肠道菌群在糖尿病认知功能障碍中的作用机制及靶向干预的研究进展

doi:10.3969/j.issn.1674-8115.2024.04.010

上海交通大学学报（医学版） ›› 2024, Vol. 44 ›› Issue (4): 494-500.doi: 10.3969/j.issn.1674-8115.2024.04.010

• 综述 • 上一篇

肠道菌群在糖尿病认知功能障碍中的作用机制及靶向干预的研究进展

杜亚格¹(), 卢言慧¹(), 安宇², 宋颖¹, 郑婕¹

^1.北京大学医学部护理学院，北京 100191
^2.首都医科大学附属北京朝阳医院内分泌科，北京 100020

收稿日期:2023-10-18 接受日期:2024-01-31 出版日期:2024-04-28 发布日期:2024-04-28
通讯作者: 卢言慧 E-mail:yuanfang166@163.com;luyanhui@bjmu.edu.cn
作者简介:杜亚格（1995—），女，博士生；电子信箱：yuanfang166@163.com。
基金资助:
国家重点研发计划(2022YFA1103602);国家自然科学基金(82003456);北京大学临床医学+X青年专项(PKU2023LCXQ009);中央高校基本科研业务费资助

Research progress in mechanisms of gut microbiota in diabetic cognitive impairment and its targeted intervention

DU Yage¹(), LU Yanhui¹(), AN Yu², SONG Ying¹, ZHENG Jie¹

^1.School of Nursing, Peking University Health Science Center, Beijing 100191, China
^2.Endocrinology Department, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China

Received:2023-10-18 Accepted:2024-01-31 Online:2024-04-28 Published:2024-04-28
Contact: LU Yanhui E-mail:yuanfang166@163.com;luyanhui@bjmu.edu.cn
Supported by:
National Key Research and Development Program of China(2022YFA1103602);National Natural Science Foundation of China(82003456);Peking University Clinical Medicine+X Youth Program(PKU2023LCXQ009);Fundamental Research Funds for the Central Universities

摘要/Abstract

摘要：

2型糖尿病进展后期可并发轻度认知功能障碍，并逐步发展为痴呆。糖尿病认知功能障碍（diabetic cognitive impairment，DCI）是糖尿病慢性并发症，相关发病机制仍有待阐明。研究发现肠道菌群失衡可通过“微生物-肠-脑轴”影响中枢神经系统，促进认知功能障碍的发生与发展，因此调控肠道菌群可能成为极具潜力的DCI的防治手段。基于此，该文梳理了肠道菌群在DCI中的作用机制，并总结了益生菌、粪菌移植、饮食与营养素、中医药等靶向肠道菌群的干预方法改善糖尿病相关的认知障碍、糖脂代谢和炎症的实验研究，从而为肠道菌群靶向干预DCI的临床应用提供参考。

关键词: 2型糖尿病, 认知功能障碍, 糖尿病认知功能障碍, 肠道菌群, 微生物-肠-脑轴

Abstract:

Diabetes mellitus type 2 might cause mild cognitive impairment in its advanced stages, potentially progressing to dementia. Diabetic cognitive impairment (DCI) stands as a chronic complication of diabetes mellitus, with its underlying pathogenesis still remaining elusive. Research has revealed that gut microbiota dysbiosis influenced the central nervous system through the "microbiota-gut-brain axis", thereby contributing to the progression of cognitive impairment. Therefore, the regulation of gut microbiota emerges as a promising approach to the prevention and treatment of DCI. This article comprehensively reviews the mechanisms through which gut microbiota influences DCI. Furthermore, it delves into experimental studies exploring targeted therapies for gut microbiota, including probiotics, fecal microbiota transplantation, dietary and nutrient interventions, as well as traditional Chinese medicine. These studies not only address diabetes-related cognitive impairment but also consider aspects such as glycolipid metabolism and inflammation. The insights gleaned from these studies provide valuable guidance for the clinical application of gut microbiota-targeted intervention in DCI.

Key words: diabetes mellitus type 2 (T2DM), cognitive impairment, diabetic cognitive impairment (DCI), gut microbiota, microbiota-gut-brain axis

中图分类号:

R259

杜亚格, 卢言慧, 安宇, 宋颖, 郑婕. 肠道菌群在糖尿病认知功能障碍中的作用机制及靶向干预的研究进展[J]. 上海交通大学学报（医学版）, 2024, 44(4): 494-500.

DU Yage, LU Yanhui, AN Yu, SONG Ying, ZHENG Jie. Research progress in mechanisms of gut microbiota in diabetic cognitive impairment and its targeted intervention[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(4): 494-500.

参考文献 54

1	中华医学会内分泌学分会, 余学锋, 赵家军, 等. 糖尿病患者认知功能障碍专家共识[J]. 中华糖尿病杂志, 2021, 13(7): 678-694.
	Chinese Society of Endocrinology, YU X F, ZHAO J J, et al. Expert consensus on diabetic cognitive dysfunction[J]. Chinese Journal of Diabetes Mellitus, 2021, 13(7): 678-694.
2	张擎, 王旭, 姚文强. 基于“气化”理论探讨自噬对糖尿病认知功能障碍的作用机制[J]. 辽宁中医杂志, 2024, 51(3): 1-7.
	ZHANG Q, WANG X, YAO W Q. Study on the mechanism of autophagy on diabetic cognitive impairment based on the theory of "Qi" [J]. Liaoning Journal of Traditional Chinese Medicine, 2024, 51(3): 1-7.
3	LIU Z G, DAI X S, ZHANG H B, et al. Gut microbiota mediates intermittent-fasting alleviation of diabetes-induced cognitive impairment[J]. Nat Commun, 2020, 11(1): 855.
4	ZHANG Y Y, LU S R, YANG Y, et al. The diversity of gut microbiota in type 2 diabetes with or without cognitive impairment[J]. Aging Clin Exp Res, 2021, 33(3): 589-601.
5	HUANG H Y, ZHAO T, LI J C, et al. Gut microbiota regulation of inflammatory cytokines and microRNAs in diabetes-associated cognitive dysfunction[J]. Appl Microbiol Biotechnol, 2023, 107(23): 7251-7267.
6	DU Y G, LI X Y, AN Y, et al. Association of gut microbiota with sort-chain fatty acids and inflammatory cytokines in diabetic patients with cognitive impairment: a cross-sectional, non-controlled study[J]. Front Nutr, 2022, 9: 930626.
7	ZHANG J W, ZHANG Y X, YUAN Y, et al. Gut microbiota alteration is associated with cognitive deficits in genetically diabetic (db/db) mice during aging[J]. Front Aging Neurosci, 2021, 13: 815562.
8	YANG Y J, ZHONG Z Q, WANG B J, et al. Early-life high-fat diet-induced obesity programs hippocampal development and cognitive functions via regulation of gut commensal Akkermansia muciniphila[J]. Neuropsychopharmacology, 2019, 44(12): 2054-2064.
9	YU F, HAN W, ZHAN G F, et al. Abnormal gut microbiota composition contributes to cognitive dysfunction in streptozotocin-induced diabetic mice[J]. Aging, 2019, 11(10): 3262-3279.
10	张薇薇. 2型糖尿病合并认知障碍的老年患者血液标志物的临床研究[D]. 济南: 山东大学, 2020.
	ZHANG W W. Clinical research on the expression of biomarkers in blood in elderly patients with type 2 diabetes mellitus and cognitive impairment[D]. Ji Nan: Shandong University, 2020.
11	LI Z H, JIANG Y Y, LONG C Y, et al. The gut microbiota-astrocyte axis: implications for type 2 diabetic cognitive dysfunction[J]. CNS Neurosci Ther, 2023, 29(Suppl 1): 59-73.
12	SHEN H P, GUAN Q B, ZHANG X L, et al. New mechanism of neuroinflammation in Alzheimer's disease: the activation of NLRP3 inflammasome mediated by gut microbiota[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2020, 100: 109884.
13	CHEN J, DING X Q, WU R Y, et al. Novel sesquiterpene glycoside from loquat leaf alleviates type 2 diabetes mellitus combined with nonalcoholic fatty liver disease by improving insulin resistance, oxidative stress, inflammation, and gut microbiota composition[J]. J Agric Food Chem, 2021, 69(47): 14176-14191.
14	RUTSCH A, KANTSJÖ J B, RONCHI F. The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology[J]. Front Immunol, 2020, 11: 604179.
15	WU S C, LIU X, JIANG R L, et al. Roles and mechanisms of gut microbiota in patients with Alzheimer's disease[J]. Front Aging Neurosci, 2021, 13: 650047.
16	LIU P F, LI H, WANG Y Q, et al. Harmine ameliorates cognitive impairment by inhibiting NLRP3 inflammasome activation and enhancing the BDNF/TrkB signaling pathway in STZ-induced diabetic rats[J]. Front Pharmacol, 2020, 11: 535.
17	JAYARAJ R L, AZIMULLAH S, BEIRAM R. Diabetes as a risk factor for Alzheimer's disease in the Middle East and its shared pathological mediators[J]. Saudi J Biol Sci, 2020, 27(2): 736-750.
18	XIE L, HELMERHORST E, TADDEI K, et al. Alzheimer's beta-amyloid peptides compete for insulin binding to the insulin receptor[J]. J Neurosci, 2002, 22(10): RC221.
19	ALLIN K H, TREMAROLI V, CAESAR R, et al. Aberrant intestinal microbiota in individuals with prediabetes[J]. Diabetologia, 2018, 61(4): 810-820.
20	TAKEUCHI T, KUBOTA T, NAKANISHI Y, et al. Gut microbial carbohydrate metabolism contributes to insulin resistance[J]. Nature, 2023, 621(7978): 389-395.
21	CHATELIER E L, NIELSEN T, QIN J J, et al. Richness of human gut microbiome correlates with metabolic markers[J]. Nature, 2013, 500(7464): 541-546.
22	吴梦竹, 张梨, 李廷林, 等. 基于心与小肠相表里探析肠道菌群与糖尿病认知障碍的关联[J]. 中国实验方剂学杂志, 2021, 27(3): 231-237.
	WU M Z, ZHANG L, LI T L, et al. Analysis on relationship between intestinal flora and diabetes cognitive impairment based on "paired relationship between heart and small intestine"[J]. Chinese Journal of Experimental Traditional Medical Formulae, 2021, 27(3): 231-237.
23	PLANEL E, TATEBAYASHI Y, MIYASAKA T, et al. Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms[J]. J Neurosci, 2007, 27(50): 13635-13648.
24	MA H L, JIANG T, TANG W X, et al. Transplantation of platelet-derived mitochondria alleviates cognitive impairment and mitochondrial dysfunction in db/db mice[J]. Clin Sci, 2020, 134(16): 2161-2175.
25	SALEM M A, BUDZYŃSKA B, KOWALCZYK J, et al. Tadalafil and bergapten mitigate streptozotocin-induced sporadic Alzheimer's disease in mice via modulating neuroinflammation, PI3K/Akt, Wnt/β- catenin, AMPK/mTOR signaling pathways[J]. Toxicol Appl Pharmacol, 2021, 429: 115697.
26	HARACH T, MARUNGRUANG N, DUTHILLEUL N, et al. Reduction of Aβ amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota[J]. Sci Rep, 2017, 7: 41802.
27	朱莉, 幸佳佳, 魏娟芳, 等. 短链脂肪酸在神经退行性疾病中的相关机制研究进展[J]. 中国全科医学, 2023, 26(24): 3061-3066.
	ZHU L, XING J J, WEI J F, et al. Research advances in the mechanism of short-chain fatty acids in neurodegenerative diseases[J]. Chinese General Practice, 2023, 26(24): 3061-3066.
28	ZHANG S S, XUE R, HU R Z. The neuroprotective effect and action mechanism of polyphenols in diabetes mellitus-related cognitive dysfunction[J]. Eur J Nutr, 2020, 59(4): 1295-1311.
29	SUN J, XU J X, LING Y, et al. Fecal microbiota transplantation alleviated Alzheimer's disease-like pathogenesis in APP/PS1 transgenic mice[J]. Transl Psychiatry, 2019, 9(1): 189.
30	裴莹, 卢燕, 李惠子, 等. 肠道菌群与阿尔茨海默病发生发展关系及防治方法的研究进展[J]. 北京医学, 2022, 44(4): 336-340.
	PEI Y, LU Y, LI H Z, et al. Research progress on the relationship between gut microbiota and the occurrence and development of Alzheimer's disease and prevention and treatment methods[J]. Beijing Medical Journal, 2022, 44(4): 336-340.
31	梁仙志, 廖旻晶, 王宏波, 等. 肠道微生物群与部分人类疾病的研究进展[J]. 基因组学与应用生物学, 2020, 39(12): 5874-5880.
	LIANG X Z, LIAO M J, WANG H B, et al. Research progress on the relation of human gut microbiota and some diseases[J]. Genomics and Applied Biology, 2020, 39(12): 5874-5880.
32	DEPOMMIER C, EVERARD A, DRUART C, et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study[J]. Nat Med, 2019, 25(7): 1096-1103.
33	VAN DER LUGT B, VAN BEEK A A, AALVINK S, et al. Akkermansia muciniphila ameliorates the age-related decline in colonic mucus thickness and attenuates immune activation in accelerated aging Ercc1-/Δ7 mice[J]. Immun Ageing, 2019, 16: 6.
34	冀瑶瑶. 副干酪乳杆菌Jlus66对肥胖小鼠糖脂代谢紊乱及认知障碍的改善作用研究[D]. 长春: 吉林大学, 2022.
	JI Y Y. Improvement of Lactobacillus paracasei Jlus66 on glucose and lipid metabolism disorders and cognitive impairment in obese mice[D]. Changchun: Jilin University, 2022.
35	HOSOMI K, SAITO M, PARK J, et al. Oral administration of Blautia wexlerae ameliorates obesity and type 2 diabetes via metabolic remodeling of the gut microbiota[J]. Nat Commun, 2022, 13(1): 4477.
36	ZHANG P P, LI L L, HAN X, et al. Fecal microbiota transplantation improves metabolism and gut microbiome composition in db/db mice[J]. Acta Pharmacol Sin, 2020, 41(5): 678-685.
37	SUN Y, BAPTISTA L C, ROBERTS L M, et al. The gut microbiome as a therapeutic target for cognitive impairment[J]. J Gerontol A Biol Sci Med Sci, 2020, 75(7): 1242-1250.
38	HERNANDEZ A R, HERNANDEZ C M, TRUCKENBROD L M, et al. Age and ketogenic diet have dissociable effects on synapse-related gene expression between hippocampal subregions[J]. Front Aging Neurosci, 2019, 11: 239.
39	HUSSEIN H M, ELYAMANY M F, RASHED L A, et al. Vitamin D mitigates diabetes-associated metabolic and cognitive dysfunction by modulating gut microbiota and colonic cannabinoid receptor 1[J]. Eur J Pharm Sci, 2022, 170: 106105.
40	ORKABY A R, CHO K, CORMACK J, et al. Metformin vs sulfonylurea use and risk of dementia in US veterans aged ≥65 years with diabetes[J]. Neurology, 2017, 89(18): 1877-1885.
41	MA X Y, XIAO W C, LI H, et al. Metformin restores hippocampal neurogenesis and learning and memory via regulating gut microbiota in the obese mouse model[J]. Brain Behav Immun, 2021, 95: 68-83.
42	LEE H, LEE Y, KIM J, et al. Modulation of the gut microbiota by metformin improves metabolic profiles in aged obese mice[J]. Gut Microbes, 2018, 9(2): 155-165.
43	WANG X Y, SUN G Q, FENG T, et al. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer's disease progression[J]. Cell Res, 2019, 29(10): 787-803.
44	LI Y, WU M Y, KONG M M, et al. Impact of donepezil supplementation on Alzheimer's disease-like pathology and gut microbiome in APP/PS1 mice[J]. Microorganisms, 2023, 11(9): 2306.
45	JO J K, LEE G, NGUYEN C D, et al. Effects of donepezil treatment on brain metabolites, gut microbiota, and gut metabolites in an amyloid β-induced cognitive impairment mouse pilot model[J]. Molecules, 2022, 27(19): 6591.
46	闫斌. 兔仙合剂对糖尿病认知功能障碍大鼠的作用及机制初探[D]. 北京: 中国医学科学院, 2020.
	YAN B. Preliminary study on the effect and mechanism of Tu-Xian mixture on diabetic cognitive impairment in rats[D]. Beijing: Chinese Academy of Medical Sciences, 2020.
47	ZHENG Y F, ZHOU X, WANG C X, et al. Effect of dendrobium mixture in alleviating diabetic cognitive impairment associated with regulating gut microbiota[J]. Biomedecine Pharmacother, 2022, 149: 112891.
48	BI T T, FENG R Q, ZHAN L B, et al. ZiBuPiYin recipe prevented and treated cognitive decline in ZDF rats with diabetes-associated cognitive decline via microbiota-gut-brain axis dialogue[J]. Front Cell Dev Biol, 2021, 9: 651517.
49	SHI J W, YIN Q S, ZHANG L, et al. Zi Shen Wan Fang attenuates neuroinflammation and cognitive function via remodeling the gut microbiota in diabetes-induced cognitive impairment mice[J]. Front Pharmacol, 2022, 13: 898360.
50	ZHENG Y F, ZHOU X, WANG C X, et al. Effect of tanshinone ⅡA on gut microbiome in diabetes-induced cognitive impairment[J]. Front Pharmacol, 2022, 13: 890444.
51	HIGARZA S G, ARBOLEYA S, ARIAS J L, et al. Akkermansia muciniphila and environmental enrichment reverse cognitive impairment associated with high-fat high-cholesterol consumption in rats[J]. Gut Microbes, 2021, 13(1): 1-20.
52	ZHU G S, GUO M, ZHAO J X, et al. Bifidobacterium breve intervention combined with environmental enrichment alleviates cognitive impairment by regulating the gut microbiota and microbial metabolites in Alzheimer's disease mice[J]. Front Immunol, 2022, 13: 1013664.
53	KANG S S, JERALDO P R, KURTI A, et al. Diet and exercise orthogonally alter the gut microbiome and reveal independent associations with anxiety and cognition[J]. Mol Neurodegener, 2014, 9: 36.
54	MOHAMMADI M, ZARE Z. Effects of treadmill exercise on cognitive functions and anxiety-related behaviors in ovariectomized diabetic rats[J]. Physiol Behav, 2020, 224: 113021.

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肠道菌群在糖尿病认知功能障碍中的作用机制及靶向干预的研究进展

Research progress in mechanisms of gut microbiota in diabetic cognitive impairment and its targeted intervention

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