以肠道菌群为靶点的耐药性癫痫的联合抗癫痫治疗策略_Journal of Epilepsy

Authors：

翟锦霞 ,  陈勇军

南华大学衡阳医学院附属南华医院神经内科（衡阳 421001）;

Corresponding author：

陈勇军, Email: 2212680954@qq.com

Keywords：

微生物组; 癫痫; 肠道微生物-脑轴; 肠道菌群

DOI：

10.7507/2096-0247.202112011

Video：

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Abstract Full text Figures/Tables Video References Cited by

肠道微生物区系和微生物群在维持体内平衡和几乎所有身体系统中都发挥重要作用。肠道菌群通过化学信号、免疫途径、神经途径等对神经发生过程及神经元兴奋通路产生影响，从而调节中枢神经系统已有各项临床及临床前研究证实肠道菌群对癫痫的预后有改善。联合肠道微生物组治疗耐药性癫痫具有很好的前景，然而其抗癫痫的潜在机制尚不清楚，本文综述了脑肠轴、肠道菌群在疾病治疗及预后的应用上的最新进展，探讨了以肠道菌群为靶点的抗癫痫的作用机制。

Citation： 翟锦霞, 陈勇军. 以肠道菌群为靶点的耐药性癫痫的联合抗癫痫治疗策略. Journal of Epilepsy, 2022, 8(3): 264-272. doi: 10.7507/2096-0247.202112011 Copy

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3. Caballero L, Silvia GM, Sita T, et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal gamma delta T cells. Nature medicine, 2016, 22(5): 516-523.
4. Viaud S, Saccheri F, Mignot G, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science, 2013, 342(6161): 971-976.
5. Cotter PD, Hill C, Ross RP. Bacteriocins: developing innate immunity for food. Nat Rev Microbiol, 2005, 3(10): 777-788.
6. Hsiao EY, McBride SW, Hsien S, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell, 2013, 155(7): 1451-1463.
7. Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science, 2015, 350(6264): 1084-1089.
8. Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science, 2015, 350(6264): 1079-1084.
9. Konishi H, Fujiya M, Tanaka H, et al. Probioticderived ferrichrome inhibits colon cancer progression via JNK-mediated apoptosis. Nat Commun, 2016, 7: 1-5.
10. Chen Z, Guo L, Zhang Y, et al. Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity. J Clin Invest, 2014, 124(8): 3391-3406.
11. Duan F, Curtis KL, March JC. Secretion of insulinotropic proteins by commensal bacteria: rewiring the gut to treat diabetes. Appl Environ Microbiol, 2008, 74(23): 7437-7438.
12. Duan FF, Liu JH, March JC. Engineered commensal bacteria reprogram intestinal cells into glucose-responsive insulin-secreting cells for the treatment of diabetes. Diabetes, 2015, 64(5): 1794-1803.
13. Liu C, Cheung W-H, Li J, et al. Understanding the gut microbiota and sarcopenia: A systematic review. Journal of Cachexia, Sarcopenia and Muscle, 2021, 12(6): 1393-1407.
14. Arun K B, Madhavan A, Sindhu R, et al. Probiotics and gut microbiome - prospects and challenges in remediating heavy metal toxicity. J Hazard Mater, 2021, 420: 126676.
15. Han H, Yi B, Zhong R, et al. From gut microbiota to host appetite: Gut microbiota-derived metabolites as key regulators. Microbiome, 2021, 9(1): 162.
16. Claesson MJ, Jeffery IB, Conde S, et al. Gut microbiota composition correlates with diet and health in the elderly. Nature, 2012, 488(7410): 178-184.
17. Chung Y C, Jin H M, Cui Y, et al. Fermented milk of Lactobacillus helveticus IDCC3801 improves cognitive functioning during cognitive fatigue tests in healthy older adults. Journal of Functional Foods, 2014, 10: 465-474.
18. Berer K, Gerdes LA, Cekanaviciute E, et al. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proceedings of the National Academy of Sciences of the United States of America, 2017, 114(40): 10719-10724.
19. Mazmanian SK, Liu CH, Tzianabos AO, et al. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell, 2005, 122(1): 107-118.
20. Berer K, Mues M, Koutrolos M, et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature, 2011, 479(7374): 538.
21. Stokes JM, Davis JH, Mangat CS, et al. Discovery of a small molecule that inhibits bacterial ribosome biogenesis. Elife, 2014, 3: e03574.
22. Humann J, Mann B, Gao G, et al. Bacterial peptidoglycan traverses the placenta to induce fetal neuroproliferation and aberrant postnatal behavior. Cell Host & Microbe, 2016, 19(6): 901.
23. Hoban A, Stilling R, Desbonnet L, et al. Regulation of prefrontal cortex myelination by the microbiota. Transl Psychiatry, 2016, 6(4): e774.
24. Geuking M, Ca Henzli J, Lawson M E, et al. Intestinal bacterial colonization induces mutualistic regulatory t cell responses. Immunity, 2011, 34(6): 794-806.
25. Xie G, Zhou Q, Qiu CZ, et al. Ketogenic diet poses a significant effect on imbalanced gut microbiota in infants with refractory epilepsy. World Journal of Gastroenterology, 2017, 23(33): 6164-6171.
26. Holmes M, Flaminio Z, Vardhan M, et al. Cross talk between drug‐resistant epilepsy and the gut microbiome. Epilepsia, 2020, 61(12): 2619-2628.
27. Round JL, Lee SM, Li J, et al. The toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science, 2011, 332(6032): 974-977.
28. Wu J, Zhang Y, Yang H, et al. Intestinal microbiota as an alternative therapeutic target for epilepsy. Can J Infect Dis Med Microbiol, 2016, 21: 1-6.
29. Bravo JA, Forsythe P, Chew MV, et al. Ingestion of lactobacillus strain regulates emotional behavior and central gaba receptor expression in a mouse via the vagus nerve. Proceedings of the National Academy of Sciences of the United States of America, 2011, 108(38): 16050-16055.
30. Morais LH, Schreiber HL, Mazmanian SK. The gut microbiota-brain axis in behaviour and brain disorders. Nat Rev Microbiol, 2021, 19(4): 241-255.
31. Ivanov, Ii, Atarashi K, Manel N, et al. Induction of intestinal th17 cells by segmented filamentous bacteria. Cell, 2009, 139(3): 485-498.
32. De Caro C, Iannone L F, Citraro R, et al. Can we 'seize' the gut microbiota to treat epilepsy? Neurosci Biobehav Rev, 2019. 107: 750-764.
33. Braniste V, Al-Asmakh M, Kowal C, et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med, 2014, 6(263): 263ra158.
34. Van De Wouw M, Boehme M, Lyte JM, et al. Short-chain fatty acids: Microbial metabolites that alleviate stress-induced brain-gut axis alterations. J Physiol, 2018, 596(20): 4923-4944.
35. Schroeder BO, Bckhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nature Medicine, 2016, 22(10): 1079.
36. Belkaid Y , Hand T, Role of the microbiota in immunity and inflammation. Cell, 2014, 157(1): 121-141.
37. Smith K, Mccoy KD, Macpherson AJ. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Seminars in Immunology, 2007, 19(2): 59-69.
38. Sharon G, Sampson T, Geschwind D, et al. The central nervous system and the gut microbiome. Cell, 2016, 167(4): 915-932.
39. Borghi E, Vignoli A. Rett syndrome and other neurodevelopmental disorders share common changes in gut microbial community: a descriptive review. International Journal of Molecular Sciences, 2019, 20(17): 4160.
40. Tremlett H, Fadrosh DW, Faruqi AA, et al. Gut microbiota in early pediatric multiple sclerosis: A case-control study. European Journal of Neurology, 2016, 23(8): 1308-1321.
41. Kang DW, Adams JB, Gregory AC, et al. Microbiota transfer therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome, 2017, 5(1): 10.
42. Forsyth C, Shannon K M, Kordower J H, et al. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early parkinson's disease. Plos One, 2011, 6(12): e28032.
43. Hilton D, Stephens M, Kirk L, et al. Accumulation of α-synuclein in the bowel of patients in the pre-clinical phase of parkinson's disease. Acta Neuropathologica, 2014, 127(2): 235-241.
44. Cattaneo A, Cattane N, Galluzzi S, et al. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiology of Aging, 2017, 49: 60-68.
45. Sun J, Wang F, Ling Z, et al. Clostridium butyricum attenuates cerebral ischemia/reperfusion injury in diabetic mice via modulation of gut microbiota. Brain Research, 2016, 1642: 180-188.
46. Bogiatzi C, Gloor G, Allen-Vercoe E, et al. Metabolic products of the intestinal microbiome and extremes of atherosclerosis. Atherosclerosis, 2018, 273: 91-97.
47. Jia Y, Liao S I, He Y, et al. Dysbiosis of gut microbiota with reduced trimethylaminenoxide level in patients with large‐artery atherosclerotic stroke or transient ischemic attack. Journal of the American Heart Association, 2015, 4(11): e002699.
48. Nagpal J, Cryan JF. Microbiota-brain interactions: moving toward mechanisms in model organisms. Neuron, 2021, 5: 152-156.
49. Godfrey JBW. Misleading presentation of epilepsy in elderly people. Age & Ageing, 1989, (1): 17-20.
50. Brodie MJ, Elder AT, Kwan P. Epilepsy in later life. Lancet Neurology, 2009, 8(11): 1019-1030.
51. Martin Y, Artaz M, Bornand-Rousselot A. Nonconvulsive status epilepticus in the elderly. Journal of the American Geriatrics Society, 2014, 52(3): 162-168.
52. Kobow K, Auvin S, Jensen F, et al. Finding a better drug for epilepsy: Antiepileptogenesis targets. Epilepsia, 2012, 53(11): 1868-1876.
53. Arul A, Tan QY. Balasubramaniam V R, et al. Gut microbiota and epilepsy:a systematic review on their relationship and possible therapeutics. ACS Chemical Neuroscience, 2020, 11(21): 256-262.
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