Abstract
There is growing concern about the role of the microbiota-gut-brain axis in neurological illnesses, and it makes sense to consider microglia as a critical component of this axis in the context of epilepsy. Microglia, which reside in the central nervous system, are dynamic guardians that monitor brain homeostasis. Microglia receive information from the gut microbiota and function as hubs that may be involved in triggering epileptic seizures. Vagus nerve bridges the communication in the axis. Essential axis signaling molecules, such as gamma-aminobutyric acid, 5-hydroxytryptamin, and short-chain fatty acids, are currently under investigation for their participation in drug-resistant epilepsy (DRE). In this review, we explain how vagus nerve connects the gut microbiota to microglia in the brain and discuss the emerging concepts derived from this interaction. Understanding microbiota-gut-brain axis in epilepsy brings hope for DRE therapies. Future treatments can focus on the modulatory effect of the axis and target microglia in solving DRE.
Graphical Abstract
Similar content being viewed by others
Data Availability
Not applicable.
References
Prinz M, Jung S, Priller J (2019) Microglia biology: one century of evolving concepts. Cell 179(2):292–311. https://doi.org/10.1016/j.cell.2019.08.053
Sheng JY, Liu S, Qin HJ et al (2018) Drug-resistant epilepsy and surgery. Curr Neuropharmacol 16(1):17–28. https://doi.org/10.2174/1570159x15666170504123316
Utz SG, See P, Mildenberger W et al (2020) Early fate defines microglia and non-parenchymal brain macrophage development. Cell 181(3):557-573.e518. https://doi.org/10.1016/j.cell.2020.03.021
Prinz M, Masuda T, Wheeler MA et al (2021) Microglia and central nervous system-associated macrophages-from origin to disease modulation. Annu Rev Immunol 39:251–277. https://doi.org/10.1146/annurev-immunol-093019-110159
Pelvig DP, Pakkenberg H, Stark AK et al (2008) Neocortical glial cell numbers in human brains. Neurobiol Aging 29(11):1754–1762. https://doi.org/10.1016/j.neurobiolaging.2007.04.013
Lenz KM, Nelson LH (2018) Microglia and beyond: innate immune cells as regulators of brain development and behavioral function. Front Immunol 9. https://doi.org/10.3389/fimmu.2018.00698
Borst K, Dumas AA, Prinz M (2021) Microglia: immune and non-immune functions. Immunity 54(10):2194–2208. https://doi.org/10.1016/j.immuni.2021.09.014
Kwan P, Arzimanoglou A, Berg AT et al (2010) Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51(6):1069–1077. https://doi.org/10.1111/j.1528-1167.2009.02397.x
Sultana B, Panzini MA, Veilleux Carpentier A et al (2021) Incidence and prevalence of drug-resistant epilepsy: a systematic review and meta-analysis. Neurology 96(17):805–817. https://doi.org/10.1212/wnl.0000000000011839
Kwan P, Schachter SC, Brodie MJ (2011) Drug-resistant epilepsy. N Engl J Med 365(10):919–926. https://doi.org/10.1056/NEJMra1004418
Devinsky O, Vezzani A, O’Brien TJ et al (2018) Epilepsy Nature reviews Disease primers 4:18024. https://doi.org/10.1038/nrdp.2018.24
Cook MJ, O’Brien TJ, Berkovic SF et al (2013) Prediction of seizure likelihood with a long-term, implanted seizure advisory system in patients with drug-resistant epilepsy: a first-in-man study. The Lancet Neurology 12(6):563–571. https://doi.org/10.1016/s1474-4422(13)70075-9
Morais LH, SchreiberMazmanian HLSK (2021) The gut microbiota-brain axis in behaviour and brain disorders. Nat Rev Microbiol 19(4):241–255. https://doi.org/10.1038/s41579-020-00460-0
Luczynski P, McVey Neufeld KA, Oriach CS et al (2016) Growing up in a bubble: using germ-free animals to assess the influence of the gut microbiota on brain and behavior. Int J Neuropsychopharmacol 19 (8). https://doi.org/10.1093/ijnp/pyw020
Yoo BB, Mazmanian SK (2017) The enteric network: interactions between the immune and nervous systems of the gut. Immunity 46(6):910–926. https://doi.org/10.1016/j.immuni.2017.05.011
Liu Y, Sanderson D, Mian MF et al (2021) Loss of vagal integrity disrupts immune components of the microbiota-gut-brain axis and inhibits the effect of Lactobacillus rhamnosus on behavior and the corticosterone stress response. Neuropharmacology 195. https://doi.org/10.1016/j.neuropharm.2021.108682
Peng AJ, Qiu XM, Lai WL et al (2018) Altered composition of the gut microbiome in patients with drug-resistant epilepsy. Epilepsy Res 147:102–107. https://doi.org/10.1016/j.eplepsyres.2018.09.013
Olson CA, Vuong HE, Yano JM et al (2018) The gut microbiota mediates the anti-seizure effects of the ketogenic diet (vol 173, pg 1728, 2018). Cell 174(2):497–497. https://doi.org/10.1016/j.cell.2018.06.051
De Caro C, Leo A, Nesci V et al (2019) Intestinal inflammation increases convulsant activity and reduces antiepileptic drug efficacy in a mouse model of epilepsy. Sci Rep 9. https://doi.org/10.1038/s41598-019-50542-0
Margolis KG, Cryan JF, Mayer EA (2021) The microbiota-gut-brain axis: from motility to mood. Gastroenterology 160(5):1486–1501. https://doi.org/10.1053/j.gastro.2020.10.066
Tan HE, Sisti AC, Jin H et al (2020) The gut-brain axis mediates sugar preference. Nature 580(7804):511–516. https://doi.org/10.1038/s41586-020-2199-7
Kakinuma Y (2021) Significance of vagus nerve function in terms of pathogenesis of psychosocial disorders. Neurochem Int 143:104934. https://doi.org/10.1016/j.neuint.2020.104934
Altmann A, Ryten M, Di Nunzio M et al (2022) A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies. Neuropathology and Applied Neurobiology 48 (1). https://doi.org/10.1111/nan.12758
Patel DC, Tewari BP, Chaunsali L et al (2019) Neuron-glia interactions in the pathophysiology of epilepsy. Nat Rev Neurosci 20(5):282–297. https://doi.org/10.1038/s41583-019-0126-4
Erny D, de Angelis ALH, Jaitin D et al (2015) Host microbiota constantly control maturation and function of microglia in the CNS. Nature Neuroscience 18 (7):965-+. https://doi.org/10.1038/nn.4030
Mossad O, Batut B, Yilmaz B et al (2022) Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N(6)-carboxymethyllysine. Nat Neurosci 25(3):295–305. https://doi.org/10.1038/s41593-022-01027-3
Shi H, Ge X, Ma X et al (2021) A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites. Microbiome 9(1):223. https://doi.org/10.1186/s40168-021-01172-0
Layden BT, Angueira AR, Brodsky M et al (2013) Short chain fatty acids and their receptors: new metabolic targets. Translational research : the journal of laboratory and clinical medicine 161(3):131–140. https://doi.org/10.1016/j.trsl.2012.10.007
Abdul Rahim MBH, Chilloux J, Martinez-Gili L et al (2019) Diet-induced metabolic changes of the human gut microbiome: importance of short-chain fatty acids, methylamines and indoles. Acta Diabetol 56(5):493–500. https://doi.org/10.1007/s00592-019-01312-x
Silva YP, Bernardi A, Frozza RL (2020) The role of short-chain fatty acids from gut microbiota in gut-brain communication. Frontiers in Endocrinology 11. https://doi.org/10.3389/fendo.2020.00025
Wenzel TJ, Gates EJ, Ranger AL et al (2020) Short-chain fatty acids (SCFAs) alone or in combination regulate select immune functions of microglia-like cells. Mol Cell Neurosci 105:103493. https://doi.org/10.1016/j.mcn.2020.103493
Caetano-Silva ME, Rund L, Hutchinson NT et al (2023) Inhibition of inflammatory microglia by dietary fiber and short-chain fatty acids. Sci Rep 13(1):2819. https://doi.org/10.1038/s41598-022-27086-x
Sherwin E, Bordenstein SR, Quinn JL et al (2019) Microbiota and the social brain. Science (New York, NY) 366 (6465). https://doi.org/10.1126/science.aar2016
de Goffau MC, Lager S, Sovio U et al (2019) Human placenta has no microbiome but can contain potential pathogens (vol 572, pg 329, 2019). Nature 574(7778):E15–E15. https://doi.org/10.1038/s41586-019-1628-y
Sender R, Fuchs S, Milo R (2016) Revised estimates for the number of human and bacteria cells in the body. Plos Biology 14 (8). https://doi.org/10.1371/journal.pbio.1002533
Ding M, Lang Y, Shu H et al (2021) Microbiota-gut-brain axis and epilepsy: a review on mechanisms and potential therapeutics. Front Immunol 12:742449. https://doi.org/10.3389/fimmu.2021.742449
Thion MS, Low D, Silvin A et al (2018) Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell 172(3):500-516.e516. https://doi.org/10.1016/j.cell.2017.11.042
Osadchiy V, Martin CR, Mayer EA (2020) Gut microbiome and modulation of CNS function. Compr Physiol 10(1):57–72. https://doi.org/10.1002/cphy.c180031
Mu X, Zhang X, Gao H et al (2022) Crosstalk between peripheral and the brain-resident immune components in epilepsy. Journal of integrative neuroscience 21(1):9. https://doi.org/10.31083/j.jin2101009
Darch H, McCafferty CP (2022) Gut microbiome effects on neuronal excitability & activity: implications for epilepsy. Neurobiol Dis 165:105629. https://doi.org/10.1016/j.nbd.2022.105629
Lindefeldt M, Eng A, Darban H et al (2019) The ketogenic diet influences taxonomic and functional composition of the gut microbiota in children with severe epilepsy. NPJ Biofilms Microbiomes 5. https://doi.org/10.1038/s41522-018-0073-2
Xie G, Zhou Q, Qiu CZ et al (2017) Ketogenic diet poses a significant effect on imbalanced gut microbiota in infants with refractory epilepsy. World J Gastroenterol 23(33):6164–6171. https://doi.org/10.3748/wjg.v23.i33.6164
Gong X, Liu X, Chen C et al (2020) Alteration of gut microbiota in patients with epilepsy and the potential index as a biomarker. Front Microbiol 11. https://doi.org/10.3389/fmicb.2020.517797
Leguia MG, Andrzejak RG, Rummel C et al (2021) Seizure cycles in focal epilepsy. JAMA Neurol 78(4):454–463. https://doi.org/10.1001/jamaneurol.2020.5370
Karoly PJ, Rao VR, Gregg NM et al (2021) Cycles in epilepsy. Nature reviews. Neurology 17(5):267–284. https://doi.org/10.1038/s41582-021-00464-1
Voigt RM, Forsyth CB, Green SJ et al (2014) Circadian disorganization alters intestinal microbiota. PLoS ONE 9(5):e97500. https://doi.org/10.1371/journal.pone.0097500
Hu L, Li G, Shu Y et al (2022) Circadian dysregulation induces alterations of visceral sensitivity and the gut microbiota in Light/Dark phase shift mice. Front Microbiol 13:935919. https://doi.org/10.3389/fmicb.2022.935919
Godinho-Silva C, Domingues RG, Rendas M et al (2019) Light-entrained and brain-tuned circadian circuits regulate ILC3s and gut homeostasis. Nature 574(7777):254–258. https://doi.org/10.1038/s41586-019-1579-3
Pizzo F, Collotta AD, Di Nora A et al (2022) Ketogenic diet in pediatric seizures: a randomized controlled trial review and meta-analysis. Expert Rev Neurother 22(2):169–177. https://doi.org/10.1080/14737175.2022.2030220
He Z, Cui BT, Zhang T et al (2017) Fecal microbiota transplantation cured epilepsy in a case with Crohn’s disease: the first report. World J Gastroenterol 23(19):3565–3568. https://doi.org/10.3748/wjg.v23.i19.3565
Rubio C, Ochoa E, Gatica F et al (2023) The role of the vagus nerve in the microbiome and digestive system in relation to epilepsy. Curr Med Chem. https://doi.org/10.2174/0109298673260479231010044020
Sharkey KA, Mawe GM (2023) The enteric nervous system. Physiol Rev 103(2):1487–1564. https://doi.org/10.1152/physrev.00018.2022
Niesler B, Kuerten S, Demir IE et al (2021) Disorders of the enteric nervous system - a holistic view. Nat Rev Gastroenterol Hepatol 18(6):393–410. https://doi.org/10.1038/s41575-020-00385-2
Obata Y, Pachnis V (2016) The effect of microbiota and the immune system on the development and organization of the enteric nervous system. Gastroenterology 151(5):836–844. https://doi.org/10.1053/j.gastro.2016.07.044
Vicentini FA, Keenan CM, Wallace LE et al (2021) Intestinal microbiota shapes gut physiology and regulates enteric neurons and glia. Microbiome 9(1):210. https://doi.org/10.1186/s40168-021-01165-z
Cignarella F, Cantoni C, Ghezzi L et al (2018) Intermittent fasting confers protection in CNS autoimmunity by altering the gut microbiota. Cell Metab 27(6):1222-1235.e1226. https://doi.org/10.1016/j.cmet.2018.05.006
Collins J, Borojevic R, Verdu EF et al (2014) Intestinal microbiota influence the early postnatal development of the enteric nervous system. Neurogastroenterol Motil 26(1):98–107. https://doi.org/10.1111/nmo.12236
Sharon G, Sampson TR, Geschwind DH et al (2016) The central nervous system and the gut microbiome. Cell 167(4):915–932. https://doi.org/10.1016/j.cell.2016.10.027
Neufeld KAM, Perez-Burgos A, Mao YK et al (2015) The gut microbiome restores intrinsic and extrinsic nerve function in germ-free mice accompanied by changes in calbindin. Neurogastroenterol Motil 27(5):627–636. https://doi.org/10.1111/nmo.12534
Neufeld KAM, Mao YK, Bienenstock J et al (2013) The microbiome is essential for normal gut intrinsic primary afferent neuron excitability in the mouse. Neurogastroenterology and Motility 25 (2):183-+. https://doi.org/10.1111/nmo.12049
Ni SJ, Yao ZY, Wei X et al (2022) Vagus nerve stimulated by microbiota-derived hydrogen sulfide mediates the regulation of berberine on microglia in transient middle cerebral artery occlusion rats. Phytother Res 36(7):2964–2981. https://doi.org/10.1002/ptr.7490
Xie Z, Zhang X, Zhao M et al (2022) The gut-to-brain axis for toxin-induced defensive responses. Cell 185(23):4298-4316.e4221. https://doi.org/10.1016/j.cell.2022.10.001
Ran C, Boettcher JC, Kaye JA et al (2022) A brainstem map for visceral sensations. Nature 609(7926):320–326. https://doi.org/10.1038/s41586-022-05139-5
Bravo JA, Forsythe P, Chew MV et al (2011) Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci USA 108(38):16050–16055. https://doi.org/10.1073/pnas.1102999108
Broncel A, Bocian R, Kłos-Wojtczak P et al (2019) GABAergic mediation of hippocampal theta rhythm induced by stimulation of the vagal nerve. Brain Res Bull 147:110–123. https://doi.org/10.1016/j.brainresbull.2019.02.010
Morais A, Liu TT, Qin T et al (2020) Vagus nerve stimulation inhibits cortical spreading depression exclusively through central mechanisms. Pain 161(7):1661–1669. https://doi.org/10.1097/j.pain.0000000000001856
Winter Y, Sandner K, Glaser M et al (2023) Synergistic effects of vagus nerve stimulation and antiseizure medication. J Neurol. https://doi.org/10.1007/s00415-023-11825-9
Yalnizoglu D, Ardicli D, Bilginer B et al (2020) Long-term effects of vagus nerve stimulation in refractory pediatric epilepsy: a single-center experience. Epilepsy & behavior : E&B 110:107147. https://doi.org/10.1016/j.yebeh.2020.107147
Schwabenland M, Brück W, Priller J et al (2021) Analyzing microglial phenotypes across neuropathologies: a practical guide. Acta Neuropathol 142(6):923–936. https://doi.org/10.1007/s00401-021-02370-8
Joshi AU, Minhas PS, Liddelow SA et al (2019) Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration. Nat Neurosci 22(10):1635–1648. https://doi.org/10.1038/s41593-019-0486-0
Kaczmarczyk R, Tejera D, Simon BJ et al (2017) Microglia modulation through external vagus nerve stimulation in a murine model of Alzheimer’s disease. J Neurochem. https://doi.org/10.1111/jnc.14284
Matcovitch-Natan O, Winter DR, Giladi A et al (2016) Microglia development follows a stepwise program to regulate brain homeostasis. Science (New York, NY) 353(6301):aad8670. https://doi.org/10.1126/science.aad8670
Cordella F, Sanchini C, Rosito M et al (2021) Antibiotics treatment modulates microglia-synapses interaction. Cells 10 (10). https://doi.org/10.3390/cells10102648
Janssens Y, Debunne N, De Spiegeleer A et al (2021) PapRIV, a BV-2 microglial cell activating quorum sensing peptide. Scientific Reports 11 (1). https://doi.org/10.1038/s41598-021-90030-y
Shen J, Guo H, Liu S et al (2023) Aberrant branched-chain amino acid accumulation along the microbiota-gut-brain axis: crucial targets affecting the occurrence and treatment of ischaemic stroke. Br J Pharmacol 180(3):347–368. https://doi.org/10.1111/bph.15965
Ma N, He T, Johnston LJ et al (2020) Host-microbiome interactions: the aryl hydrocarbon receptor as a critical node in tryptophan metabolites to brain signaling. Gut microbes 11(5):1203–1219. https://doi.org/10.1080/19490976.2020.1758008
Liu Y, Sanderson D, Mian MF et al (2021) Loss of vagal integrity disrupts immune components of the microbiota-gut-brain axis and inhibits the effect of Lactobacillus rhamnosus on behavior and the corticosterone stress response. Neuropharmacology 195:108682. https://doi.org/10.1016/j.neuropharm.2021.108682
Hoogland ICM, Houbolt C, van Westerloo DJ et al (2015) Systemic inflammation and microglial activation: systematic review of animal experiments. Journal of neuroinflammation 12. https://doi.org/10.1186/s12974-015-0332-6
Khan S, Nobili L, Khatami R et al (2018) Circadian rhythm and epilepsy. The Lancet Neurology 17(12):1098–1108. https://doi.org/10.1016/s1474-4422(18)30335-1
Wang XL, Wolff SEC, Korpel N et al (2020) Deficiency of the circadian clock gene Bmal1 reduces microglial immunometabolism. Front Immunol 11:586399. https://doi.org/10.3389/fimmu.2020.586399
Iweka CA, Seigneur E, Hernandez AL et al (2023) Myeloid deficiency of the intrinsic clock protein BMAL1 accelerates cognitive aging by disrupting microglial synaptic pruning. J Neuroinflammation 20(1):48. https://doi.org/10.1186/s12974-023-02727-8
Hiragi T, Ikegaya Y, Koyama R (2018) Microglia after Seizures and in Epilepsy. Cells 7(4). https://doi.org/10.3390/cells7040026
Chen Z, Trapp BD (2016) Microglia and neuroprotection. J Neurochem 136(Suppl 1):10–17. https://doi.org/10.1111/jnc.13062
Tu D, Velagapudi R, Gao Y et al (2023) Activation of neuronal NADPH oxidase NOX2 promotes inflammatory neurodegeneration. Free Radical Biol Med 200:47–58. https://doi.org/10.1016/j.freeradbiomed.2023.03.001
Wyatt SK, Witt T, Barbaro NM et al (2017) Enhanced classical complement pathway activation and altered phagocytosis signaling molecules in human epilepsy. Exp Neurol 295:184–193. https://doi.org/10.1016/j.expneurol.2017.06.009
Feng L, Murugan M, Bosco DB et al (2019) Microglial proliferation and monocyte infiltration contribute to microgliosis following status epilepticus. Glia 67(8):1434–1448. https://doi.org/10.1002/glia.23616
Engel J, Thompson PM, Stern JM et al (2013) Connectomics and epilepsy. Curr Opin Neurol 26(2):186–194. https://doi.org/10.1097/WCO.0b013e32835ee5b8
Lariviere S, Rodriguez-Cruces R, Royer J et al (2020) Network-based atrophy modeling in the common epilepsies: a worldwide ENIGMA study. Sci Adv 6 (47). https://doi.org/10.1126/sciadv.abc6457
Sisodiya SM, Whelan CD, Hatton SN et al (2022) The ENIGMA-Epilepsy working group: mapping disease from large data sets. Hum Brain Mapp 43(1):113–128. https://doi.org/10.1002/hbm.25037
Zhang B, Zou J, Han LR et al (2018) The specificity and role of microglia in epileptogenesis in mouse models of tuberous sclerosis complex. Epilepsia 59(9):1796–1806. https://doi.org/10.1111/epi.14526
Somani A, El-Hachami H, Patodia S et al (2021) Regional microglial populations in central autonomic brain regions in SUDEP. Epilepsia 62(6):1318–1328. https://doi.org/10.1111/epi.16904
Wu W, Li Y, Wei Y et al (2020) Microglial depletion aggravates the severity of acute and chronic seizures in mice. Brain Behav Immun 89:245–255. https://doi.org/10.1016/j.bbi.2020.06.028
Kaestner E, Reyes A, Chen A et al (2021) Atrophy and cognitive profiles in older adults with temporal lobe epilepsy are similar to mild cognitive impairment. Brain 144(1):236–250. https://doi.org/10.1093/brain/awaa397
Sen A, Capelli V, Husain M (2018) Cognition and dementia in older patients with epilepsy. Brain 141:1592–1608. https://doi.org/10.1093/brain/awy022
Schartz ND, Wyatt-Johnson SK, Price LR et al (2018) Status epilepticus triggers long-lasting activation of complement C1q–C3 signaling in the hippocampus that correlates with seizure frequency in experimental epilepsy. Neurobiol Dis 109(Pt A):163–173. https://doi.org/10.1016/j.nbd.2017.10.012
Aronica E, Boer K, van Vliet EA et al (2007) Complement activation in experimental and human temporal lobe epilepsy. Neurobiol Dis 26(3):497–511. https://doi.org/10.1016/j.nbd.2007.01.015
Wei Y, Chen T, Bosco DB et al (2021) The complement C3–C3aR pathway mediates microglia-astrocyte interaction following status epilepticus. Glia 69(5):1155–1169. https://doi.org/10.1002/glia.23955
Merlini M, Rafalski VA, Ma K et al (2021) Microglial G(i)-dependent dynamics regulate brain network hyperexcitability. Nat Neurosci 24(1):19–23. https://doi.org/10.1038/s41593-020-00756-7
Ding X, Zhou J, Zhao L et al (2022) Intestinal flora composition determines microglia activation and improves epileptic episode progress. Front Cell Infect Microbiol 12:835217. https://doi.org/10.3389/fcimb.2022.835217
Bui A, Kim HK, Maroso M et al (2015) Microcircuits in epilepsy: heterogeneity and hub cells in network synchronization. Cold Spring Harbor perspectives in medicine 5 (11). https://doi.org/10.1101/cshperspect.a022855
Royer J, Bernhardt BC, Lariviere S et al (2022) Epilepsy and brain network hubs. Epilepsia 63(3):537–550. https://doi.org/10.1111/epi.17171
Cryan JF, O’Riordan KJ, Cowan CSM et al (2019) The microbiota-gut-brain axis. Physiol Rev 99(4):1877–2013. https://doi.org/10.1152/physrev.00018.2018
Heiss CN, Manneras-Holm L, Lee YS et al (2021) The gut microbiota regulates hypothalamic inflammation and leptin sensitivity in Western diet-fed mice via a GLP-1R-dependent mechanism. Cell Reports 35 (8). https://doi.org/10.1016/j.celrep.2021.109163
Valdearcos M, Robblee MM, Benjamin DI et al (2014) Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function. Cell Rep 9(6):2124–2138. https://doi.org/10.1016/j.celrep.2014.11.018
Fujita Y, Yamashita T (2019) The effects of leptin on glial cells in neurological diseases. Frontiers in Neuroscience 13. https://doi.org/10.3389/fnins.2019.00828
Wang SZ, Yu YJ, Adeli K (2020) Role of gut microbiota in neuroendocrine regulation of carbohydrate and lipid metabolism via the microbiota-gut-brain-liver axis. Microorganisms 8 (4). https://doi.org/10.3390/microorganisms8040527
Ang QY, Alexander M, Newman JC et al (2020) Ketogenic diets alter the gut microbiome resulting in decreased intestinal Th17 cells. Cell 181(6):1263-1275.e1216. https://doi.org/10.1016/j.cell.2020.04.027
Ouédraogo O, Rébillard RM, Jamann H et al (2021) Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug-resistant epilepsy. Epilepsia 62(1):176–189. https://doi.org/10.1111/epi.16742
Platt MP, Bolding KA, Wayne CR et al (2020) Th17 lymphocytes drive vascular and neuronal deficits in a mouse model of postinfectious autoimmune encephalitis. Proc Natl Acad Sci USA 117(12):6708–6716. https://doi.org/10.1073/pnas.1911097117
Lin PJ, Lin AL, Tao KY et al (2021) Intestinal Klebsiella pneumoniae infection enhances susceptibility to epileptic seizure which can be reduced by microglia activation. Cell Death Discovery 7 (1). https://doi.org/10.1038/s41420-021-00559-0
Vezzani A, Fujinami RS, White HS et al (2016) Infections, inflammation and epilepsy. Acta Neuropathol 131(2):211–234. https://doi.org/10.1007/s00401-015-1481-5
Brown DG, Soto R, Yandamuri S et al (2019) The microbiota protects from viral-induced neurologic damage through microglia-intrinsic TLR signaling. Elife 8. https://doi.org/10.7554/eLife.47117
Holden SS, Grandi FC, Aboubakr O et al (2021) Complement factor C1q mediates sleep spindle loss and epileptic spikes after mild brain injury. Science (New York, NY) 373(6560):eabj2685. https://doi.org/10.1126/science.abj2685
Clarke G, Grenham S, Scully P et al (2013) The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 18(6):666–673. https://doi.org/10.1038/mp.2012.77
Holmes M, Flaminio Z, Vardhan M et al (2020) Cross talk between drug-resistant epilepsy and the gut microbiome. Epilepsia 61(12):2619–2628. https://doi.org/10.1111/epi.16744
Vezzani A, French J, Bartfai T et al (2011) The role of inflammation in epilepsy. Nat Rev Neurol 7(1):31–40. https://doi.org/10.1038/nrneurol.2010.178
Wang J, Liang J, Deng J et al (2021) Emerging role of microglia-mediated neuroinflammation in epilepsy after subarachnoid hemorrhage. Mol Neurobiol 58(6):2780–2791. https://doi.org/10.1007/s12035-021-02288-y
Weidner LD, Kannan P, Mitsios N et al (2018) The expression of inflammatory markers and their potential influence on efflux transporters in drug-resistant mesial temporal lobe epilepsy tissue. Epilepsia 59(8):1507–1517. https://doi.org/10.1111/epi.14505
Rana A, Musto AE (2018) The role of inflammation in the development of epilepsy. J Neuroinflammation 15(1):144. https://doi.org/10.1186/s12974-018-1192-7
Sanz P, Garcia-Gimeno MA (2020) Reactive glia inflammatory signaling pathways and epilepsy. International journal of molecular sciences 21(11). https://doi.org/10.3390/ijms21114096
Shemer A, Scheyltjens I, Frumer GR et al (2020) Interleukin-10 prevents pathological microglia hyperactivation following peripheral endotoxin challenge. Immunity 53(5):1033-1049.e1037. https://doi.org/10.1016/j.immuni.2020.09.018
Bagheri S, Heydari A, Alinaghipour A et al (2019) Effect of probiotic supplementation on seizure activity and cognitive performance in PTZ-induced chemical kindling. Epilepsy & behavior : E&B 95:43–50. https://doi.org/10.1016/j.yebeh.2019.03.038
Wang W, Gao R, Ren Z et al (2022) Global trends in research of glutamate in epilepsy during past two decades: a bibliometric analysis. Front Neurosci 16:1042642. https://doi.org/10.3389/fnins.2022.1042642
Strandwitz P (2018) Neurotransmitter modulation by the gut microbiota. Brain Res 1693(Pt B):128–133. https://doi.org/10.1016/j.brainres.2018.03.015
Kong Q, Chen Q, Mao X et al (2022) Bifidobacterium longum CCFM1077 ameliorated neurotransmitter disorder and neuroinflammation closely linked to regulation in the kynurenine pathway of autistic-like rats. Nutrients 14 (8). https://doi.org/10.3390/nu14081615
Shetty AK, Upadhya D (2016) GABA-ergic cell therapy for epilepsy: advances, limitations and challenges. Neurosci Biobehav Rev 62:35–47. https://doi.org/10.1016/j.neubiorev.2015.12.014
Upadhya D, Hattiangady B, Castro OW et al (2019) Human induced pluripotent stem cell-derived MGE cell grafting after status epilepticus attenuates chronic epilepsy and comorbidities via synaptic integration. Proc Natl Acad Sci USA 116(1):287–296. https://doi.org/10.1073/pnas.1814185115
Barker-Haliski M, White HS (2015) Glutamatergic mechanisms associated with seizures and epilepsy. Cold Spring Harb Perspect Med 5(8):a022863. https://doi.org/10.1101/cshperspect.a022863
Nikbakht F, Mohammadkhanizadeh A, Mohammadi E (2020) How does the COVID-19 cause seizure and epilepsy in patients? The potential mechanisms. Multiple sclerosis and related disorders 46:102535. https://doi.org/10.1016/j.msard.2020.102535
Pascual O, Ben Achour S, Rostaing P et al (2012) Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc Natl Acad Sci USA 109(4):E197-205. https://doi.org/10.1073/pnas.1111098109
Delpech JC, Saucisse N, Parkes SL et al (2015) Microglial activation enhances associative taste memory through purinergic modulation of glutamatergic neurotransmission. J Neurosci 35(7):3022–3033. https://doi.org/10.1523/jneurosci.3028-14.2015
Yano JM, Yu K, Donaldson GP et al (2015) Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161(2):264–276. https://doi.org/10.1016/j.cell.2015.02.047
Gao K, Mu CL, Farzi A et al (2020) Tryptophan metabolism: a link between the gut microbiota and brain. Adv Nutr 11(3):709–723. https://doi.org/10.1093/advances/nmz127
Gross ER, Gershon MD, Margolis KG et al (2012) Neuronal serotonin regulates growth of the intestinal mucosa in mice. Gastroenterology 143(2):408-417.e402. https://doi.org/10.1053/j.gastro.2012.05.007
Murphy SE, Norbury R, Godlewska BR et al (2013) The effect of the serotonin transporter polymorphism (5-HTTLPR) on amygdala function: a meta-analysis. Mol Psychiatry 18(4):512–520. https://doi.org/10.1038/mp.2012.19
Ye L, Bae M, Cassilly CD et al (2021) Enteroendocrine cells sense bacterial tryptophan catabolites to activate enteric and vagal neuronal pathways. Cell Host Microbe 29(2):179-196.e179. https://doi.org/10.1016/j.chom.2020.11.011
Girardi G, Zumpano D, Goshi N et al (2023) Cultured vagal afferent neurons as sensors for intestinal effector molecules. Biosensors 13 (6). https://doi.org/10.3390/bios13060601
Agus A, Planchais J, Sokol H (2018) Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 23(6):716–724. https://doi.org/10.1016/j.chom.2018.05.003
Lin WH, Huang HP, Lin MX et al (2013) Seizure-induced 5-HT release and chronic impairment of serotonergic function in rats. Neurosci Lett 534:1–6. https://doi.org/10.1016/j.neulet.2012.12.007
Kopeikina E, Dukhinova M, Yung AWY et al (2020) Platelets promote epileptic seizures by modulating brain serotonin level, enhancing neuronal electric activity, and contributing to neuroinflammation and oxidative stress. Prog Neurobiol 188:101783. https://doi.org/10.1016/j.pneurobio.2020.101783
Shi H, Yu Y, Lin D et al (2020) Beta-glucan attenuates cognitive impairment via the gut-brain axis in diet-induced obese mice. Microbiome 8 (1). https://doi.org/10.1186/s40168-020-00920-y
Shi H, Ge X, Ma X et al (2021) A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites. Microbiome 9 (1). https://doi.org/10.1186/s40168-021-01172-0
Song L, Sun Q, Zheng H et al (2022) Roseburia hominis alleviates neuroinflammation via short-chain fatty acids through histone deacetylase inhibition. Mol Nutr Food Res 66 (18). https://doi.org/10.1002/mnfr.202200164
Hoyles L, Snelling T, Umlai UK et al (2018) Microbiome-host systems interactions: protective effects of propionate upon the blood-brain barrier. Microbiome 6(1):55. https://doi.org/10.1186/s40168-018-0439-y
Liu C, Cheng X, Zhong S et al (2022) Long-term modification of gut microbiota by broad-spectrum antibiotics improves stroke outcome in rats. Stroke and Vascular Neurology 7(5):381–389. https://doi.org/10.1136/svn-2021-001231
Ferraris C, Meroni E, Casiraghi MC et al (2021) One month of classic therapeutic ketogenic diet decreases short chain fatty acids production in epileptic patients. Front Nutr 8:613100. https://doi.org/10.3389/fnut.2021.613100
Lupori L, Cornuti S, Mazziotti R et al (2022) The gut microbiota of environmentally enriched mice regulates visual cortical plasticity. Cell Rep 38(2). https://doi.org/10.1016/j.celrep.2021.110212
Pan W, Zhao J, Wu J et al (2023) Dimethyl itaconate ameliorates cognitive impairment induced by a high-fat diet via the gut-brain axis in mice. Microbiome 11 (1). https://doi.org/10.1186/s40168-023-01471-8
Qiao L, Chen Y, Song X et al (2022) Selenium nanoparticles-enriched Lactobacillus casei ATCC 393 prevents cognitive dysfunction in mice through modulating microbiota-gut-brain axis. Int J Nanomed 17:4807–4827. https://doi.org/10.2147/ijn.S374024
Sadler R, Cramer JV, Heindl S et al (2020) Short-chain fatty acids improve poststroke recovery via immunological mechanisms. J Neurosci 40(5):1162–1173. https://doi.org/10.1523/jneurosci.1359-19.2019
Shao J, Ma X, Qu L et al (2023) Ginsenoside Rh4 remodels the periphery microenvironment by targeting the brain-gut axis to alleviate depression-like behaviors. Food Chemistry 404. https://doi.org/10.1016/j.foodchem.2022.134639
Li H, Xiang Y, Zhu Z et al (2021) Rifaximin-mediated gut microbiota regulation modulates the function of microglia and protects against CUMS-induced depression-like behaviors in adolescent rat. Journal of neuroinflammation 18(1). https://doi.org/10.1186/s12974-021-02303-y
Wang ZJ, Bergqvist C, Hunter JV et al (2003) In vivo measurement of brain metabolites using two-dimensional double-quantum MR spectroscopy–exploration of GABA levels in a ketogenic diet. Magn Reson Med 49(4):615–619. https://doi.org/10.1002/mrm.10429
Calderón N, Betancourt L, Hernández L et al (2017) A ketogenic diet modifies glutamate, gamma-aminobutyric acid and agmatine levels in the hippocampus of rats: A microdialysis study. Neurosci Lett 642:158–162. https://doi.org/10.1016/j.neulet.2017.02.014
Yue Q, Cai MF, Xiao B et al (2021) A high-tryptophan diet reduces seizure-induced respiratory arrest and alters the gut microbiota in DBA/1 mice. Front Neurol 12. https://doi.org/10.3389/fneur.2021.762323
Medel-Matus JS, Lagishetty V, Santana-Gomez C et al (2022) Susceptibility to epilepsy after traumatic brain injury is associated with preexistent gut microbiome profile. Epilepsia 63(7):1835–1848. https://doi.org/10.1111/epi.17248
Das TK, Ganesh BP (2023) Interlink between the gut microbiota and inflammation in the context of oxidative stress in Alzheimer’s disease progression. Gut microbes 15(1):2206504. https://doi.org/10.1080/19490976.2023.2206504
Funding
This work was supported by grants from the Natural Science Fund of Guangdong Province (2017A030313597), Natural Science Fund of Guangzhou in Basic and Applied Research (202201010875), and Southern Medical University (S202012121088S, X202012121354, 202212121027, S202212121113S).
Author information
Authors and Affiliations
Contributions
JW: conceptualization; JW, YL, and NJ: methodology; JW, YL, CT: formal analysis; JW, YL, and NJ: investigation; JW, YL, and N: writing—original draft; YL, CT: visualization; JW, HL: supervision; JW: funding acquisition.
Corresponding author
Ethics declarations
Ethics Approval
Not applicable.
Consent to Participate
Not applicable.
Consent for Publication
All authors read and approved the final manuscript.
Competing Interests
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Liu, Y., Jia, N., Tang, C. et al. Microglia in Microbiota-Gut-Brain Axis: A Hub in Epilepsy. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04022-w
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s12035-024-04022-w