Microbiota shaping — the effects of probiotics, prebiotics, and fecal microbiota transplant on cognitive functions: A systematic review

Table 1 Summarizing of all selected studies

Ref.	Study design	Setting	Characteristics of the studied population	Number of participants (M/F)	Intervention	Comparison	Duration of intervention	Outcomes	Compliance
Agahi et al[23], 2018	RCT	Cities: Emam Ali, Golabchi, Miad, Barekat; Country: Iran	Patients with Alzheimer disease; Age: 65-90 yr; Control group: 80.57 ± 1.79 yr; Intervention group: 79.70 ± 1.72 yr	Total: 48; Control group = 23 (10/13); Intervention group = 25 (7/18)	1 capsule with L. fermentum, L. plantarum, B. lactis and 1 capsule with L. acidophilus, B. bifidum, and B. longum (3 × 109 CFU)	Placebo	12 wk	TYM	-
Akbari et al[24], 2016	RCT	Cities: Golabchi, Sadeghyeh; Country: Iran	Patients with Alzheimer disease; Age: 60-95 yr; Control group: 82.00 ± 1.69 yr; Intervention group: 77.67 ± 2.62 yr	Total: 60; Control group = 30 (24/6); Intervention group = 30 (24/6)	200 mL/d probiotic milk containing L. acidophilus, L. casei, B. bifidum, and L. fermentum (2 × 109 CFU each)	Placebo	12 wk	MMSE	-
Bagga et al[25], 2018	RCT	City: Graz Country: Austria	Healthy volunteers; Age: 20-40 yr; Control group (placebo): 27.25 ± 5.78 yr; No intervention group: 23.87 ± 4.97 yr; Intervention group: 28.27 ± 4.2 yr	Total: 45; Control group = 15 (9/6); No intervention group = 15 (7/8); Intervention group = 15 (7/8)	1 sachet/d with 3 g freeze-dried powder containing L. casei W56, L. acidophilus W22, L. paracasei W20, B. lactis W51, L. salivarius W24, L. lactis W19, B. lactis W52, L. plantarum W62 and B. bifidum W23(7.5 × 106 CFU/g)	Placebo or no intervention	4 wk	PANAS, SCL-90, ADS, LEIDS, RM task, ED task	-
Bajaj et al[26], 2014	RCT	City: Richmond, Virginia Country: United States	Patients with hepatic encephalopathy; Age: 18-65 yr; Control group: 58.5 ± 4.5 yr; Intervention group: 58.4 ± 3.8 yr	Total: 30; Control group = 16 (12/4); Intervention group = 14 (10/4)	L. rhamnosus GG (ATCC 53103)(> 50 billion CFU/gm)	Placebo	8 wk	NCT-A, NCT-B, DS, BDT	-
Bajaj et al[27], 2017	RCT	City: Richmond, Virginia Country: United States	Patients with hepatic encephalopathy; Mean age: 62 yr; Control group: 62.9 ± 9.8 yr; Intervention group: 64.5 ± 5.1 yr	Total: 20; Control group = 10 (10/0); Intervention group = 10 (10/0)	FMT units (90 mL total) instilled by enema and retained for 30 min	Standard of care	20 wk	EncephalApp-Stroop, PHES	-
Bajaj et al[28], 2019	RCT	City: Richmond, Virginia Country: United States	Patients with hepatic encephalopathy; Control group: 64.2 ± 6.2 yr; Intervention group: 63.3 ± 4.2 yr	Total: 20; Control group = 10 (8/2); Intervention group = 10 (8/2)	FMT capsules (550 μL of stool and buffer solution)	Placebo	20 wk	EncephalApp-Stroop, PHES	-
Benton et al[29], 2007	RCT	City: Swansea Country: Wales	Healthy volunteers; Age: 48-79 yr; Average age 61.8 ±7.3 yr	Total: 126 (51/75)	65 mL of milk drink containing L. casei Shirota (108/mL)	Placebo	3 wk	POMS, WMS, VFT, NART, Ability to recall the capital cities of countries	-
Buigues et al[30], 2016	RCT	City: Valencia Country: Spain	People with frailty syndrome; Age: 66-90 yr; Control group: 73.4 ± 1.8 yr; Intervention group: 74.2 ± 1.6 yr	Total: 50; Control group = 22 (6 /16); Intervention group = 28 (9/19)	7.5 g/d of Darmocare Pre® (Inulin 3375 mg, FOS 3488)	Placebo	13 wk	MMSE	-
Capitão et al[31], 2020	RCT	Cities: Swindon, Milton Keynes, London Country: United Kingdom	Healthy scholars; Age: 7-9 yr; Control group: 9.12 ± 1.02 yr; Intervention group: 8.54 ± 0.79 yr	Total: 35; Control group = 18 (12/6); Intervention group = 17 (12/5)	5.5 g/d of Bimuno (B-GOS, Lactose, Glucose, Galactose)	Placebo	12 wk	BAS-III, CogTrackTM battery, STAIC, MFQ	High (> 80%)
Ceccarelli et al[32], 2017	RCT	City: Rome Country: Italy	HIV-1 infected individuals; Median age: 48 (IQR: 38-54) yr; Intervention group: 45 (35-52.5) yr; Control group: 43 (38.2-53) yr	Total: 35; Control group = 26 (24/2); Intervention group = 9 (9/0)	Sachet containing L. plantarum DSM 24730 S. thermophilus DSM 24731, B. breve DSM 24732, L. paracasei DSM 24733, L. delbrueckii subsp. bulgaricus DSM 24734, L. acidophilus DSM 24735 B. longum DSM 24736, and B. infantis DSM 24737(450 × 109 bacteria)	Control group	24 wk	ROCF, RAVLT, STEP, VST, PVF, SVF, SPM, DS, CBTT, AAT, TMT A, TMT B	-
Chung et al[33], 2014	RCT	City: Jeonju Country: Korea	Healthy volunteers; Age: 60-75 yr; Control group: 64.50 ± 4.84 yr; Intervention group (500 mg): 64.50 ± 2.17 yr; Intervention group (1000 mg): 64.43 ± 4.47 yr; Intervention group (2000 mg): 66.56 ± 4.98 yr	Total: 36; Control group = 10 (4/6); Intervention group (500 mg) = 10 (9/1); Intervention group (1000 mg) = 7 (2/5); Intervention group (2000 mg) = 9 (5/4)	Daily doses of 500, 1000, or 2000 mg. of tablet containing L. helveticus IDCC3801	Placebo	12 wk	DS, SRT, VLT, RVIP, SCWT	> 70%
Inoue et al[34], 2018	RCT	City; Hyogo prefecture, Country: Japan	Healthy volunteers; Average age: 70.3 ± 3.1 yr; Control group: 70.9 ± 3.2 yr; Intervention group: 69.9 ± 3.0 yr	Total: 38; Control group = 18 (7/11); Intervention group = 20 (7/13)	Sachet containing lyophilised powder of B. longum BB536, B. infantis M-63, B. breve M-16V and B.breve B-3 (1.25 × 1010 CFU each)	Placebo	12 wk	MoCA, Modified flanker task, PHQ-9, GAD-7	> 99%
Hwang et al[35], 2019	RCT	City: Jeonju Country: South Korea	People with mild cognitive impairment; Age: 55-85 yr; Control group: 69.2 ± 7.00 yr; Intervention group: 68.0 ± 5.12 yr	Total: 100; Control group = 50 (14/36); Intervention group = 50 (20/30)	Mixture of fermented soybean powder and L. plantarum C29 (1.25 × 1010 CFU/g)	Placebo	12 wk	VLT, DS, ACPT	> 90%
Kelly et al[36], 2017	RCT	City: Cork Country: Ireland	Healthy volunteers; Age: 20-33 yr; Placebo/Probiotic group: 23.6 ± 0.97 yr; Probiotic/Placebo group: 25.64 ± 1.14 yr	Total: 29; Placebo/Probiotic group = 15 (15/0); Probiotic/Placebo group = 14 (14/0)	Active capsules contained corn starch, magnesium stearate, silicon dioxide and L. Rhamnosus(1 × 109 CFU)	Placebo	8 wk	MOT, PAL, AST, RVIP, ERT, Emotional Stroop	-
Kobayashi et al[37], 2019	RCT	City: Tokyo Country: Japan	People with memory complaints; Age: 50-80 yr; Control group: 61.6 ± 6.37 yr; Intervention group: 61.5 ± 6.83 yr	Total: 117; Control group = 58 (29/29); Intervention group = 59 (29/30)	1 capsule per day with B. breve A1 (> 2 × 1010 CFU)	Placebo	12 wk	RBANS, MMSE	-
Lew et al[38], 2019	RCT	Cities: Penang, Kubang Kerian Country: Malaysia	Stressed adults; Age: 18-60 yr; Control group: 32.1 ± 11.4 yr; Intervention group: 31.3 ± 10.8 yr	Total: 103; Control group = 51 (12/39); Probiotic group = 52 (12/40)	L. plantarum P8 (1010 CFU/sachet per day)	Placebo	12 wk	PSS-10, DASS-42, CBB	-
Ohsawa et al[39], 2018	RCT	Country: Japan	People with forgetfulness; 50-70 yr; Control group: 57.8 ± 5.9 yr; Intervention group: 58.5 ± 6.5 yr	Total: 60; Control group = 29 (13/16); Intervention group = 31 (13/18)	One bottle per day (190 g per bottle) of a L. helveticus-fermented milk contained 2.4 mg of lactononadecapeptide	Placebo	8 wk	RBANS, POMS	-
Papalini et al[40], 2019	RCT	City: Nijmegen Country: The Netherlands	Healthy volunteers; Age:18-40 yr; Control group: 22 yr (SE = 0.5); Intervention group: 21 yr (SE = 0.4)	Total: 58; Control group = 29 (0/29); Intervention group = 29 (0/29)	2 g/d of powder diluted in water or milk containing B. bifidum W23, B. lactis W51, B. lactis W52, L. acidophilus W37, L. brevis W63, L. casei W56, L. salivarius W24, L. lactis W19 L. lactis W58(5 × 109 CFU)	Placebo	4 wk	BDI, LEIDS-r, Emotional face-word Stroop task, Emotional face-matching paradigm, SCWT, DS, SECPT	-
Roman et al[41], 2018	RCT	City: Almerìa Country: Spain	Fibromyalgia patients; Control group: 50.27 ± 2.03 yr; Intervention group: 55.00 ± 2.09 yr	Total: 31; Control group = 15 (2/13); Intervention group = 16 (1/15)	4 pills/d containing L. Rhamnosus GG®, L. casei, L. acidophilus, and B. Bifidus (6 × 106 bacteria per capsule)	Placebo	8 wk	MMSE, BDI, IGT, Two-choice Task	-
Rudzki et al[42], 2019	RCT	City: Bialystok Country: Poland	People with major depression; Control group: 38.90 (12) yr (SD); Intervention group: 39.13 (9.96) yr	Total: 60; Control group = 30 (10/20); Intervention group = 30 (7/23)	2 capsules/d containing L. plantarum 299v (10 × 109 CFU per capsule)	Placebo	8 wk	HAM-D 17, SCL-90, PSS-10, APT, RFFT, TMT A, TMT B, CVLT Stroop Test parts A and B	-
Smith et al[43], 2015	RCT	City: Cardiff Country: Galles	Healthy volunteers; Age: 19-30 yr; Mean age 23.0 yr	Total: 47 (19/28)	One sachet of Inulin per day (5 mg)	Placebo	4 h	Mood, Performance Tasks, Memory Tasks, Psychomotor Tasks, Selective Attention Tasks, Sustained Attention Task	-
Tamtaji et al[44], 2019	RCT	City: Kashan, Shahrekord Country: Iran	Patients with Alzheimer disease; Age: 55-100 yr; Control group: 78.5 ± 8.0 yr; Intervention group (Selenium): 78.8 ± 10.2 yr; Intervention group (Selenium + probiotic): 76.2 ± 8.1 yr	Total: 79; Control group = 26; Intervention group (Selenium) = 26; Intervention group (Selenium + probiotic) = 27	Selenium (200 μg/d) and probiotic containing L. acidophilus, B. bifidum, and B. longum (2 × 109 CFU/d each)	Placebo or only selenium (200 μg/d)	12 wk	MMSE	100%
Tamtaji et al[45], 2019	RCT	City: Kashan Country: Iran	Patients with Parkinson disease; Age: 50-90 yr; Control group: 67.7 ± 10.2 yr; Intervention group: 68.2 ± 7.8 yr	Total: 60; Control group = 30; Intervention group = 30	Probiotic containing L. acidophilus, B. bifidum, L. reuteri, and L. fermentum (each 2 × 109 CFU/g)	Placebo	12 wk	MDS-UPDRS	90%

AAT: Aachener Aphasia Test; ACPT: Auditory Continuous Performance Test; ADS: Allgemeine Depressionsskala; APT: Attention and Perceptivity Test; AST: Attention Switching Task; BAS-III: British Ability Scales III; BDI: Beck Depression Inventory; BDT: Block Design Test; CBB: Cogstate Brief Battery; CBTT: Corsi Block Tapping Test; CFU: Colony-forming unit; CVLT: California Verbal Learning Test; DASS-42: Depression Anxiety and Stress Scale questionnaire; DS: Digit Symbol Test; ED: Emotional Decision Making; ERT: Emotion Recognition Task; F: Female; GAD-7: Generalised Anxiety Disorder Questionnaire-7; HAM-D 17: Hamilton Depression Rating-17; IGT: Iowa Gambling Task; LEIDS: Leiden Index of Depression Severity; M: Male; MDS-UPDRS: Movement Disorders Society-Unified Parkinson's Disease Rating Scale; MMSE: Mini Mental State Evaluation; MoCA: Montreal Cognitive Assessment instrument; MOT: Motor Screening Test; NART: National Adult Reading Test; NCT-A: Number Connection Test A; NCT-B: Number Connection Test B; PAL: Paired Associates Learning; PANAS: Positive and Negative Affect Schedule; PHES: Psychometric Hepatic Encephalopathy Score; PHQ-9: Patient Health Questionnaire-9; POMS: Profile of Mood States; PSS-10: Perceived Stress Scale-10; PVFT: Phonological Verbal Fluency (PVF) test; RAVLT: Rey Auditory Verbal Learning Test; RBANS: Repeatable Battery for the Assessment of Neuropsychological Status; RCT: Randomized controlled trial; RFFT: Ruff Figural Fluency Test; RM: Emotional Recognition Memory; ROCF: Rey-Osterrieth Complex Figure Test; RVIP: Rapid Visual Information-Processing task; SCL-90: Symptom Checklist 90; SCWT: Stroop Color and Word Test; SECPT: Socially Evaluated Cold Pressor Test; SPM: Raven’s Standard Progressive Matrices; SRT: Story Recall Test; STAIC: State-Trait Anxiety Inventory for Children; STEP: Test of Time and Weights Estimation; SVF: Semantic Verbal Fluency test; TMT-A: Trail Making Test A; TMT-B: Trail Making Test B; TYM: Test your memory; VFT: Verbal Fluency test; WMS: Wechsler Memory Scale MFQ: Children Mood and Feelings Questionnaire; VLT: Verbal Learning Test; VST: Visual Search Test.