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01-12-2021 | Stroke | Review Article

Influence of the gut microbiome on inflammatory and immune response after stroke

Authors: Qin Huang, Jian Xia

Published in: Neurological Sciences | Issue 12/2021

Abstract

Researches on the bidirectional communications between the gut microbiota and brain, termed the gut-brain axis, often bring about discoveries and drive the development of medicine and biology for stroke. Following stroke, the gut-brain axis is perturbed significantly on dysbiotic gut microbiome, intestinal dysfunction, enteric nervous system, increased gut permeability, and activated immune cells in the gut, which in turn results in infiltration of pro-inflammatory cells or bacterial toxins into brain tissue through impaired blood–brain barrier (BBB), finally exacerbated brain infarction. Herein, we illuminate the changes in the immune system and highlight the possible mechanisms of the gut microbiota to regulate inflammatory and immune processes in the context of stroke. We conducted a systematic literatures search in PubMed, Web of Science, Embase, and guideline-specific databases until May 2021 using the following key terms: gut microbiota, stroke, immune, and inflammation.

Liesz A et al (2009) Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 15(2):192–199PubMedCrossRef

Shichita T et al (2009) Pivotal role of cerebral interleukin-17-producing gammadelta T cells in the delayed phase of ischemic brain injury. Nat Med 15(8):946–950PubMedCrossRef

Osadchiy V, Martin CR, Mayer EA (2019) The gut-brain axis and the microbiome: mechanisms and clinical implications. Clin Gastroenterol Hepatol 17(2):322–332PubMedCrossRef

Crapser J et al (2016) Ischemic stroke induces gut permeability and enhances bacterial translocation leading to sepsis in aged mice. Aging-Us 8(5):1049–1063CrossRef

Chen R et al (2019) Puerariae Lobatae Radix with Chuanxiong Rhizoma for treatment of cerebral ischemic stroke by remodeling gut microbiota to regulate the brain–gut barriers. J Nutr Biochem 65:101–114PubMedCrossRef

Chen R et al (2019) Transplantation of fecal microbiota rich in short chain fatty acids and butyric acid treat cerebral ischemic stroke by regulating gut microbiota. Pharmacol Res 148:104403–104403PubMedCrossRef

Yin J, et al (2015) Dysbiosis of gut microbiota with reduced trimethylamine-N-oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack. J Am Heart Assoc 4(11):e002699

Singh V et al (2016) Microbiota dysbiosis controls the neuroinflammatory response after stroke. J Neurosci 36(28):7428–7440PubMedPubMedCentralCrossRef

Yamashiro K et al (2017) Gut dysbiosis is associated with metabolism and systemic inflammation in patients with ischemic stroke. PLoS One 12(2):e0171521PubMedPubMedCentralCrossRef

10.

Spychala MS et al (2018) Age-related changes in the gut microbiota influence systemic inflammation and stroke outcome. Ann Neurol 84(1):23–36PubMedPubMedCentralCrossRef

11.

Wang W et al (2018) The characteristics analysis of intestinal microecology on cerebral infarction patients and its correlation with apolipoprotein E. Medicine (Baltimore) 97(41):e12805CrossRef

12.

Winek K et al (2016) Depletion of cultivatable gut microbiota by broad-spectrum antibiotic pretreatment worsens outcome after murine stroke. Stroke 47(5):1354–1363PubMedPubMedCentralCrossRef

13.

Benakis C et al (2016) Commensal microbiota affects ischemic stroke outcome by regulating intestinal gamma delta T cells. Nat Med 22(5):516–523PubMedPubMedCentralCrossRef

14.

Singh V et al (2018) The gut microbiome primes a cerebroprotective immune response after stroke. J Cereb Blood Flow Metab 38(8):1293–1298PubMedPubMedCentralCrossRef

15.

Chamorro A et al (2012) The immunology of acute stroke. Nat Rev Neurol 8(7):401–410PubMedCrossRef

16.

Lee J, et al. (2020) Gut microbiota-derived short-chain fatty acids promote post-stroke recovery in aged mice. Circ Res 127(4):453–465

17.

Zhang P et al (2021) Atorvastatin alleviates microglia-mediated neuroinflammation via modulating the microbial composition and the intestinal barrier function in ischemic stroke mice. Free Radic Biol Med 162:104–117PubMedCrossRef

18.

Benakis C et al (2020) Distinct commensal bacterial signature in the gut is associated with acute and long-term protection from ischemic stroke. Stroke 51(6):1844–1854PubMedPubMedCentralCrossRef

19.

Zeng X, et al (2019) Higher risk of stroke is correlated with increased opportunistic pathogen load and reduced levels of butyrate-producing bacteria in the gut. Front Cell Infect Microbiol 9:4

20.

Haak BW, et al (2020) Disruptions of anaerobic gut bacteria are associated with stroke and post-stroke infection: a prospective case-control study. Transl Stroke Res 12(4):581–592

21.

Wang H-X, Wang Y-P (2016) Gut microbiota-brain axis. Chin Med J 129(19):2373–2380PubMedPubMedCentralCrossRef

22.

Ji W et al (2017) Analysis of intestinal microbial communities of cerebral infarction and ischemia patients based on high throughput sequencing technology and glucose and lipid metabolism. Mol Med Rep 16(4):5413–5417PubMedPubMedCentralCrossRef

23.

Huang L, et al. (2019) Analysis of microbiota in elderly patients with acute cerebral infarction. PeerJ 7:e6928

24.

Li N, et al (2019) Change of intestinal microbiota in cerebral ischemic stroke patients. BMC Microbiol 19(1):191

25.

Fan W-T et al (2016) Diversity of intestinal microflora in patients with depression after stroke. Nan Fang Yi Ke Da Xue Xue Bao 36(10):1305–1311PubMed

26.

Stanley D et al (2016) Translocation and dissemination of commensal bacteria in post-stroke infection. Nat Med 22(11):1277–1284PubMedCrossRef

27.

Nan Y, et al. (2019) Diversity analysis of intestinal flora in patients with ischemic stroke at different stages. Chongqing Medicine 1671–8348

28.

Caso JR et al (2009) Colonic bacterial translocation as a possible factor in stress-worsening experimental stroke outcome. Am J Physiol Regul Integr Comp Physiol 296(4):R979–R985PubMedCrossRef

29.

Jeon J, et al (2020) Dynamic changes in the gut microbiome at the acute stage of ischemic stroke in a pig model. Front Neurosci 14: 587986

30.

Chen Y et al (2019) Persistence of gut microbiota dysbiosis and chronic systemic inflammation after cerebral infarction in cynomolgus monkeys. Front Neurol 10:661PubMedPubMedCentralCrossRef

31.

Xu K, et al (2021) Rapid gut dysbiosis induced by stroke exacerbates brain infarction in turn. Gut

32.

Cai W, et al (2021) Gut microbiota from patients with arteriosclerotic CSVD induces higher IL-17A production in neutrophils via activating ROR gamma t. Sci Adv 7(4)

33.

Matsuura J et al (2019) Analysis of gut microbiota in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Journal of Clinical Biochemistry and Nutrition 65(3):240–244PubMedPubMedCentralCrossRef

34.

Ling Y et al (2020) Structural change of gut microbiota in patients with post-stroke comorbid cognitive impairment and depression and Its correlation with clinical features. J Alzheimers Dis 77(4):1595–1608PubMedCrossRef

35.

Xu R et al (2019) Dysbiosis of the intestinal microbiota in neurocritically ill patients and the risk for death. Crit Care 23(1):195PubMedPubMedCentralCrossRef

36.

Sadler R et al (2017) Microbiota differences between commercial breeders impacts the post-stroke immune response. Brain Behav Immun 66:23–30PubMedCrossRef

37.

Sadler R et al (2019) Short-chain fatty acids improve post-stroke recovery via immunological mechanisms. J Neurosci 40(5):1162–1173

38.

Houlden A et al (2016) Brain injury induces specific changes in the caecal microbiota of mice via altered autonomic activity and mucoprotein production. Brain Behav Immun 57:10–20PubMedPubMedCentralCrossRef

39.

Winek K, Meisel A, Dirnagl U (2016) Gut microbiota impact on stroke outcome: fad or fact? J Cereb Blood Flow Metab 36(5):891–898PubMedPubMedCentralCrossRef

40.

Groschwitz KR, Hogan SP (2009) Intestinal barrier function: molecular regulation and disease pathogenesis. J Allergy Clin Immunol 124(1):3–22

41.

Erny D et al (2015) Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 18(7):965–977PubMedPubMedCentralCrossRef

42.

Stanley D, Moore RJ, Wong CHY (2018) An insight into intestinal mucosal microbiota disruption after stroke. Sci Rep 8(1):568PubMedPubMedCentralCrossRef

43.

Zhang F et al (2020) Protective effect of Tong-Qiao-Huo-Xue decoction on inflammatory injury caused by intestinal microbial disorders in stroke rats. Biol Pharm Bull 43(5):788–800PubMedCrossRef

44.

Vinolo MA et al (2009) Short-chain fatty acids stimulate the migration of neutrophils to inflammatory sites. Clin Sci (Lond) 117(9):331–338CrossRef

45.

Zhang D et al (2015) Neutrophil ageing is regulated by the microbiome. Nature 525(7570):528–532PubMedPubMedCentralCrossRef

46.

Clarke TB et al (2010) Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat Med 16(2):228-U137PubMedPubMedCentralCrossRef

47.

Brandsma E et al (2019) A proinflammatory gut microbiota increases systemic inflammation and accelerates atherosclerosis. Circ Res 124(1):94–100PubMedCrossRef

48.

Goncalves P, Araujo JR, Di Santo JP (2018) A cross-talk between microbiota-derived short-chain fatty acids and the host mucosal immune system regulates intestinal homeostasis and inflammatory bowel disease. Inflamm Bowel Dis 24(3):558–572PubMedCrossRef

49.

Saemann MD et al (2000) Anti-inflammatory effects of sodium butyrate on human monocytes: potent inhibition of IL-12 and up-regulation of IL-10 production. FASEB J 14(15):2380–2382PubMedCrossRef

50.

Millard AL et al (2002) Butyrate affects differentiation, maturation and function of human monocyte-derived dendritic cells and macrophages. Clin Exp Immunol 130(2):245–255PubMedPubMedCentralCrossRef

51.

Martinez FO et al (2008) Macrophage activation and polarization. Frontiers in Bioscience-Landmark 13:453–461CrossRef

52.

Haghikia A et al (2018) Gut microbiota-dependent trimethylamine N-oxide predicts risk of cardiovascular events in patients with stroke and is related to proinflammatory monocytes. Arterioscler Thromb Vasc Biol 38(9):2225–2235PubMedPubMedCentralCrossRef

53.

Sun J et al (2016) Clostridium butyricum pretreatment attenuates cerebral ischemia/reperfusion injury in mice via anti-oxidation and anti-apoptosis. Neurosci Lett 613:30–35PubMedCrossRef

54.

Sun J et al (2016) Clostridium butyricum attenuates cerebral ischemia/reperfusion injury in diabetic mice via modulation of gut microbiota. Brain Res 1642:180–188PubMedCrossRef

55.

Sun J et al (2015) Neuroprotective effect of sodium butyrate against cerebral ischemia/reperfusion injury in mice. Biomed Res Int 2015:395895PubMedPubMedCentralCrossRef

56.

Zhou Z, et al (2020) Sodium butyrate attenuated neuronal apoptosis via GPR41/Gbetagamma/PI3K/Akt pathway after MCAO in rats. J Cereb Blood Flow Metab 41(2):267–281

57.

Peng J et al (2018) Interaction between gut microbiome and cardiovascular disease. Life Sci 214:153–157PubMedCrossRef

58.

Tang WH et al (2013) Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 368(17):1575–1584PubMedPubMedCentralCrossRef

59.

Tan C et al (2020) Dynamic changes and prognostic value of gut microbiota-dependent trimethylamine-N-oxide in acute ischemic stroke. Front Neurol 11:29PubMedPubMedCentralCrossRef

60.

Wu C et al (2018) Elevated trimethylamine N-oxide related to ischemic brain lesions after carotid artery stenting. Neurology 90(15):E128–E1290CrossRef

61.

Tilg H (2016) A gut feeling about thrombosis. N Engl J Med 374(25):2494–2496PubMedCrossRef

62.

Wang Z et al (2015) Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163(7):1585–1595PubMedPubMedCentralCrossRef

63.

Miao J et al (2015) Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis. Nat Commun 6:6498PubMedCrossRef

64.

Guo Y et al (2016) Dose-response effect of berberine on bile acid profile and gut microbiota in mice. BMC Complement Altern Med 16(1):394PubMedPubMedCentralCrossRef

65.

Pathak P et al (2018) Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology 68(4):1574–1588PubMedCrossRef

66.

Fiorucci S et al (2010) Bile acid-activated receptors in the treatment of dyslipidemia and related disorders. Prog Lipid Res 49(2):171–185PubMedCrossRef

67.

Velagapudi VR et al (2010) The gut microbiota modulates host energy and lipid metabolism in mice. J Lipid Res 51(5):1101–1112PubMedPubMedCentralCrossRef

68.

Chevre R, Silvestre-Roig C, Soehnlein O (2018) Nutritional modulation of innate immunity: the fat-bile-gut connection. Trends Endocrinol Metab 29(10):686–698PubMedCrossRef

69.

Guo C et al (2016) Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity 45(4):802–816PubMedCrossRef

70.

Alishahi M, et al (2019) NLRP3 inflammasome in ischemic stroke: as possible therapeutic target. Int J Stroke 14(6):574–591

71.

Rothhammer V, et al (2016) Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med. 22(6): p. 586-+

72.

Cason CA, et al (2018) Plasma microbiome-modulated indole- and phenyl-derived metabolites associate with advanced atherosclerosis and postoperative outcomes. J Vasc Surg 68(5): 1552-+

73.

Natividad JM et al (2018) Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome. Cell Metab 28(5):737-749.e4PubMedCrossRef

74.

Darlington LG et al (2007) Altered kynurenine metabolism correlates with infarct volume in stroke. Eur J Neurosci 26(8):2211–2221PubMedCrossRef

75.

Veldhoen M et al (2008) The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453(7191):106–109PubMedCrossRef

76.

Marsh BJ, Williams-Karnesky RL, Stenzel-Poore MP (2009) Toll-like receptor signaling in endogenous neuroprotection and stroke. Neuroscience 158(3):1007–1020PubMedCrossRef

77.

Singh V et al (2016) HMGB1 as a key mediator of immune mechanisms in ischemic stroke. Antioxid Redox Signal 24(12):635–651PubMedCrossRef

78.

McCusker RH, Kelley KW (2012) Immune-neural connections: how the immune system’s response to infectious agents influences behavior. J Exp Biol 216(1):84–98CrossRef

79.

Park MJ, et al (2019) Reproductive senescence and ischemic stroke remodel the gut microbiome and modulate the effects of estrogen treatment in female rats. Transl Stroke Res 11(4):812–830

80.

Carnevale R et al (2018) Localization of lipopolysaccharide from Escherichia coli into human atherosclerotic plaque. Sci Rep 8(1):3598PubMedPubMedCentralCrossRef

81.

Mayerhofer R et al (2017) Diverse action of lipoteichoic acid and lipopolysaccharide on neuroinflammation, blood-brain barrier disruption, and anxiety in mice. Brain Behav Immun 60:174–187PubMedCrossRef

82.

Nemet I et al (2020) A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell 180(5):862.e22-877.e22CrossRef

83.

Meng Y, et al (2019) Effects of different diets on microbiota in the small intestine mucus and weight regulation in rats. Sci Rep 9(1):8500

84.

Wilck N et al (2017) Salt-responsive gut commensal modulates TH17 axis and disease. Nature 551(7682):585–589PubMedPubMedCentralCrossRef

85.

Faraco G et al (2018) Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response. Nat Neurosci 21(2):240–249PubMedPubMedCentralCrossRef

86.

Matt SM et al (2018) Butyrate and dietary soluble fiber improve neuroinflammation associated with aging in mice. Front Immunol 9:1832PubMedPubMedCentralCrossRef

87.

Zmora N, Suez J, Elinav E (2019) You are what you eat: diet, health and the gut microbiota. Nat Rev Gastroenterol Hepatol 16(1):35–56PubMedCrossRef

88.

Allen JM et al (2018) Exercise training-induced modification of the gut microbiota persists after microbiota colonization and attenuates the response to chemically-induced colitis in gnotobiotic mice. Gut Microbes 9(2):115–130PubMedCrossRef

89.

Allen JM et al (2018) Exercise alters gut microbiota composition and function in lean and obese humans. Med Sci Sports Exerc 50(4):747–757PubMedCrossRef

90.

Chen J et al (2018) Physical exercise, gut, gut microbiota, and atherosclerotic cardiovascular diseases. Lipids Health Dis 17(1):17PubMedPubMedCentralCrossRef

91.

Cerda B et al (2016) Gut microbiota modification: another piece in the puzzle of the benefits of physical exercise in health? Front Physiol 7:51PubMedPubMedCentralCrossRef

92.

Stanford KI et al (2017) Maternal exercise improves glucose tolerance in female offspring. Diabetes 66(8):2124–2136PubMedPubMedCentralCrossRef

93.

Stanford KI et al (2018) Paternal exercise improves glucose metabolism in adult offspring. Diabetes 67(12):2530–2540PubMedPubMedCentralCrossRef

94.

Scheiman J et al (2019) Meta-omics analysis of elite athletes identifies a performance-enhancing microbe that functions via lactate metabolism. Nat Med 25(7):1104–1109PubMedPubMedCentralCrossRef

95.

Sanders ME (2008) Probiotics: definition, sources, selection, and uses. Clin Infect Dis 46 Suppl 2: p. S58–61; discussion S144–51

96.

Smits HH et al (2005) Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin. J Allergy Clin Immunol 115(6):1260–1267PubMedCrossRef

97.

Rezazadeh L et al (2019) Effects of probiotic yogurt on glycemic indexes and endothelial dysfunction markers in patients with metabolic syndrome. Nutrition 62:162–168PubMedCrossRef

98.

Sabico S et al (2019) Effects of a 6-month multi-strain probiotics supplementation in endotoxemic, inflammatory and cardiometabolic status of T2DM patients: a randomized, double-blind, placebo-controlled trial. Clinical nutrition (Edinburgh, Scotland) 38(4):1561–1569CrossRef

99.

Zeng W et al (2019) Cutting edge: probiotics and fecal microbiota transplantation in immunomodulation. J Immunol Res 2019:1603758PubMedPubMedCentralCrossRef

100.

Villena J, Kitazawa H (2017) Editorial: immunobiotics-interactions of beneficial microbes with the immune system. Front Immunol 8:1580PubMedPubMedCentralCrossRef

101.

Gibson GR et al (2007) Dietary modulation of the human colonic microbiota: updating the concept of prebiotics. Nutr Res Rev 17(2):259–275CrossRef

102.

Cheng YC et al (2017) Polyphenols and oxidative stress in atherosclerosis-related ischemic heart disease and stroke. Oxid Med Cell Longev 2017:8526438PubMedPubMedCentralCrossRef

103.

McLoughlin RF et al (2017) Short-chain fatty acids, prebiotics, synbiotics, and systemic inflammation: a systematic review and meta-analysis. Am J Clin Nutr 106(3):930–945PubMed

104.

Zhang JC et al (2017) Delayed treatment with green tea polyphenol EGCG promotes neurogenesis after ischemic stroke in adult mice. Mol Neurobiol 54(5):3652–3664PubMedCrossRef

105.

Dou Z et al (2019) Neuroprotection of resveratrol against focal cerebral ischemia/reperfusion injury in mice through a mechanism targeting gut-brain axis. Cell Mol Neurobiol 39(6):883–898PubMedCrossRef

106.

Liu Y et al (2020) The association of post-stroke cognitive impairment and gut microbiota and its corresponding metabolites. J Alzheimers Dis 73(4):1455–1466PubMedCrossRef

107.

Wong AC, Levy M (2019) New approaches to microbiome-based therapies. mSystems 4(3):e00122-19

108.

Lange K et al (2016) Effects of antibiotics on gut microbiota. Dig Dis 34(3):260–268PubMedCrossRef

109.

Westendorp WF, et al (2011) Post-stroke infection: a systematic review and meta-analysis. Bmc Neurol 11:110

110.

Westendorp WF et al (2015) The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial. Lancet 385(9977):1519–1526PubMedCrossRef

111.

Gupta A, Khanna S (2017) Fecal microbiota transplantation. JAMA 318(1):102–102PubMedCrossRef

112.

Burrello C et al (2018) Therapeutic faecal microbiota transplantation controls intestinal inflammation through IL10 secretion by immune cells. Nat Commun 9(1):5184PubMedPubMedCentralCrossRef

113.

Ekmekciu I et al (2017) Immune responses to broad-spectrum antibiotic treatment and fecal microbiota transplantation in mice. Front Immunol 8:397PubMedPubMedCentralCrossRef

114.

Winek K, Dirnagl U, Meisel A (2016) The gut microbiome as therapeutic target in central nervous system diseases: implications for stroke. Neurotherapeutics 13(4):762–774PubMedPubMedCentralCrossRef

Title: Influence of the gut microbiome on inflammatory and immune response after stroke
Authors: Qin Huang
Jian Xia
Publication date: 01-12-2021
Publisher: Springer International Publishing
Keywords: Stroke
Respiratory Microbiota
Published in: Neurological Sciences / Issue 12/2021
Print ISSN: 1590-1874
Electronic ISSN: 1590-3478
DOI: https://doi.org/10.1007/s10072-021-05603-6

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Influence of the gut microbiome on inflammatory and immune response after stroke

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