Table 3.
Human studies listed in alphabetical order describing interventions on the gut microbiota and the effects on cognition, brain structures and function, and stress.
| Author/Year | Participants/Sample * (Age M ± SD Years) | Sex (M/F) | Study Design | Treatment/Intervention | Dose/Frequency | Assessment | Main Findings—Microbiome Link |
|---|---|---|---|---|---|---|---|
| Bagga et al., (2019) [43] | n = 45 healthy (26.2 ± 4.8); n = 15 no intervention (26.9 ± 5.0); n = 15 PLA (27.3 ± 5.8); n = 15 PRO (28.3 ± 4.2) | 7/8 9/6 7/8 (22/23) |
RDBPC, parallel design study |
Ecologic®825 9 strains: Lactoba-cillus casei W56, L. acidophilus W22, L. paracasei W20, Bifidobacterium lactis W51, L. salivarius W24, Lactococcus lactis W19, B. lactis W52, L. plantarum W62 and B. bifidum W23 (PRO), maize starch and maltodextrins (PLA) or no intervention. See Bagga et al., 2018 [62] | 3 g sachet; 7.5 × 106 (PRO) or PLA once daily; 4 weeks. See Bagga et al., 2018 [62] | fMRI resting state and diffusion. | Decrease in functional connectivity in DMN, SN, VIN and MFGN (link to depression and stress disorders) vs. PLA and/or CON. |
| Berding et al., (2020) [44] |
n = 18 healthy (26 ± 1.3). Note: n = 6 withdrew |
0/18 | RDBPC, crossover design study | Litesse®Ultra (>90%PDX polymer) (PRE) or Maltodextrin (PLA) | 12.5 g sachet; PRE or PLA, once daily; 4 weeks, washout 4 weeks before cross over, another intervention 4 weeks | CANTAB tasks MTT, RVP, PAL, SSP, IED, ERT, faecal sample (16S rRNA sequencing), salivary cortisol, cytokines, acute stress response (cold pressor task). | Improved IED (cognitive flexibility) and RVP (sustained attention). |
| Carbuhn et al., (2018) [45] | n = 17 healthy; n = 8 PRO, n = 9 PLA; age NI. Note: n = 3 withdrew(2PRO/1PLA) | 0/17 | Two-group stratified randomisation, double-blind, placebo-controlled design | B. longum 35624 (PRO) or maltodextrin (PLA) | 4 mg capsule; 1 × 109 CFU PRO or PLA once daily; 6 weeks | Inflammation (12 cytokines), LPS and LPS Binding Protein, sIgA, cognitive stress-recovery assessment. | No significant effect on exercise performance or immune function. Differences in cognitive outlook between PRO and PLA, especially during intense training phase. |
| Chong et al., (2019) [46] |
n = 111 (18–60), PLA n = 55 (32.1 ± 11.0); PRO n = 56 (31.1 ± 7.8) Note: n = 12 withdrew or excluded |
NI | RDBPC, parallel design study |
Lactobacillus plantarum DR7 (PRO) or maltodextrin (PLA) | 2 g sachet; 1 × 109 CFU PRO or PLA once daily; 12 weeks | CogState Brief Battery, PSS-10, DASS-42, cortisol, cytokines, plasma neurotransmitters. | Reduced symptoms of stress and anxiety, improved several cognitive and memory functions, reduced levels of plasma cortisol and pro-inflammatory cytokines. |
| Hoffman et al., (2019) [47] |
n = 15 soldiers; PAR: n = 8 (20.0 ± 0.6); PLA n = 7 (20.2 ± 0.6). Note: n = 1 withdrew, but included in reported avg. age for PLA |
15/0 | Double-blind, parallel design study |
Inactivated Bacillus coagulans, (PAR called Staimune) or PLA (details not specified) | 1 × 109 CFU PAR or PLA once daily; 2 weeks | Serum cortisol, testosterone; IL-10., TNFα, IFNγ. | No significant differences between groups. Note: 2 weeks intervention not adequate; not adequately powdered. Trend findings identified. |
| Liu et al., (2020) [48] |
n = 111; <30: PLA n = 32 (24.9 ± 2.9); PRO n = 27 (24.8 ± 2.8). >30: PLA n = 23 (41.7 ± 9.5); PRO n = 29 (37.0 ± 6.0). Note: n = 13 withdrew or lost to follow up (6PRO/7PLA) |
NI | RDBPC | Lactobacilllus plantarum DR7 (PRO) or maltodextrin (PLA) | 2 g sachet; 1 × 109 CFU PRO or PLA once daily; 12 weeks | Faecal microbiota (16S rRNA), gastrointestinal symptoms, stress neurotransmitters. | Changes of gut microbiota along different taxonomic levels; reflective changes in neurotransmitter serotonin and dopamine pathways enzyme gene expression. |
| Ma et al., (2021) [60] | n = 79; PRO n = 43; PLA n = 36; age for updated dataset NI. Previous study Lew et al., (2019) [63]. Note: n = 24 did not provide faecal samples not included in analysis (9PRO/15PLA) | 18/61 | RDBPC (as per Lew [63]) | L. plantarum P-8 (PRO) or maltodextrin (PLA) | 2 g sachet; 2 × 1010 CFU PRO or PLA once daily; 12 weeks | Shotgun metagenomics, metabolomics for gut-brain. | Enhanced diversity of neurotransmitter synthesizing/consuming SGBs and the levels of some predicted microbial neuroactive metabolites (e.g., SCFAs, gamma-aminobutyric acid, arachidonic acid, and sphingomyelin). |
| Moloney et al., (2021) [49] | n = 20 healthy; (20.7 ± 0.28 SEM). Note: n = 10 withdrew or excluded | 20/0 | RDBPC, cross-over design |
B. longum AH1714 (PRO) or corn starch, magnesium stearate, hypromellose & titanium Dioxide (PRO) |
Capsule; 1 × 109 CFU PRO or PLA once daily for 8 weeks, 4 weeks washout before cross over, daily for another 8 weeks | PSQI, PSS-10, CANTAB (visual memory and learning (PAL), sustained attention (RVP), working memory (SSP), emotional recognition (ERT) and social cognition (RMIE)), BDI-II, faecal microbiota (16S rRNA), salivary cortisol. | Stated findings included: no statistical improvement in any cognitive element or the alleviation of stress/anxiety symptomology. INTERPRET CAUTIOUSLY: Immunological data indicated wash-out period was not sufficient = data not reliable. |
| Nishida et al., (2019) [50] |
n = 60; PAR n = 31 (24.9 ± 0.5); PLA n = 29 (25.3 ± 0.6) |
PAR: 21/10 PLA: 20/9 | RDBPC, parallel design | Lactobacillus gasseri CP2305 (heat-inactivated) (PAR) or maltose, dextrin, starch, veg oil (PLA) | Per 2 tables; 1 × 1010 CFU PAR or PLA, twice daily (2 tablets per day); 24 weeks | STAI, GHQ-28, HADS, PSQI, VAS, salivary cortisol and IgA, CgA, EEG (sleep), faecal SCFA, faecal microbiota (16S rRNA). | CP2305: reduced anxiety; improved sleep quality; reduced GHQ-depression subscores; reduced anxiety and depression (HADS); reduced reactivity physiologically from stress; improved irritability and abdominal discomfort; mitigated changes in microbiota due to stress. |
| Ostadmohammadi et al., (2019) [51] |
n = 60; healthy with PCOS; Vit D + PRO n = 30 (24.4 ± 4.7); PL n = 30 (25.4 ± 5.1) |
0/60 | RDBPC, parallel design | Vitamin D + Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus reuteri and Lactobacillus fermentum (PRO) or corn starch and oil (PLA) | 50,0000 IU Vit D every 2 weeks + 8 × 109 CFU (2 x109 CFU/g for each strain) PRO or PLA once daily; 12 weeks | Hormonal profiles, Mental health (BDI, GHQ-28, DASS, PSQI), biomarkers of inflammation and oxidative stress (serum hs-CRP, plasma TAC, GSH and MDA). | Reduced BDI, GHQ and DASS scores compared to placebo. Did not change PSQI score. Reduced testosterone, hirsutism, hs-CRP and MDA levels and increased antioxidant defenses compared to placebo. |
| Park et al., (2019) [52] | n = 39; healthy 18–65 years. SYN n = 31 (32.9 ± 17.6); PLA n = 32 (31.8 ± 16.3). Note: n = 3 from PLA excluded. n size used for avg. age and sex ratio are smaller. | SYN: 8/23; PLA: 11/21 | RDBPC, parallel design | Fermented Saccharina japonica (kelp extract; FSJ postbiotic) by Lactobacillus brevis (paraprobiotic) (SYN) or lactose (PL)) | Each active capsule contained 500 mg standardized fermented lactobacillus FSJ, 2 x capsules daily; 4 weeks | BDI, K-WAIS, operation-word span task and raven’s test-based quantitative EEG test. Serum amyloid-β, SOD. | Non-significant between groups on cog tests and biochemical measures. FSJ treated group significantly increased the percentage of correct answers and concentration for space perception for memory ability and space perception ability. |
| Sawada et al., (2019) [53] | n = 49, healthy athletes 18–22 years. PAR n = 24 (19.8 ± 1.4); PLA n = 25 (20.1 ± 1.1). | 49/0 | RDBPC, parallel design | Lactobacillus gasseri CP2305 (heat inactivated) in excipient (PRA) or excipient (PLA). Excipient = isotonic sports drink containing sweetener, acidifier, flavorings, Vit C, and minerals (Na, Ca, K, Mg) | 200 mL beverage; 1 × 1010 PRA or PLA once daily; 12 weeks | CFS, STAI, HADS, GHQ- 28, PSQI, stress and immune markers (salivary Cg A and immune cells), faecal microbiota (16S rRNA) | CP2305 decreased STAI-state and STAI-trait, improved fatigue, anxiety and depressive mood. Minor changes in bacteria composition |
| Schaafsma et al., (2021) [54] | n = 69; healthy with sleep problems age 30–50 years (M39). Note: n = 1 lost to follow-up. n = 69 for ITT analysis and n = 64 and 47 for PP and mod-PP analysis, respectively. | NI | RDBPC, cross-over design | Dairy-based product (DP) containing protein (Lactium®), prebiotic (Galacto-oligosaccharides (BiotisTM GOS), 70% pure GOS, and vitamins and minerals (PRE) or protein (Lactium®), vitamins and minerals (PLA) | Sachet; 5.2 g GOS PRE or PLA, once daily; 3 weeks. 3 weeks washout before cross over, another intervention 3 weeks |
DASS, PSQI, salivary cortisol; faecal microbiota (16 S rRNA, 1st crossover period only); note: altered endpoint of day 14 was reported on instead of day 21. | Data indicated wash-out was not sufficient and carry-over effects = data contamination. DP reduced salivary cortisol and stimulated Bifidobacterium (faecal). INTERPRET CAUTIOUSLY: contained sucralose which would have confounded gut microbiota; washout not sufficient. |
| Siegel & Conklin (2020) [55] | n = 79 (19.7); PLA n = 39 (19.9 ± 1.1); PRO n = 40 (19.4 ± 1.0) | 58/21 | RDBPC, parallel design, pilot | B. longum (PRO) or corn starch (PLA) | 400 mg; ~4.0 × 1010 CFUs or PLA, twice daily for 7 days | PSS-10; CES-D; STAI. | Non-significant changes in stress, depressive symptoms or anxiety. INTERPRET CAUTIOUSLY: intervention time-period not sufficient to elicit mental wellbeing matrices assessed. |
| Smith (2019) [56] | n = 53; 19–54 years (22). No further details provided. | 12/39 | Placebo controlled cross-over study (blinding NI) | Inulin; Oligofructose-enriched inulin (Orafti®Synergy1) (PRE) or maltodextrin (PLA) | 13 g (8 g + 5 g, split over 12 h) Acute testing, cross-over assessment next day | Mood (alertness, hedonic tone and anxiety), episodic memory, logical reasoning, semantic processing, SRT, attention lapse, cognitive vigilance | Effect of inulin was (morning): Reduced alertness, reduction in hedonic tone, poorer recall accuracy (episodic memory) and slowed semantic processing. Acute effect, not microflora influence. INTERPRET CAUTIOUSLY: Not a true prebiotic effect—timeline for effect too acute. |
| Soldi et al., (2018) [57] | n = 50; 20–35 years. Note: n = 6 withdrew/discontinued/antibiotics | NI | RDBPC, cross-over design | Lactoflorene® Plus: Lactobacillus acidophilus LA-5®, Bifidobacterium animalis subsp. lactis, BB-12®, Lactobacillus paracasei subsp. paracasei, L. CASEI 431®, Bacillus coagulans BC513, zinc, B vitamins (niacin, B1, B2, B5, B6, B12 and folic acid) (PRO) or zinc, B vitamins (niacin, B1, B2, B5, B6, B12 and folic acid) (PLA) | 10 mL liquid; 2 x 109 CFU PRO or PLA, twice daily for 45 days; washout 25 d; crossover to other intervention for 45 days | Salivary stress markers (α-amylase, cortisol, chromogranin A) and immunological parameters (sIgA, NK cell activity, IL-8, IL-10, TNF-α) in faeces, faecal microbiota (16S rRNA), gastrointestinal symptoms. | No direct effect on salivary stress markers or NK cell activity. Reduced abdominal pain and increased faecal IgA and IL-10 levels. Increased anti-inflammatory and reduced pro–inflammatory bacteria with probiotic, reductions in abdominal pain. NK cells indicate wash-out period not adequate. INTERPRET CAUTIOUSLY: It appears that due to this most results would be skewed. |
| Venkataram et al., (2020) [58] | n = 74 healthy (21.4 ± 1.5); PRO n = 36 (21.2 ± 1.6); PLA n = 38 (21.6 ± 1.3). Note: n = 6 not allocated a treatment (4PRO/2PLA). | 17/63 Note n size used for sex ratio based on original n = 80. |
RDBPC, parallel design | Bacillus coagulans Unique IS2, L. rhamnosus UBLR58, B. lactis UBBLa70, L. plantarum UBLP40 (2 billion CFU each); B. breve UBBr01, B. infantis UBBI01 (1 billion CFU each) capsule with glutamine or microcrystalline cellulose (PLA) | Capsule; 1–2 × 1010 CFU PRO + 250 mg glutamine or PLA twice daily for 28 days | PSS-10, DASS, STAI, serum cortisol. | Reduced stress on PSS-10, DASS, and STAI in students facing examination. Early morning, fasting serum cortisol levels decreased compared to placebo. |
| Wang et al., (2019) [59] | n = 40 healthy; 18–50 years; PRO n = 20 (31.0 ± 2.3); PLA n = 20 (33.0 ± 2.8). Note: n = 3 excluded from PRO (antibiotics) | PRO: 7/13; PLA: 7/13 | RDBPC, parallel design | Bifidobacterium longum 1714™ (Zenflore; PRO) or maltodextrin (PLA) | 2 g sachet; 1 × 109 CFU or PLA once daily; 4 weeks | Resting state MEG, MEG during CBG, SF36, social stress induced by CBG, measured by NTS, MQ, and SEP. | B. longum 1714 altered resting-state brain activity, and induced change in neural activity correlated with increased energy/vitality. No treatment effect on SF36 or stress. |
| Wilms et al., (2020) [35] | n = 24 heathy adults (38.2 ± 7.8) | Adults (8/16) | RDBPC, cross-over design |
Biotis™ galacto-oligosaccharide (GOS) powder (PRE) or maltodextrin (PLA) | 7.2 g sachet; 5 g of pure GOS (PRE) or PLA, 3 times daily; washout 4–6 weeks; crossover to other intervention for 4 weeks | Faecal microbiota (16S rRNA) and SCFA, breath volatiles, stimulated cytokines, CRP, MDA, TEAC and uric acid in plasma. | GOS affected microbiota composition, accompanied by increases in bifidobacteria and decreased microbial diversity in healthy adults. Faecal and breath metabolites, immune and oxidative stress markers were not affected by GOS. |
* Participants/Sample number reflects final numbers/completions. Acronyms previously not determined: probiotic (PRO); placebo (PLA); synbiotic (SYN); parabiotic (PAR); prebiotic (PRE); control (CON); not indicated (NI); randomised, double-blind, placebo-controlled trial (RDBPC); intention–to-treat (ITT); per-protocol (PP); modified per-protocol (mod-PP); colony forming units (CFU); default mode network (DMN); salience network (SN); visual network (VIN); middle and superior frontal gyrus network (MFGN); symptoms checklist-90 (SCL-90); allgemeine depressions-skala (ADS); leiden index of depression severity (LEIDS); cambridge cognition assessment battery tasks (CANTAB): motor screening test (MTT); rapid visual information processing (RVP); paired associates learning (PAL); spatial span (SSP); intra-extra dimensional set shift (IED); emotion eecognition task (ERT); read the mind in the eyes (RMIE) task; lypopolysaccharide (LPS); high sensitivity C-reactive protein (hs-CRP), total antioxidant activity (TAC), glutathione (GSH) and malondialdehyde (MDA); perceived stress scale-10 inventory (PSS-10); chalder fatigue scales (CFS); spielberger state-trait-anxiety-inventory (STAI); hospital anxiety and depression scale (HADS); 28-item general health questionnaire (GHQ- 28); pittsburgh Sleep Quality Index (PSQI); Standard Error Mean (SEM); salivary immunoglobulin-A (sIgA); Natural Killer T-cell (NK); interleukin (IL-); tumour necrosis factor (TNF); visual analogue scale (VAS); chromogranin A (CgA); encephalogram (EEG); short chain fatty acid (SCFA); polycystic ovary syndrome (PCOS); korean wechsler adult intelligence scale (K-WAIS); superoxide dismutase (SOD); simple reaction time (SRT); magnetoencephalography (MEG); short-form 36 (SF36); cyberball game (CBG); need threat scale (NTS); mood questionnaire (MQ); subjective “exclusion perception” (SEP); centre for epidemiological studies depression scale (CES-D); trolox equivalent antioxidant capacity (TEAC).