Table 2.

Studies of Probiotic Effects on Central Nervous System Functions in Humans

Study	Participants	Probiotic	Dosage (CFU/day) and duration	CNS function	Outcome	Secondary outcome
Takada et al,50 2016	140 healthy students	L. casei Shirota YIT 9029	1 × 109 8 weeks	STAI	No difference of STAI score	Change in salivary cortisol level before exam ↓ Decrease in physical symptoms ↓
Mohammadi et al,52 2015	70 petrochemical workers	probiotic yogurt (L. acidophilus LA5 + B. lactis Bb12) + placebo capsule; Conventional yogurt (S. thermophilus and L. bulgaricus.) + probiotic capsule (L. casei, L. acidophilus, L. rhamnosus, L. bulgaricus, B. breve, B. longum, S. thermophilus)	probiotic yogurt: 107 in total Probiotic capsule: 3 × 103, 3 × 107, 7 × 109, 5 × 108, 2 × 1010; 109, 3 × 108, respectively (2.88 × 1010 in total)/6 weeks	GHQ DASS HPA axis activity	Improvement of GHQ and DASS in probiotics yogurt and probiotics capsule groups; no difference in HPA axis activity	NA
Steenbergen et al,53 2015	40 healthy volunteers	Ecologic Barrier: B. bifidum W23, B. lactis W52, L. acidophilus W37, L. brevis W63, L. casei W56, L. salivarius W24, Lactococcus lactis (W19 and W58).	5 × 109 4 weeks	LEIDS-r BDI BAI	Improvement of total score and item ‘rumination’ of LEIDS-r. No difference of scores of Beck Depression and Beck Anxiety Inventory	NA
Dickerson et al,54 2014	65 schizophrenia patients	L. rhamnosus GG (ATCC 53103+ B. animalis subsp. lactis Bb12	2 × 109 14 weeks	PANSS	No difference of toll score or positive, negative or general scores.	Severe difficulty in bowel movement ↓
Vaghef-Mehrabany et al,55 2014	46 patients with rheumatoid arthritis	L. casei 01	108 8 weeks	STAI	No difference of STAI score	Dietary: NA Cytokines: pro inflammatory cytokine TNF-α, IL-6, and IL-12 ↓, anti-inflammatory cytokine IL-10 ↑
Dapoigny et al,56 2012	50 IBS patients	L. casei subsp. rhamnosus LCR35	6 × 108 4 weeks	HADS	No difference in HADS score	IBS severity score: only clinically relevant decreased in subtype IBS-D ↓ Presence of Lactobacillus in feces: 85% of patients
Simrén et al,57 2010	74 IBS patients	Milk fermented with yoghurt bacteria L. bulgaricus + S. thermophilus and containing L. paracasei F19 + L. acidophilus La5 + B. lactis Bb12	2 × 1010 8 weeks	HADS	No difference of HADS score	Diet: same among groups
Whorwell et al,58 2006	362 female IBS patients	B. infantis 35624	106, 108, 1010 4 weeks	HADS	No difference in any of the dosages	IBS symptom: ↓ in 108 group
Reale et al,59 2012	72 male smokers	L. casei Shirota	4 × 1010 3 weeks	STAI	No difference in STAI score	Natural killer cell activity ↑ CD16+ cell ↑ BMI: NA Bowel function ↑
Parracho et al,60 2010	15 children (4–16Y) with ASD	L. plantarum WCFS1	4.5 × 1010 3 weeks	DBC	No significant difference in DBC score	Bowel function: only different in stool consistency Fecal microbiota: Lactobacillus Lab 158 ↑, Clostridium Erec482 ↓
Messaoudi et al,39 2011	55 healthy volunteers	L. helveticus R0052 + B. longum R0175	3 × 109 4 weeks	HSCL-90 HADS PSS CCL	Improvement of anxiety, depression and problem solving, and reduced UFC level in probiotics group	Median urinary free cortisol ↓
Messaoudi et al,61 2011	25 healthy volunteers (with lower UFC levels than median value at baseline	L. helveticus R0052 + B. longum R0175	3 × 109 4 weeks	HSCL-90 HADS PSS CCL	Improvement of anxiety and depression in probiotics group	NA
Rao et al,51 2009	35 CFS patients	L. casei Shirota	2.4 × 1010 8 weeks	BDI BAI	Decreased anxiety symptoms in probiotic group	Fecal microbiota: aerobes ↑, anaerobes ↑ Bifidobacteria ↑, Lactobacillus ↑
Benton et al,62 2007	124 healthy volunteers	L. casei Shirota (containing milk)	6.5 × 109 10/20 days	Questionnaire-based POMS Episodic memory (Wechsler Memory Scale) Retrieval from long-term memory Verbal fluency Eating-associated behavior NART	Improved mood in the bottom third of the POMS depressed/elated distribution at baseline in probiotics group after 20 days Improved memory in probiotics group after 20 days	NA
Tillisch et al,63 2013	36 healthy females	FMPP (B. lactis I-2494 [DN-173 010], containing yogurt starters include S. thermophilus I–1630, L. bulgaricus I–1632 and I–1519) and Lactococcus lactis subsp lactis I–1631	B. lactis : 1.25 × 1010 S. thermophilus and L. bulgaricus : 1.2 × 109 4 weeks	Standard emotional faces-attention task for fMRI	Decreased activity to emotional faces in a large distributed network Changes in midbrain connectivity during resting state	NA

STAI, State-Trait Anxiety Inventory; NA, not applicable; GHQ, General Health Questionnaire; DASS, Depression Anxiety and Stress Scale; HPA, hypothalamic-pituitary-adrenal; BMI, body mass index; LEIDS-r, Leiden Index of Depression Sensitivity-Revised; BDI, Beck Depression Inventory; BAI, Beck Anxiety Inventory; PANSS, Positive and Negative Symptom Scale; IBS, irritable bowel syndrome; HADS, Hospital Anxiety and Depression Scale; ASD, autism spectrum disorder; IBS-D, diarrhea-predominant IBS; DBC, Development Behavior Checklist; HSCL-90, Hopkins Symptom Checklist; PSS, Perceived Stress Scale; CCL, Coping Checklist; UFC, urinary free cortisol; CFS, chronic fatigue syndrome; POMS, questionnaire-based Profile of Mood State; NART, National Adult Reading Rest; FMPP, fermented milk product with probiotic; fMRI, functional magnetic resonance imaging; B. animalis, Bifidobacterium animalis; B. breve, Bifidobacterium breve; B. bifidum, Bifidobacterium bifidum; B. infantis, Bifidobacterium infantis; B. lactis, Bifidobacterium lactis; B. longum, Bifidobacterium longum; L. acidophilus, Lactobacillus acidophilus; L. brevis, Lactobacillus brevis; L. bulgaricus, Lactobacillus bulgaricus; L. casei, Lactobacillus casei; L. helveticus, Lactobacillus helveticus; L. paracasei, Lactobacillus paracasei; L. plantarum, Lactobacillus plantarum; L. rhamnosus, Lactobacillus rhamnosus; L. salivarius, Lactobacillus salivarius; S. thermophiles, Streptococcus thermophiles.