O microbioma intestinal nas doenças neuropsiquiátricas

MEJÍA-GRANADOS, Diana Marcela; VILLASANA-SALAZAR, Benjamín; COAN, Ana Carolina; RIZZI, Liara; BALTHAZAR, Marcio Luiz Figueredo; GODOI, Alexandre Barcia de; CANTO, Amanda Morato do; ROSA, Douglas Cescon da; SILVA, Lucas Scárdua; TACLA, Rafaella do Rosario; DAMASCENO, Alfredo; DONATTI, Amanda; AVELAR, Wagner Mauad; SOUSA, Alessandro; LOPES-CENDES, Iscia

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Sumário

VIEW AND REVIEW • Arq. Neuro-Psiquiatr. 80 (02) • Fev 2022 • https://doi.org/10.1590/0004-282X-ANP-2021-0052 copiar

O microbioma intestinal nas doenças neuropsiquiátricas

Autoria SCIMAGO INSTITUTIONS RANKINGS

RESUMO

Antecedentes:

Os transtornos neuropsiquiátricos são uma importante causa de morte e invalidez no mundo. Os mecanismos subjacentes a esses transtornos incluem uma constelação de etiologias estruturais, infecciosas, imunológicas, metabólicas e genéticas. Avanços nas técnicas de sequenciamento do DNA têm demonstrado que a composição do microbioma entérico é dinâmica e desempenha um papel fundamental não apenas na homeostase do hospedeiro, mas também em várias doenças. O microbioma entérico atua como mediador na sinalização das vias metabólica, neuroimune e neuroendócrina.

Objetivo:

Apresentar os estudos mais recentes sobre a possível influência do microbioma intestinal nas diversas doenças neuropsiquiátricas e discutir tanto os resultados quanto a eficácia dos tratamentos que envolvem a manipulação do microbioma intestinal.

Métodos:

foram examinadas algumas das evidências pré-clínicas e clínicas e estratégias terapêuticas associadas à manipulação do microbioma intestinal.

Resultados:

os táxons-alvo foram descritos e agrupados a partir dos principais estudos para cada doença.

Conclusões:

Entender a fundo a complexidade das interações ecológicas no intestino e sua associação com a suscetibilidade a certas doenças agudas e crônicas pode levar ao desenvolvimento de novos biomarcadores diagnósticos com base em alvos moleculares. Além disso, o estudo do microbioma intestinal pode auxiliar na otimização de tratamentos não farmacológicos emergentes, tais como o transplante de microbiota fecal, o uso de probióticos e intervenções nutricionais personalizadas. Dessa forma, terapias alternativas poderiam ser usadas para reduzir o impacto dos transtornos neuropsiquiátricos na saúde pública. Esperamos que esse conhecimento seja útil para médicos que cuidam de pacientes com diversos transtornos neuropsiquiátricos.

Palavras-chave:
Microbioma Gastrointestinal; Metagenômica; Doenças do Sistema Nervoso; Transplante; Medicina de Precisão

Title of the study	Sample size	Main findings	References
Cross-reactivity between related sequences found in Acinetobacter sp., Pseudomonas aeruginosa, myelin basic protein, and myelin oligodendrocyte glycoprotein in multiple sclerosis	n=71 (26 patients with MS; 20 patients with unilateral hemiplegia due to a cerebrovascular accident; 25 controls)	Antibodies to mimicry peptides from Acinetobacter, P. aeruginosa, myelin basic protein, and myelin oligodendrocyte glycoprotein were significantly elevated in patients compared to controls.	Hughes et al.²³23. Hughes LE, Smith PA, Bonell S, Natt RS, Wilson C, Rashid T, et al. Cross-reactivity between related sequences found in Acinetobacter sp., Pseudomonas aeruginosa, myelin basic protein and myelin oligodendrocyte glycoprotein in multiple sclerosis. J Neuroimmunol. 2003 Nov;144(1-2):105-15. https://doi.org/10.1016/s0165-5728(03)00274-1 https://doi.org/https://doi.org/10.1016/...
Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models	n=142 (stool samples from 71 patients with MS and 71 controls)	Increased Akkermansia muciniphila and Acinetobacter calcoaceticus in patients, which induced pro-inflammatory responses. Reduced Parabacteroides distasonis in patients with stimulated anti-inflammatory IL-10-expressing human CD4+CD25+ T cells and IL-10+FoxP3+ Tregs in mice. Microbiota transplants from patients into germ-free mice induced more severe experimental autoimmune encephalomyelitis compared with controls.	Cekanaviciute et al.²⁴24. Cekanaviciute E, Yoo BB, Runia TF, Debelius JW, Singh S, Nelson CA, et al. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proc Natl Acad Sci U S A. 2017 Oct;114(40):10713-8. https://doi.org/10.1073/pnas.1711235114 https://doi.org/https://doi.org/10.1073/...
Gut microbiota in multiple sclerosis: Possible influence of immunomodulators	n=15 (7 patients with MS and eight controls)	Lower abundance of Faecalibacterium in patients. Different community composition in patients treated with Glatiramer acetate regarding Bacteroidaceae, Faecalibacterium, Ruminococcus, Lactobacillaceae, Clostridium, and other Clostridiales. Untreated patients had an increase in the Akkermansia, Faecalibacterium, and Coprococcus genera after vitamin D supplementation compared to the other groups.	Cantarel et al.²⁶26. Cantarel BL, Waubant E, Chehoud C, Kuczynski J, Desantis TZ, Warrington J, et al. Gut microbiota in multiple sclerosis: Possible influence of immunomodulators. J Investig Med. 2015 Jun;63(5):729-34. https://doi.org/10.1097/JIM.0000000000000192 https://doi.org/https://doi.org/10.1097/...
Alterations of the human gut microbiome in multiple sclerosis	n=103 (60 patients with RRMS and 43 controls)	Increased abundances of Prevotella and Sutterella in patients using a disease-modifying treatment and decreased Sarcina, compared with untreated patients.	Jangi et al.²⁷27. Jangi S, Gandhi R, Cox LM, Li N, Von Glehn F, Yan R, et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. 2016 Jun;7:1-11. https://doi.org/10.1038/ncomms12015 https://doi.org/https://doi.org/10.1038/...
Associations between the gut microbiota and host immune markers in pediatric multiple sclerosis and controls	n=24 (15 pediatric patients with RRMS and nine controls).	There was no difference in immune markers (Th2, Th17, and Tregs) between patients and controls, although there were divergent gut microbiota associations. There was a positive correlation between richness and Th17 in patients. Bacteroidetes were inversely associated with Th17 in patients, and Fusobacteria correlated with Tregs in controls.	Tremlett et al.²⁸29. Saresella M, Mendozzi L, Rossi V, Mazzali F, Piancone F, LaRosa F, et al. Immunological and clinical effect of diet modulation of the gut microbiome in multiple sclerosis patients: A pilot study. Front Immunol. 2017 Oct;8:1-11. https://doi.org/10.3389/fimmu.2017.01391 https://doi.org/https://doi.org/10.3389/...
Immunological and Clinical Effect of Diet Modulation of the Gut Microbiome in Multiple Sclerosis Patients: A Pilot Study	n=20 (20 patients with RRMS with follow-up of 12 months)	In the group with HV/LP diet compared to the western diet group, the Lachnospiraceae family was more abundant, IL-17-producing and PD-1-expressing T CD4+ lymphocytes were significantly decreased. The relapse rate in 12 months and the EDSS score were significantly reduced.	Saresella et al.²⁹29. Saresella M, Mendozzi L, Rossi V, Mazzali F, Piancone F, LaRosa F, et al. Immunological and clinical effect of diet modulation of the gut microbiome in multiple sclerosis patients: A pilot study. Front Immunol. 2017 Oct;8:1-11. https://doi.org/10.3389/fimmu.2017.01391 https://doi.org/https://doi.org/10.3389/...

Species	Diagnosis (n, age)/Stroke model (n)	Biological sample	Methods	Main shifts in gut microbiota composition (genus/phylum)	References
Human	- 531 Finnish males - 45-70 years old - From the general population of the METabolic Syndrome In Men (METSIM) study	- Stool - Fasting blood samples	- 16S rRNA gene amplification - NMR spectroscopy - liquid chromatography with on-line tandem mass spectrometry (LC-MS/MS)	- ↑ Prevotella and Peptococcaceae were associated with ↑ plasmatic TMAO - ↑ Unclassified Clostridales was associated with ↑ plasmatic TMAO and ↑ glutamine levels - ↑ Tenericutes and Christensenellaceae were associated with ↑ acetate levels, ↑ HDL levels, ↓ BMI, and ↓ TG - ↑ Christensenellaceae associated with ↓ leucine and ↓ isoleucine - ↑ Blautia and Dorea were associated with high serum levels of glycerol, monounsaturated fatty acids, and saturated fatty acids - ↑ Methanobacteriaceae and Coprococcus was associated with lower levels of TGs	Org et al.³⁷37. Org E, Blum Y, Kasela S, Mehrabian M, Kuusisto J, Kangas AJ, et al. Relationships between gut microbiota, plasma metabolites, and metabolic syndrome traits in the METSIM cohort. Genome Biol. 2017 Apr;18(1):70. https://doi.org/10.1186/s13059-017-1194-2 https://doi.org/https://doi.org/10.1186/...
Human	- 349 Dutch ischemic and hemorrhagic stroke patients, median age 71 years - Collected within 24 h of hospital admission - 51 Dutch outpatient age- and sex-matched non-stroke controls, median age 72 years	- Plasma protein biomarkers - Rectal swabs	- H-NMR spectroscopy - LC-MS - 16S rRNA amplicon sequencing	-↑ Escherichia/Shigella, Peptoniphilus, Ezakiella, and Enterococcus (potentially invasive aerobic bacterial genera) in patients with ischemic stroke and cerebral hemorrhage. - ↑ Blautia, Subdoligranulum, and Bacteroides in controls and patients with a TIA. - Stroke patients displayed a higher prevalence of TMA-producing bacteria and lower plasma levels of TMAO - Loss of butyrate-producing bacteria in stroke patients	Haak et al.³⁸38. Haak BW, Westendorp WF, van Engelen TSR, Brands X, Brouwer MC, Vermeij JD, et al. Disruptions of anaerobic gut bacteria are associated with stroke and post-stroke infection: a prospective case-control study. Transl Stroke Res. 2020 Oct;1-12. https://doi.org/10.1007/s12975-020-00863-4 https://doi.org/https://doi.org/10.1007/...
Human	- 30 Chinese patients with cerebral ischemic stroke (21 males, nine females) - 30 healthy Chinese control (18 males, 12 females) - Mean age in CI was 60.47±10.57 vs. 64.17±12.67 in the control group	- Fecal samples - Blood levels of HDL, LDL, GLUC, UA, TG, and HCY	- Amplification of the V1-V2 region of the 16S rRNA gene	- ↑ Short-chain fatty acids producers such as Odoribacter, Akkermansia, Ruminococcaceae_UCG_005, norank_p_Flavobacteriaceae, norank_p_Parcubacteria, and Victivallis in the CI group.	Li et al.³⁹39. Li N, Weng X, Sun C, Wu X, Lu M, Si Y, et al. Change of intestinal microbiota in cerebral ischemic stroke patients. BMC Microbiol. 2019 Aug;19(1):1-8. https://doi.org/10.1186/s12866-019-1552-1 https://doi.org/https://doi.org/10.1186/...
Human	- 12 Swedish patients with symptomatic atherosclerotic plaques (who had undergone carotid endarterectomy for minor ischemic stroke, transient ischemic attack or amaurosis fugax) - 13 Swedish sex- and age-matched controls.	- Stool samples - Serum b-Carotene and lycopene	- Shotgun metagenomics.	- ↑ Collinsella was enriched in patients with symptomatic atherosclerosis - Genes encoding peptidoglycan synthesis were enriched in patients - Depletion of genes encoding phytoene dehydrogenase in patients - ↓ b-carotene (antioxidant) in patients	Karlsson et al.⁴¹41. Karlsson FH, Fåk F, Nookaew I, Tremaroli V, Fagerberg B, Petranovic D, et al. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nat Commun. 2012 Dec;3(1):1245. https://doi.org/10.1038/ncomms2266 https://doi.org/https://doi.org/10.1038/...
C57BL/6J and Rag1/ mice	- Two distinct models of acute MCA occlusion: fMCAo and fMCAo	- Mice feces	- 16S rRNA amplicon	- ↓ Species diversity and bacterial overgrowth of bacteroidetes were identified as hallmarks of poststroke dysbiosis - Dysbiotic microbiome induces: ↓ intestinal motility, intestinal barrier dysfunction, a pro-inflammatory T-cell polarization in the intestine, and ischemic brain - Therapeutic FMT improves stroke outcome	Singh et al.⁴²42. Singh V, Roth S, Llovera G, Sadler R, Garzetti D, Stecher B, et al. Microbiota dysbiosis controls the neuroinflammatory response after stroke. J Neurosci. 2016 Jul;36(28):7428-40. https://doi.org/10.1523/JNEUROSCI.1114-16.2016 https://doi.org/https://doi.org/10.1523/...
Human	- Chinese patients with large-artery atherosclerotic ischemic stroke and TIA (322 provided blood samples and 141 provided fecal samples). - Chinese asymptomatic controls (231 provided blood samples and 94 provided fecal samples). - 18 to 80 years	- Blood TMAO levels - Fresh fecal sample	- LC-MS - Pyrosequencing of 16S rRNA tags	- ↑ Opportunistic pathogens, such as Enterobacter, Megasphaera, Oscillibacter, and Desulfovibrio in stroke and transient ischemic attack group. - ↓ Commensal or beneficial genera including Bacteroides, Prevotella, and Faecalibacterium in patients group. - ↓ TMAO level in the stroke and transient ischemic attack patients	Yin et al.⁴⁵45. Yin J, Liao SX, He Y, Wang S, Xia GH, Liu FT, et al. 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. 2015 Nov;4(11):e002699. https://doi.org/10.1161/JAHA.115.002699 https://doi.org/https://doi.org/10.1161/...
Human (males) and C57BL/6 mice	- Stroke cohort: 104 Chinese patients with acute ischemic stroke and 90 healthy Chinese individuals - Validation cohort: 83 Chinese patients and 70 healthy Chinese individuals - 18 to 80 years. - Experimental Stroke MCA occlusion (mice) - Stroke Dysbiosis Index (SDI) model	- Fecal samples	- 16S rRNA gene V4 region	- ↑ Butyricimonas, Un Rikenellaceae, Un Ruminococcaceae, Oscillospira, Bilophila, Un Enterobacteriaceae and Parabacteroides and ↓ Fecalibacterium, Clostridiaceae, and Lachnospira in patients with higher SDI - SDI was significantly higher in stroke patients than in healthy controls - A higher SDI increased the probability of unfavorable outcomes. - Mice that received FMT from high-SDI patients developed severe brain injury with elevated IL-17+ γδ T cells in the gut compared to mice receiving FMT from low-SDI patients	Xia et al.⁴⁶46. Xia GH, You C, Gao XX, Zeng XL, Zhu JJ, Xu KY, et al. Stroke dysbiosis index (SDI) in gut microbiome are associated with brain injury and prognosis of stroke. Front Neurol. 2019 Apr;10:397. https://doi.org/10.3389/fneur.2019.00397 https://doi.org/https://doi.org/10.3389/...

Species	Diagnosis (n, age)	Intervention	Biological Sample	Methods	Main shifts in gut microbiota composition (genus/phylum)/Outcome	Reference
Human	- 25 American AD patients and 88 asymptomatic control group. - Age- and sex-matched (mean ±70.3)	NA	- Fecal samples - CSF biomarkers included Aβ42/Aβ40, phosphorylated tau (p-tau), the ratio of p-tau/Aβ42, and chitinase-3-like protein 1 (YKL-40)	- 16S rRNA sequencing (V4)	- Decreased richness and diversity in the AD group - ↑ In the phylum Bacteroidetes and Bacteroides at genus level in the AD group - ↓ Actinobacteria phylum and Bifidobacterium genus in the AD group. - Significant associations between CSF biomarker YKL-40 and abundance of Bacteroides, Turicibacter, and SMB53 (family Clostridiaceae) in the AD group	Vogt et al.⁵²52. Vogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC, et al. Gut microbiome alterations in Alzheimer’s disease. Sci Rep. 2017 Oct;7(1):13537. https://doi.org/10.1038/s41598-017-13601-y https://doi.org/https://doi.org/10.1038/...
Human	- 97 Chinese subjects: 33 AD, 32 aMCI, and 32 HC - Aged 50 to 85 years	NA	- Fecal samples	16S rRNA Miseq sequencing (V3-V4 region)	- ↓ Microbial diversity in the AD group - Proteobacteria was highly enriched in the AD group - The models based on the abundance of family Enterobacteriaceae could distinguish AD from both aMCI (AUC=0.688) and HC (AUC=0.698)	Liu et al.⁵³53. Liu P, Wu L, Peng G, Han Y, Tang R, Ge J, et al. Altered microbiomes distinguish Alzheimer’s disease from amnestic mild cognitive impairment and health in a Chinese cohort. Brain Behav Immun. 2019 Aug;80:633-43. https://doi.org/10.1016/j.bbi.2019.05.008 https://doi.org/https://doi.org/10.1016/...
Human	- 17 American participants (11 had mild cognitive impairment and 6 were cognitively normal) - Age: 64.6±6.4 years	- MMKD versus for 6-weeks separated by 6-weeks washout periods	- Fecal samples - Short-chain fatty acids (SCFAs), Aβ-40, Aß-42, total tau, and Tau-p181 before and after diet interventions	- 16S rRNA gene sequencing (V4 region) - HPLC	- ↑ Abundance of Proteobacteria in MCI group - At the family level MCI group had ↑ abundance of Enterobacteriaceae and Mogibacteriaceae - ↑ Abundance of genera Phascolarctobacterium and Coprococcus in MCI group. - Proteobacteria correlate positively with the Aβ-42/Aβ-40 ratio in the MCI group - ↑ Abundance of Enterobacteriaceae, Akkermansia, Slackia, Christensenellaceae, and Erysipelotriaceae on MMKD - MMKD slightly reduces fecal lactate and acetate while increasing propionate and butyrate	Nagpal et al.⁵⁶56. Nagpal R, Neth BJ, Wang S, Craft S, Yadav H. Modified Mediterranean-ketogenic diet modulates gut microbiome and short-chain fatty acids in association with Alzheimer’s disease markers in subjects with mild cognitive impairment. EBioMedicine. 2019 Sep;47:529-42. https://doi.org/10.1016/j.ebiom.2019.08.032 https://doi.org/https://doi.org/10.1016/...

Species	Diagnosis (n, age)/Epilepsy model (n)	Intervention	Biological Sample	Methods	Main shifts in gut microbiota composition (genus/phylum)/Outcome	Reference
Swiss Webster mice	- 6-Hz-induced seizure model of refractory epilepsy - Kcna1 ^-/- mouse model for TLE and SUDEP - 3-4-week-old male and female mice	KD for 14 days	- Fecal and blood samples - FMT	- 16S rDNA profiling - Metabolomics - Bacterial FISH	-↑ Relative abundance of Akkermansia muciniphila and Parabacteroides - ↑ GABA/glutamate in the hippocampus - ↓ γ-glutamylated amino acids in both colonic lumenal content and sera	Olson et al.⁶¹61. Olson CA, Vuong HE, Yano JM, Liang QY, Nusbaum DJ, Hsiao EY. The gut microbiota mediates the anti-seizure effects of the ketogenic diet. Cell. 2018 Jun;173(7):1728-1741.e13. https://doi.org/10.1016/j.cell.2018.04.027 https://doi.org/https://doi.org/10.1016/...
Human	- 12 Swedish children with drug-resistant epilepsy, 3 to 15 years old - 11 healthy Swedish controls (patients’ parents)	- Classic KD for three months	- Blood levels of glucose and β-hydroxybutyric acid - Fecal samples	Shotgun metagenomic	- ↓ Bifidobacterial, Actinobacteria, E. rectale and Dialister - ↑ Relative abundance of E. coli	Lindefeldt et al.⁶²62. Lindefeldt M, Eng A, Darban H, Bjerkner A, Zetterström CK, Allander T, et al. The ketogenic diet influences taxonomic and functional composition of the gut microbiota in children with severe epilepsy. NPJ Biofilms Microbiomes. 2019 Jan;5(1):1-13. https://doi.org/10.1038/s41522-018-0073-2 https://doi.org/https://doi.org/10.1038/...
Human	- 20 Chinese patients with refractory epilepsy - 14 males, six females - Median age 4.2 years	- Classic KD for six months	- Fecal samples - Blood glucose and ketones levels	- V3 and V4 amplification of the 16S rRNA gene	- Overall, KD reduced gut biodiversity - ↓ Abundance of Firmicutes and Actinobacteria and ↑ Bacteroides - Clostridiales, Ruminococcaceae, Rikenellaceae, Lachnospiraceae, and Alistipes were enriched in the refractory group	Zhang et al.⁶³63. Zhang Y, Zhou S, Zhou Y, Yu L, Zhang L, Wang Y. Altered gut microbiome composition in children with refractory epilepsy after ketogenic diet. Epilepsy Res. 2018 Sep;145:163-8. https://doi.org/10.1016/j.eplepsyres.2018.06.015 https://doi.org/https://doi.org/10.1016/...
Human	- 14 Chinese children with refractory epilepsy-30 age-matched healthy infants	- Classic KD for one week	- Fecal samples	16S rRNA sequencing	- 64% of epileptic infants improved (50% decrease in seizure frequency) - ↑ Bacteroides, Prevotella, and Bifidobacterium after treatment. - ↓ Proteobacteria after KD	Xie et al.⁶⁴64. Xie G, Qian Z, Qiu C-Z, Dai W-K, Wang H-P, Li Y-H, et al. Ketogenic diet poses a significant effect on imbalanced gut microbiota in infants with refractory epilepsy. World J Gastroenterol. 2017 Sep;23(33):6164-71. https://doi.org/10.3748/wjg.v23.i33.6164 https://doi.org/https://doi.org/10.3748/...
Human	- 8 Korean children with refractory epilepsy aged 1 to 7 years - 32 age-matched healthy controls	NA	-Fecal samples	- 16S rRNA gene (V3-V4) sequencing	- ↓ Bacteroidetes, Proteobacteria and ↑ Actinobacteria in epileptic group - ↓ Microbial richness in epileptic patients. - Biomarkers for refractory epilepsy were: Enterococcus faecium, Bifidobacterium longum, and Eggerthella lenta	Lee et al.⁶⁶66. Lee K, Kim N, Shim JO, Kim G-H. Gut bacterial dysbiosis in children with intractable epilepsy. J Clin Med. 2021 Jan;10(1):5. https://doi.org/10.3390/jcm10010005 https://doi.org/https://doi.org/10.3390/...
Human	- 30 Turkey patients with idiopathic focal epilepsy (16 men, 14 women, mean age of 41.3 years) - 10 healthy controls (mean age 31.7)	NA	- Fresh stool samples	- 16s rDNA (V3-V4) sequencing	-↑Proteobacteria in patients - ↑Campylobacter, Delftia, Haemophilus, Lautropia, Neisseria in IFE group	Şafak et al.⁶⁷67. Şafak B, Altunan B, Topçu B, Eren Topkaya A. The gut microbiome in epilepsy. Microb Pathog. 2020 Feb;139:103853. https://doi.org/10.1016/j.micpath.2019.103853 https://doi.org/https://doi.org/10.1016/...
Human	- Chinese patients (males and females) with epilepsy - Drug-resistant (n=42) - Drug-sensitive (n=49) - 65 healthy controls - 5 to 50 years old	NA	- Fecal samples	- V3-V4 amplification of the 16S rRNA gene	- ↑ Abundance of Verrucomicrobia and rare microbiota in patients with DRE - ↑ Bifidobacteria and Lactobacillus in patients with ≤4 seizures per year	Peng et al.⁶⁸68. Peng A, Qiu X, Lai W, Li W, Zhang L, Zhu X, et al. Altered composition of the gut microbiome in patients with drug-resistant epilepsy. Epilepsy Res. 2018 Nov;147:102-7. https://doi.org/10.1016/j.eplepsyres.2018.09.013 https://doi.org/https://doi.org/10.1016/...
Human	- Chinese participants. - Exploration cohort: 55 patients and 46 controls - Validation cohort 13 patients and ten controls - Ages ranged from 15 to 60 years - Create a model to distinguish DRE from DSE	NA	- Fecal samples	- 16S rRNA (V3-V4) sequencing	- ↓ Alfa diversity in patients - At the phylum level, patients had: ↑ Actinobacteria and Verrucomicrobia, and ↓ Proteobacteria - At the genus level, patients demonstrated: ↑ Prevotella_9, Blautia, and Bifidobacterium - The phylum Cyanobacteria and genus Parabacteroides were depleted in the DRE group - Fecal microbiota could serve as a potential biomarker for disease diagnosis	Gong et al.⁶⁹69. Gong X, Liu X, Chen C, Lin J, Li A, Guo K, et al. Alteration of gut microbiota in patients with epilepsy and the potential index as a biomarker. Front Microbiol. 2020 Sep;11:517797. https://doi.org/10.3389/fmicb.2020.517797 https://doi.org/https://doi.org/10.3389/...
Human	- Pilot study - 45 patients with DRE - Mean age 44 years	A mixture of 8 bacterial species (probiotics) daily for four months	Levels of cD-14, interleukin 6, and γ-aminobutyric acid were analyzed	NA	28.9% of all patients displayed a greater than 50% reduction in the number of seizures	Gómez-Eguílaz et al.⁷⁰70. Gómez-Eguílaz M, Ramón-Trapero JL, Pérez-Martínez L, Blanco JR. The beneficial effect of probiotics as a supplementary treatment in drug-resistant epilepsy: A pilot study. Benef Microbes. 2018 Dec;9(6):875-81. https://doi.org/10.3920/BM2018.0018 https://doi.org/https://doi.org/10.3920/...
Human	- 6 Dutch patients with DRE - 10-16 years old	- Antibiotics exposure	NA	NA	- Patients without seizures (short-term) during antibiotic treatment	Braakman and van Ingen⁷¹71. Braakman HMH, van Ingen J. Can epilepsy be treated by antibiotics? J Neurol. 2018 Aug;265(8):1934-6. https://doi.org/10.1007/s00415-018-8943-3 https://doi.org/https://doi.org/10.1007/...

Species	Diagnosis (n, age)	Intervention	Biological Sample	Methodology	Main shifts in gut microbiota composition (genus/phylum)/Outcome	Reference
Human	- 55 Finnish patients with PD (mean age 67.63±5.21 years) - 56 controls (mean age 66.38±6.73 years)	NA	- Fecal and plasma samples	- V3-V4 regions of the 16S rRNA gene - Gas chromatograph	- ↑ Calprotectin and ↓ SCFAs in the stool of participants with PD (sex-dependent manner) - Fecal zonulin correlated positively with fecal NGAL - Butyric acid levels were higher in PD patients with the Prevotella enterotype	Aho et al.⁷⁴74. Aho VTE, Houser MC, Pereira PAB, Chang J, Rudi K, Paulin L, et al. Relationships of gut microbiota, short-chain fatty acids, inflammation, and the gut barrier in Parkinson’s disease. Mol Neurodegener. 2021 Feb;16(1):6. https://doi.org/10.1186/s13024-021-00427-6. https://doi.org/https://doi.org/10.1186/...
Human	- 64 Finnish patients with Parkinson’s (mean age 65.2±5.52) - 64 Finnish control individuals (mean age 64.45±6.9)	NA	- Fecal samples	16S rRNA gene sequencing (V3-V4 region)	- Progressed PD patients had a Firmicutes-dominated enterotype more often than stable patients or control subjects - ↓ Abundance of Prevotella in faster-progressing PD patients	Aho et al.⁷⁵75. Aho VTE, Pereira PAB, Voutilainen S, Paulin L, Pekkonen E, Auvinen P, et al. Gut microbiota in Parkinson’s disease: temporal stability and relations to disease progression. EBioMedicine. 2019 Jun;44:691-707. https://doi.org/10.1016/j.ebiom.2019.05.064 https://doi.org/https://doi.org/10.1016/...
	- Samples were collected twice, on average 2.5 years apart
Human	- 51 Chinese PD patients (mean age 62.4±8.2 years) - 48 age-matched, healthy controls (mean age 62.2±9.2 years)	NA	- Fecal samples	- 16S-rRNA gene sequencing (V4 region)	- PD patients showed decreased species richness, phylogenetic diversity, β-diversity, and altered relative abundance in several taxa - ↑ Akkermansia and ↓ Lactobacillus in PD patients	Li et al.⁷⁶76. Li C, Cui L, Yang Y, Miao J, Zhao X, Zhang J, et al. Gut microbiota differs between parkinson’s disease patients and healthy controls in northeast China. Front Mol Neurosci. 2019 Jul;12:171. https://doi.org/10.3389/fnmol.2019.00171 https://doi.org/https://doi.org/10.3389/...
Human	- 72 Finnish PD patients (mean age 65.3±5.5) - 72 control subjects (mean age 64.5±6.9)	NA	- Fecal samples	- 16S rRNA gene Pyrosequencing (V1-V3 regions)	- ↓ Abundance of Prevotellaceae in feces of PD patients (by 77.6% as compared with controls) - The relative abundance of Enterobacteriaceae was positively associated with the severity of postural instability and gait difficulty	Scheperjans et al.⁷⁷77. Scheperjans F, Aho V, Pereira PAB, Koskinen K, Paulin L, Pekkonen E, et al. Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord. 2015 Mar;30(3):350-8. https://doi.org/10.1002/mds.26069 https://doi.org/https://doi.org/10.1002/...

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[1] Correspondence: Iscia Lopes-Cendes; Email: icendes@unicamp.br.