulation of the blood–brain barrier in diabetes.Diabetes Metab J 2022; 46:222-238.
[33]	Zhang X, Yin X, Zhang J, Li A, Gong H, Luo Q, et al.High-resolution mapping of brain vasculature and its impairment in the hippocampus of Alzheimer’s disease mice.Natl Sci Rev 2019; 6:1223-1238.
[34]	Kim SY, Buckwalter M, Soreq H, Vezzani A, Kaufer D.Blood–brain barrier dysfunction-induced inflammatory signaling in brain pathology and epileptogenesis: blood–brain barrier dysfunction.Epilepsia 2012; 53:37-44.
[35]	Takata F, Nakagawa S, Matsumoto J, Dohgu S.Blood–brain barrier dysfunction amplifies the development of neuroinflammation: understanding of cellular events in brain microvascular endothelial cells for prevention and treatment of BBB dysfunction.Front Cell Neurosci 2021; 15:661838.
[36]	Li P, Liu S, Lu M, Bandyopadhyay G, Oh D, Imamura T, et al.Hematopoietic-derived galectin-3 causes cellular and systemic insulin resistance.
[37]	Ma J, Feng R, Tan X, Ma C, Shou J, Fu J, et al.Excretion of berberine and its metabolites in oral administration in rats.J Pharm Sci 2013; 102:4181-4192.
[38]	Walker AW, Duncan SH, McWilliam EC Leitch, Child MW, Flint HJ.pH and peptide supply can radically alter bacterial populations and short-chain fatty acid ratios within microbial communities from the human colon.Appl Environ Microbiol 2005; 71:3692-3700.
[39]	Feng W, Ao H, Peng C.Gut microbiota, short-chain fatty acids, and herbal medicines.Front Pharmacol 2018; 9:1354.
[40]	Scales BS, Dickson RP, Huffnagle GB.A tale of two sites: how inflammation can reshape the microbiomes of the gut and lungs.J Leukoc Biol 2016; 100:943-950.
[41]	Engelmann C, Sheikh M, Sharma S, Kondo T, Loeffler-Wirth H, Zheng YB, et al.Toll-like receptor 4 is a therapeutic target for prevention and treatment of liver failure.J Hepatol 2020; 73:102-112.
[42]	Tuttle KR.Linking metabolism and immunology: diabetic nephropathy is an inflammatory disease.J Am Soc Nephrol 2005; 16:1537-1538.
[43]	Zhou W, Ke S, Li W, Yuan J, Li X, Jin R, et al.Mapping the function of whole‐brain projection at the single neuron level.Adv Sci 2022; 9:2202553.
[44]	Zhao M, Wei H, Li C, Zhan R, Liu C, Gao J, et al.Gut microbiota production of trimethyl-5-aminovaleric acid reduces fatty acid oxidation and accelerates cardiac hypertrophy.Nat Commun 2022; 13:1757.
[45]	Zhang ZW, Cong L, Peng R, Han P, Ma SR, Pan LB, et al.Transformation of berberine to its demethylated metabolites by the CYP51 enzyme in the gut microbiota.J Pharm Anal 2021; 11:628-637.
[46]	Morrison DJ, Preston T.Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism.Gut Microbes 2016; 7:189-200.
[47]	Diks S, Richel D, Peppelenbosch M.LPS signal transduction: the picture is becoming more complex.Curr Top Med Chem 2004; 4:1115-1126.
[48]	Li Z, Geng YN, Jiang JD, Kong WJ.Antioxidant and anti-inflammatory activities of berberine in the treatment of diabetes mellitus.Evid Based Compl Alt 2014; 2014:1-12.
[49]	Pedrosa LF, Raz A, Fabi JP.The complex biological effects of pectin: galectin-3 targeting as potential human health improvement?.Biomolecules 2022; 12:289.
[50]	Burguillos MA, Svensson M, Schulte T, Boza-Serrano A, Garcia-Quintanilla A, Kavanagh E, et al.Microglia-secreted galectin-3 acts as a Toll-like receptor 4 ligand and contributes to microglial activation.Cell Rep 2015; 10:1626-1638.