基于脑肠轴探究缺血性脑卒中与肠道菌群免疫的研究进展

doi:10.3969/j.issn.1674-490X.2024.01.002

摘要/Abstract

摘要： 人体肠道内定居着大量的微生物群,他们参与机体免疫稳态的调节,并与缺血性脑卒中的发生发展密切相关。脑肠轴的发现将肠道与大脑联系在一起,在人类的健康与疾病过程中发挥重要作用。现综述脑肠轴的调节机制、卒中后肠道菌群及其代谢物的调节以及基于脑肠轴对缺血性脑卒中后的大脑和肠道免疫反应的可能机制。这些研究为探索卒中后肠道和大脑免疫治疗的新方向和改善脑卒中预后提供了重要意义。

关键词: 缺血性脑卒中, 肠道菌群, 脑肠轴, 免疫

Abstract: It has been shown that the human gut is settled with a large microbiota, which is involved in the regulation of the body's immune homeostasis and is closely related to the development of ischaemic stroke. The discovery of the microbial-gut-brain axis links the gut to the brain and plays an important role in human health and disease processes. This paper reviews the regulatory mechanisms of the microbial-gut-brain axis, the modulation of gut flora and its metabolites after stroke, and the possible mechanisms of the brain-gut axis based on brain and gut immune responses after ischaemic stroke. These studies provide important implications for exploring new directions of gut and brain immunotherapy after stroke and improving stroke prognosis.

Key words: ischaemic stroke, gut flora, microbe-gut-brain axis, immunity

中图分类号:

徐玉洁,高娟,王井辉,任涵,王子文,耿硕. 基于脑肠轴探究缺血性脑卒中与肠道菌群免疫的研究进展[J]. 医学研究与教育, 2024, 41(1): 9-17.

参考文献

[1] GBD 2016 Stroke Collaborators. Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016[J]. Lancet Neurol, 2019, 18(5): 439-458. DOI: 10.1016/S1474-4422(19)30034-1.
[2] MA Q F, LI R, WANG L J, et al. Temporal trend and attributable risk factors of stroke burden in China, 1990-2019: an analysis for the Global Burden of Disease Study 2019[J]. Lancet Public Health, 2021, 6(12): e897-e906. DOI: 10.1016/S2468-2667(21)00228-0.
[3] HUANG Q, XIA J. Influence of the gut microbiome on inflammatory and immune response after stroke[J]. Neurol Sci, 2021, 42(12): 4937-4951. DOI: 10.1007/s10072-021-05603-6.
[4] ZHANG S X. Microglial activation after ischaemic stroke[J]. Stroke Vasc Neurol, 2019, 4(2): 71-74. DOI: 10.1136/svn-2018-000196.
[5] LEE J, D'AIGLE J, ATADJA L, et al. Gut microbiota-derived short-chain fatty acids promote poststroke recovery in aged mice[J]. Circ Res, 2020, 127(4): 453-465. DOI: 10.1161/CIRCRESAHA.119.316448.
[6] MOHAJERI M H, LA FATA G, STEINERT R E, et al. Relationship between the gut microbiome and brain function[J]. Nutr Rev, 2018, 76(7): 481-496. DOI: 10.1093/nutrit/nuy009.
[7] DURGAN D J, LEE J, MCCULLOUGH L D, et al. Examining the role of the microbiota-gut-brain axis in stroke[J]. Stroke, 2019, 50(8): 2270-2277. DOI: 10.1161/STROKEAHA.119.025140.
[8] SCHNEIDER C, OKUN J G, SCHWARZ K V, et al. Trimethylamine-N-oxide is elevated in the acute phase after ischaemic stroke and decreases within the first days[J]. Eur J Neurol, 2020, 27(8): 1596-1603. DOI: 10.1111/ene.14253.
[9] ZHANG H Y, HUANG Y Y, LI X J, et al. Dynamic process of secondary pulmonary infection in mice with intracerebral hemorrhage[J]. Front Immunol, 2021, 12: 767155. DOI: 10.3389/fimmu.2021.767155.
[10] FUNG T C, OLSON C A, HSIAO E Y. Interactions between the microbiota, immune and nervous systems in health and disease[J]. Nat Neurosci, 2017, 20(2): 145-155. DOI: 10.1038/nn.4476.
[11] HU W J, KONG X Y, WANG H, et al. Ischemic stroke and intestinal flora: an insight into brain-gut axis[J]. Eur J Med Res, 2022, 27(1): 73. DOI: 10.1186/s40001-022-00691-2.
[12] BONAZ B. Anti-inflammatory effects of vagal nerve stimulation with a special attention to intestinal barrier dysfunction[J]. Neurogastroenterol Motil, 2022, 34(10): e14456. DOI: 10.1111/nmo.14456.
[13] BONAZ B, SINNIGER V, PELLISSIER S. Therapeutic potential of vagus nerve stimulation for inflammatory bowel diseases[J]. Front Neurosci, 2021, 15: 650971. DOI: 10.3389/fnins.2021.650971.
[14] YE D Y, HU Y T, ZHU N, et al. Exploratory investigation of intestinal structure and function after stroke in mice[J]. Mediators Inflamm, 2021, 2021: 1315797. DOI: 10.1155/2021/1315797.
[15] WEERTH C D. Do bacteria shape our development? Crosstalk between intestinal microbiota and HPA axis[J]. Neurosci Biobehav Rev, 2017, 83: 458-471. DOI: 10.1016/j.neubiorev.2017.09.016.
[16] TURNBULL A V, RIVIER C L. Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action[J]. Physiol Rev, 1999, 79(1): 1-71. DOI: 10.1152/physrev.1999.79.1.1.
[17] STRANDWITZ P, KIM K H, TEREKHOVA D, et al. GABA-modulating bacteria of the human gut microbiota[J]. Nat Microbiol 2019, 4(3): 396-403. DOI: 0.1038/s41564-018-0307-3
[18] SIVAPRAKASAM S, PRASAD P D, SINGH N. Benefits of short-chain fatty acids and their receptors in inflammation and carcinogenesis[J]. Pharmacol Ther, 2016, 164: 144-151. DOI: 10.1016/j.pharmthera.2016.04.007.
[19] HAASE S, HAGHIKIA A, WILCK N, et al. Impacts of microbiome metabolites on immune regulation and autoimmunity[J]. Immunology, 2018, 154(2): 230-238. DOI: 10.1111/imm.12933.
[20] SADLER R, CRAMER J V, HEINDL S, et al. Short-chain fatty acids improve poststroke recovery via immunological mechanisms[J]. J Neurosci, 2020, 40(5): 1162-1173. DOI: 10.1523/JNEUROSCI.1359-19.2019.
[21] QIU L, TAO X Y, XIONG H, et al. Lactobacillus plantarum ZDY04 exhibits a strain-specific property of lowering TMAO via the modulation of gut microbiota in mice[J]. Food Funct, 2018, 9(8): 4299-4309. DOI: 10.1039/c8fo00349a.
[22] FEDOTCHEVA N, OLENIN A, BELOBORODOVA N. Influence of microbial metabolites on the nonspecific permeability of mitochondrial membranes under conditions of acidosis and loading with calcium and iron ions[J]. Biomedicines, 2021, 9(5): 558. DOI: 10.3390/biomedicines9050558.
[23] DIN A U, HASSAN A, ZHU Y, et al. Amelioration of TMAO through probiotics and its potential role in atherosclerosis[J]. Appl Microbiol Biotechnol, 2019, 103(23/24): 9217-9228. DOI: 10.1007/s00253-019-10142-4.
[24] BOINI K M, HUSSAIN T, LI P L, et al. Trimethylamine-N-oxide instigates NLRP3 inflammasome activation and endothelial dysfunction[J]. Cell Physiol Biochem, 2017, 44(1): 152-162. DOI: 10.1159/000484623.
[25] ROAGER H M, LICHT T R. Microbial tryptophan catabolites in health and disease[J]. Nat Commun, 2018, 9: 3294. DOI: 10.1038/s41467-018-05470-4.
[26] WLODARSKA M, LUO C W, KOLDE R, et al. Indoleacrylic acid produced by commensal Peptostreptococcus species suppresses inflammation[J]. Cell Host Microbe, 2017, 22(1): 25-37. DOI: 10.1016/j.chom.2017.06.007.
[27] ARYA A K, HU B R. Brain-gut axis after stroke[J]. Brain Circ, 2018, 4(4): 165-173. DOI: 10.4103/bc.bc_32_18.
[28] BANKS W A, GRAY A M, ERICKSON M A, et al. Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit[J]. J Neuroinflammation, 2015, 12: 223. DOI: 10.1186/s12974-015-0434-1.
[29] HOYLES L, SNELLING T, UMLAI U K, et al. Microbiome-host systems interactions: protective effects of propionate upon the blood-brain barrier[J]. Microbiome, 2018, 6(1): 55. DOI: 10.1186/s40168-018-0439-y.
[30] TANG A T, CHOI J P, KOTZIN J J, et al. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations[J]. Nature, 2017, 545(7654): 305-310. DOI: 10.1038/nature22075.
[31] LI N, WANG X C, SUN C C, et al. Change of intestinal microbiota in cerebral ischemic stroke patients[J]. BMC Microbiol, 2019, 19(1): 191. DOI: 10.1186/s12866-019-1552-1.
[32] STANLEY D, MASON L J, MACKIN K E, et al. Translocation and dissemination of commensal bacteria in post-stroke infection[J]. Nat Med, 2016, 22(11): 1277-1284. DOI: 10.1038/nm.4194.
[33] SINGH V, SADLER R, HEINDL S, et al. The gut microbiome primes a cerebroprotective immune response after stroke[J]. J Cereb Blood Flow Metab, 2018, 38(8): 1293-1298. DOI: 10.1177/0271678X18780130.
[34] KLEGERIS A. Regulation of neuroimmune processes by damage- and resolution-associated molecular patterns[J]. Neural Regen Res, 2021, 16(3): 423-429. DOI: 10.4103/1673-5374.293134.
[35] RUHNAU J, SCHULZE J, DRESSEL A, et al. Thrombosis, neuroinflammation, and poststroke infection: the multifaceted role of neutrophils in stroke[J]. J Immunol Res, 2017, 2017: 5140679. DOI: 10.1155/2017/5140679.
[36] ZHOU K C, WU J Y, CHEN J, et al. Schaftoside ameliorates oxygen glucose deprivation-induced inflammation associated with the TLR4/Myd88/Drp1-related mitochondrial fission in BV2 microglia cells[J]. J Pharmacol Sci,2019, 139(1):15-22. DOI: 10.1016/j.jphs.2018.10.012.
[37] XIONG X Y, LIU L, YANG Q W. Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke[J]. Prog Neurobiol, 2016, 142: 23-44. DOI: 10.1016/j.pneurobio.2016.05.001.
[38] KRZYSZCZYK P, KANG H J, KUMAR S, et al. Anti-inflammatory effects of haptoglobin on LPS-stimulated macrophages: role of HMGB1 signaling and implications in chronic wound healing[J]. Wound Repair Regen, 2020, 28(4): 493-505. DOI: 10.1111/wrr.12814.
[39] SHEN X Y, GAO Z K, HAN Y, et al. Activation and role of astrocytes in ischemic stroke[J].Front Cell Neurosci, 2021, 15: 755955. DOI: 10.3389/fncel.2021.755955.
[40] BENAKIS C, BREA D, CABALLERO S, et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells[J]. Nat Med, 2016, 22(5): 516-523. DOI: 10.1038/nm.4068.
[41] ZHANG D H, REN J X, LUO Y, et al. T cell response in ischemic stroke: from mechanisms to translational insights[J]. Front Immunol, 2021, 12: 707972. DOI: 10.3389/fimmu.2021.707972.
[42] HALWANI R, SULTANA A, VAZQUEZ-TELLO A, et al. Th-17 regulatory cytokines IL-21, IL-23, and IL-6 enhance neutrophil production of IL-17 cytokines during asthma[J]. J Asthma, 2017, 54(9): 893-904. DOI: 10.1080/02770903.2017.1283696.
[43] WU Y J, LI J X, SHOU J Y, et al. Diverse functions and mechanisms of regulatory T cell in ischemic stroke[J]. Exp Neurol, 2021, 343: 113782. DOI: 10.1016/j.expneurol.2021.113782.
[44] ITO M, KOMAI K, MISE-OMATA S, et al. Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery[J]. Nature, 2019, 565(7738): 246-250. DOI: 10.1038/s41586-018-0824-5.
[45] MALONE K, AMU S, MOORE A C, et al. The immune system and stroke: from current targets to future therapy[J]. Immunol Cell Biol, 2019, 97(1): 5-16. DOI: 10.1111/imcb.12191.
[46] DOYLE K P, QUACH L N, SOLÉ M, et al. B-lymphocyte-mediated delayed cognitive impairment following stroke[J]. J Neurosci, 2015, 35(5): 2133-2145. DOI: 10.1523/JNEUROSCI.4098-14.2015.
[47] SHICHITA T, SUGIYAMA Y, OOBOSHI H, et al. Pivotal role of cerebral interleukin-17-producing gammadelta T cells in the delayed phase of ischemic brain injury[J]. Nat Med, 2009, 15(8): 946-950. DOI: 10.1038/nm.1999.