Table 1.

Summary of the MGB axis in neurological diseases.

	Abundance of microbiota
Neurological diseases	Increased	Decreased	Pathogenesis	Gut microbiota-based diagnosis	Gut microbiota-targeting intervention
Migraine	Phylum: Firmicutes Genus: Streptococcus[38] and Pseudomonas[38] Species: Rothia mucilaginosa[38] Haemophilus parainfluenzae,[38] Blautia hydrogenotrophica,[39] Clostridium spp.,[39] Eggerthella lenta,[39] Flavonifractor plautii,[39] and Ruminococcus gnavus[39]	Genus: Faecalibacterium[39] Species: Faecalibacterium prausnitzii,[39]Bifidobacterium adolescentis,[39]Methanobrevibacter smithii,[39]Bacteroides spp.,[39]Clostridium sp. L2_50,[39]Coprococcus catus,[39]Eubacterium hallii,[39]Eubacterium ramulus,[39]Odoribacter splanchnicus,[39]Prevotella copri,[39]Ruminococcus callidus,[39]Ruminococcus champanellensis,[39]Ruminococcus obeum,[39] and Sutterella wadsworthensis[39]	Gut microbiota dysbiosis contributes to migraine via metabolic dysfunctions and insufficient SCFA synthesis[39]; Gut microbiota dysbiosis contributes to migraine-like pain via TNF-α upregulation,[40,41]∗ c-Fos upregulation,[41]∗ and calcitonin gene-related peptide downregulation[41] in the trigeminal nociceptive system	–	Probiotic Lactobacillus casei Shirota relieves migraine symptoms at 4 months follow-up[42]; a multispecies probiotic containing Bifidobacterium spp. and Lactobacillus spp. induces a ≥2 days reduction in migraine days in 12/31 patients in the probiotics group vs. 7/29 in the placebo group[43]; a multispecies probiotic containing 14 strains of Bifidobacterium spp., Lactobacillus spp., and Streptococcus spp. is effective to improve migraine headache in both chronic and episodic migraineurs[44]
ICH	Phylum: Firmicutes/Bacteroidetes[49] Family: Nocardiaceae,[46]∗ Helicobacteraceae,[46]∗ Veillonellaceae,[46]∗ Bacteroidaceae,[46]∗ and Akkermansiaceae[46]∗ Genus: Bacteroides,[49] Acidaminococcus,[49] and Bacteroides ovatus[49] Species: Bacteroides fragilis[49]	Phylum: Firmicutes[46]∗ and Verrucomicrobia[49] Family: Barnesiellaceae[46]∗ and Moraxellaceae[46]∗ Genus: Prevotella,[49]Akkermansia,[49] and Blautia[49] Species: Prevotella copri,[49]Akkermansia muciniphila,[49] and Ruminococcus callidus[49]	Gut microbiota dysbiosis regulates ICH outcomes via destruction of the gut mucosa, delayed small intestinal motility, intestinal barrier dysfunction, T cell translocation, and increased inflammatory responses and oxidative stress[45,46]∗	–	Transplantation of healthy fecal microbiome ameliorates the ICH-induced neurobehavioral impairment in the subacute phase and later phases[46]∗
Cerebral infarction	Phylum: Proteobacteria[52] and Bacteroidetes[53]∗ Family: Enterobacteriaceae,[51] Ruminococcaceae,[51] Veillonellaceae,[51] and Lachnospiraceae[51] Genus: Escherichia/Shigella,[52]Peptoniphilus,[52]Ezakiella,[52]Enterococcus,[52] and Prevotella[53]∗ Species: Escherichia coli[51]∗	Phylum: Firmicutes,[52] Bacteroidetes,[52] and Firmicutes[53]∗ Family: Bacteroidaceae[51] and Prevotellaceae[51] Genus: Blautia,[52]Subdoligranulum,[52]Bacteroides,[52]Anaerostipes,[52]Faecalibacterium,[53]∗Streptococcus,[53]∗Lactobacillus,[53]∗ and Oscillospira[53]∗	Gut microbiota dysbiosis contributes to stroke via gut–immune–brain axis[52]; ischemic stroke rapidly triggers gut microbiome dysbiosis with Enterobacteriaceae overgrowth that in turn exacerbates brain infarction by accelerating systemic inflammation[51]∗; in addition, gut microbiota dysbiosis regulates cerebral infarction by intestinal mucosal barrier disruption and systemic inflammation activation[53]∗	Enterobacteriaceae is an independent risk factor for stroke patients with poor primary outcomes[51]	Reconstructing the gut microbiota by transplanting fecal bacteria rich in SCFAs and supplementing with butyric acid were found to be effective treatments for cerebral ischemic stroke;[54]∗ a prebiotic and a cocktail of four SCFA-producers (Lactobacillus fermentum, Clostridium symbiosum, Faecalibacterium prausnitzii, and Bifidobacterium longum) alleviate poststroke neurological deficits and inflammation, and elevated gut, brain and plasma SCFA concentrations in aged stroke mice[55]∗
MCI	Phylum: Bacteroidetes[59] Class: Bacteroidia[59] Order: Bacteroidales[59] Family: Veillonellaceae[59] and Bacteroidaceae[59] Genus: Escherichia,[58]Lactobacillus,[58]Escherichia/Shigella[56]Bacteroides,[59] and Prevotella[64]	Genus: Bacteroides,[58]. Blautia,[59]Faecalibacterium,[64]Anaerostipes,[64] and Ruminoccocus[64] Species: Eubacterium rectale[56] and Bacteroides fragilis[56]	Gut microbiota dysbiosis contributes to MCI and/or AD via peripheral inflammatory activation,[56] blood-brain barrier impairment, neuroinflammation promotion, and neurodegeneration,[58] as well as intrinsic brain activity alterations[59]	Using the cutoff values from random forest models with all different genera fecal inputs, 28 of 30 patients with MCI could be identified correctly with a sensitivity of 93%[58]	–
AD	Phylum: Actinobacteria and Verrucomicrobia Family: 13 bacteria (e.g., Bifidobacteriaceae, Verrucomicrobiaceae, Coriobacteriaceae, Erysipelotrichaceae, Enterococcaceae, Corynebacteriaceae, etc.) Genus: six genera (Dorea, Lactobacillus, Streptococcus, Bifidobacterium, Blautia, and Escherichia),[58] 16 genera (e.g., Bifidobacterium, Akkermansia, Clostridium, Enterococcus, Eggerthella, Olsenella, etc.)[60]	Phylum: Firmicutes Family: Ruminococcaceae, Lachnospiraceae, and Clostridiaceae Genus: five genera (Alistipes, Bacteroides, Parabacteroides, Sutterella, and Paraprevotella),[58] eight genera (e.g., Faecalibacterium, Roseburia, Dialister, Romboutsia, Coprococcus, Butyricicoccus, etc.)[60]	The biosynthesis and the metabolism of fatty acids might participate in the mechanisms by which gut microbiota regulates AD-related changes through immunomodulatory[60] suppression of astrocyte activation around Aβ plaques was also observed[61]	–	A Bifidobacterium spp. probiotic alleviates AD-related pathological changes and behaviors[62]∗; a fermented milk product with probiotic containing Bifidobacterium animalis subsp Lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis subsp Lactis improves the brain activity of AD patients[63]; specific strains of Faecalibacterium prausnitzii improves Aβ-induced cognitive impairment in Alzheimer's-type dementia[64]∗
PD	Phylum: Verrucomicrobia[65] and Proteobacteria[65] Family: Verrucomicrobiaceae,[65] Enterobacteriaceae,[65] Christensenellaceae,[65] Lactobacillaceae,[65,70] Coriobacteriaceae,[65,70] Bifidobacteriaceae,[65,70] Desulfovibrionaceae,[70] Rikenellaceae,[70] and Oscillospiraceae[70] Genus: Akkermansia,[65]Oscillospira,[65]Desulfovibrio,[70]Oscillibacter,[70]Lactobacillus,[70]Alistipes,[70]Bifidobacterium,[70] and Collinsella[70] Species: Bifidobacterium dentium[70] and Bifidobacterium longum[70]	Family: Lachnospiraceae[65] Genus: Roseburia[65,70] and Ruminococcus[65]	Gut microbiota regulates the formation of α-Syn that was influenced by ubiquitin system, the upregulation of the xenobiotic degradation pathways,[65] and the gut-to-brain spread of α-synucleinopathy[67,68] and the neuroinflammation,[68] as well as the δ-secretase elicited apoptosis in nigral dopaminergic neurons,[69] which participate in the pathogenesis of PD; gut microbiota–derived epitope peptides involves in the pathogenesis of PD via abnormalities in immunity and glutamate and propionate metabolism[70]	–	–
MS	Phylum: Actinobacteria[72,75] and Verrucomicrobia[73] Family: Christensenellaceae,[72] Sphingobacteriaceae,[74] Caulobacteraceae,[74] and Pseudomonadaceae[74] Genus: Bilophilia,[72]Bifidobacterium,[72]Desulfovibrio,[72]Methanobrevibacter,[73]Akkermansia,[73]Psuedomonas,[74]Mycoplana,[74]Haemophilus,[74]Blautia,[74]Dorea,[74] and Pedobacter[74]	Family: Lachnospiraceae,[72] Ruminococcaceae,[72] Coriobacteriaceae,[74] and Porphyromonadaceae,[74] Genus: Butyricimonas,[73]Slackia,[73]Collinsella,[73]Parabacteroides,[74]Adlercreutzia,[74]Prevotella,[74,75]Collinsella,[74]Faecalibacterium,[75] and Anaerostipes[75]	Gut microbiota involves in the pathogenesis of PD via the abnormalities in glutathione metabolism and LPS biosynthesis,[72] the dendritic cell maturation, interferon signaling and NF-kB signaling pathways,[73] as well as fatty acid biosynthesis[74] and inflammatory response[75]	–	A probiotic mixture VSL3 containing strains of Lactobacillus, Bifidobacterium, and Streptococcus spp.-induced anti-inflammatory peripheral immune response that is associated with improved disease outcome in MS patients[76,77]; a mixture of human gut-derived 17 Clostridia strains and their metabolite, butyrate, improves the clinical outcome of EAE via inducing lower histopathological features in the CNS and enhanced anti-inflammatory responses[78]∗; gut microbiota-derived PA improved clinical outcomes of MS by an immunomodulatory mechanism[79]
NMOSD	Genus: Flavonifractor,[80]Streptococcus,[80,81,83]Shigella,[81]Lachnoclostridium,[82]Oscillibacter,[83] and Veillonella[83] Species: Clostridium bolteae,[82]Alistipes,[81,84]Haemophilus,[81,84]Butyricimonas,[81,84] and Rothia[81,84]	Genus: Faecalibacterium,[80,81]Lachnospiracea_incertae_sedis,[80]Prevotella,[80]Blautia,[80]Roseburia,[80]Romboutsia,[80]Coprococcus,[80]Fusicatenibacter,[80]Clostridium,[81,84]Parabacteroides,[81,84]Oxalobacter,[81,84] and Burkholderia[81,84]	Gut microbiota involves in the pathogenesis of NMOSD via the abnormalities in inflammatory response,[81,82] and the disruption in intestinal barrier[84]	These microbial biomarkers have predictive power to distinguish NMOSD from controls with a sensitivity of 93%[80]; nine genus-level microbial biomarkers identify the NMOSD patients from controls with a sensitivity of 97%[83]	–
MG	34 increased OTUs[87]: Bacteroidaceae (9 OTUs), Lachnospiraceae (9 OTUs), Veillonellaceae (3 OTUs), and Prevotellaceae (3 OTUs) Species: 16 species[89]	46 decreased OTUs[87]: Lachnospiraceae (23 OTUs), Ruminococcaceae (8 OTUs), Erysipelotrichaceae (4 OTUs), Peptostreptococcaceae (3 OTUs), and Clostridiaceae_1 (3 OTUs) Genus: Clostridium[88] Species: Fusobacterium prausnitzii[88] and nine species[89]	Gut microbiota involves in the pathogenesis of NMOSD via the disturbances in amino acid metabolism, nucleotide metabolism, and microbial metabolism pathways,[87] as well as the SCFAs’ production[89]	A marker panel composed of four genera (Clostridiaceae, Lachnospiraceae, Erysipelotrichaceae, and Bacteroidaceae) and six fecal metabolites (leucine, cytosine, oxalic acid, N-acetyltryptophan, d-glyceric acid, and xanthine) discriminates between MG patients and healthy controls with 100% accuracy[87]; a microbial panel composed of five species (Fusobacterium mortiferum, Prevotella stercorea, Prevotella copri, Megamonas funiformis, and Megamonas hypermegale) distinguishes the MG patients from healthy controls with a sensitivity of 94% in cross-validation and 84% in the independent validation cohort[89]	Treatment with Bifidobacterium and Lactobacillus probiotic strains alleviates MG-associated symptoms in EAMG and EAE models by inflammatory regulation[90]∗
Epilepsy	Phylum: Proteobacteria[91] Genus: Campylobacter,[91]Delftia,[91]Haemophilus,[91]Lautropia,[91]Neisseria,[91] and Cronobacter[94]	Phylum: Firmicutes,[91] Bacteroidetes,[91] and Actinobacteria[91] Genus: Blautia,[91]Coprococcus,[91]Faecalibacterium,[91]Ruminococcus,[91]Bacteroides,[91,94]Parabacteroides,[91]Bifidobacterium,[91,94]Collinsella,[91] and Prevotella[94]	Gut microbiota dysbiosis participates in the etiology of epilepsy via autoimmune mechanisms and inflammation[91]		Transplantation of the KD-associated microbiota, and treatment with Akkermansia and Parabacteroides, each reduces spontaneous recurrent seizures[93]∗; transplantation of fecal microbiota from healthy volunteers cures epilepsy in a case with Crohn's disease[97]
ASD	Phylum: Bacteroidetes[98] Family: Lachnospiraceae[25]∗ Genus: Akkermansia[25]∗ and Sutterella[25]∗ Species: Eisenbergiella tayi,[25]∗Veillonella parvula,[100] and Lactobacillus rhamnosus[100]	Phylum: Firmicutes[98] Genus: Streptococcus,[98]Veillonella,[98]Escherichia,[98]Actinomyces,[98]Parvimonas,[98]Bulleidia,[98] and Peptoniphilus[98] Species: Bacteroides ovatus,[25]∗Parabacteroides merdae,[25]∗Bifidobacterium longum,[100] and Prevotella copri[100]	Maternal intestinal bacteria promote Th17 cell differentiation to release IL-17A that subsequently induces autism in offspring mice via influencing neurodevelopment[99]∗; in patients, gut microbiota dysbiosis participates in the pathogenesis of ASD via increase in intestinal permeability, abnormalities in metabolic pathways,[98] deficiency in microbial detoxification, glutathione depletion, and mitochondrial dysfunction.[100] Microbial metabolite p-cresol regulates ASD core behavioral symptoms via suppression of dopaminergic neurons’ activity[102]	Microbiota-associated detoxification enzymes discriminate ASD from control subjects with a diagnostic power of 88%[100]	Administration of microbial-derived metabolites, taurine and 5-aminovaleric acid, improves the ASD-like behaviors in these mice[25]∗; Transplantation of fecal microbiota from healthy controls to ASD patients relieves the ASD symptoms, and Eubacterium coprostanoligenes can enhance the FMT response[103]
MDD	Family: Actinomycineae,[24,105] Coriobacterineae,[24] Lactobacillaceae,[24] Streptococcaceae,[24,105] Eubacteriaceae,[24] Lachnospiraceae,[24,105] Ruminococcaceae,[24,105] Porphyromonadaceae,[105] Clostridiaceae,[105] Erysipelotrichaceae,[105] and Enterobacteriaceae,[109] Genus: Clostridium[106,108,110]Holdemania,[106]Adlercreutzia,[106]Eggerthella,[106,107]Parabacteroides,[106]Streptococcus,[106–108,110]Ruminococcus,[106]Bifidobacterium,[106–108]Blautia,[106]Alistipes,[109]Bacteroides,[108]Oscillibacter,[108]Prevotella,[110] and Klebsiella,[110] Species: Bacteroides stercoris CAG:120,[114]Bacteroides stercoris,[114]Bacteroides dorei,[114]Bacteroides vulgatus,[114]Bacteroides fragilis,[114]Bacteroides thetaiotaomicron,[114]Bacteroides eggerthii,[114] and Bacteroides ovatus[114]	Family: Bacteroidaceae,[24] Rikenellaceae,[24,105] Lachnospiraceae,[24] Acidaminococcaceae,[24] Veillonellaceae,[24] Sutterellaceae,[24,105] Prevotellaceae,[105] Oscillospiraceae,[105] and Enterobacteriaceae,[105] Genus: Megamonas,[106] Sutterella,[106]Prevotella,[106]Faecalibacterium,[109]Bifidobacterium,[111] and Lactobacillus[111] Species: Blautia obeum,[114]Blautia sp. GD8,[114]Blautia wexlerae,[114]Blautia sp. Marseille-P2398,[114] and Blautia sp. CAG:237[114]	Gut microbiota dysbiosis participates in the pathogenesis of MDD through regulating many molecular metabolic pathways, e.g., carbohydrate, GABA, phenylalanine, tryptophan,[24,114] glycerophospholipids, and sphingolipids metabolism,[118] as well as the CREB, Ras/MAPK signaling pathways,[119–122] and endocannabinoid signaling pathway[123]	26 differential OTUs belonging mainly to the Lachnospiraceae (8 OTUs), Bacteroidaceae (7 OTUs), Pseudomonadaceae (3 OTUs), and Ruminococcaceae (3 OTUs) distinguishes the subjects with MDD from those with HC with a high diagnostic accuracy of 96%[113]; a combinatorial marker panel of these six biomarkers discriminates MDD from healthy controls with high classification power in both the discovery (AUC = 0.98) and validation sets (AUC = 0.90)[114]	Oral administration of Lactobacillus plantarum PS128 relives the depressive symptoms of MDD patients[115,116]; the encapsulated microbial therapeutic (MET-2) containing 40 strains of bacteria reduces mean MADRS and GAD-7 scores in MDD patients[117]

The references indicated with an asterisk (^∗) represent studies conducted with animals.

α-Syn: α-synuclein; Aβ: Amyloid β-protein; AD: Alzheimer's disease; ASD: Autism spectrum disorder; AUC: Area under curve; CNS: Central nervous system; CREB: cAMP-response element binding protein; EAE: Experimental autoimmune encephalomyelitis; EAMG: Experimental autoimmune myasthenia gravis; FMT: Fecal microbiota transplantation; GABA: γ-aminobutyric acid; GAD-7: Generalized anxiety disorder; HC: Healthy control; ICH: Intracerebral hemorrhage; IL: Interleukin; KD: Ketogenic diet; LPS: Lipopolysaccharide; MADRS: Montgomery-Asberg depression rating scale; MAPK: Mitogen-activated protein kinase; MCI: Mild cognitive impairment; MDD: Major depressive disorder; MG: Myasthenia gravis; MGB: Microbiota–gut–brain; MS: Multiple sclerosis; NF-κB: Nuclear factor kappa beta; NMOSD: Neuromyelitis optica spectrum disorders; OTUs: Operational taxonomic units; PA: Propionic acid; PD: Parkinson's disease; SCFAs: Short chain fatty acids; Th17: T helper 17; TNF-α: Tumor necrosis factor-α; –: Not reported.