Table 1.

Studies of Effects of Probiotics on Central Nervous System Functions in Animals

Study	Animal	CNS function	Probiotic (species, dosage [CFU/day], duration)	Outcome (behavioral level)	Secondary outcome
Liu et al,20 2016	ELS mice Naïve mice	Locomotor activity (open-field test) Anxiety (open-field test, elevated plus maze) Depression (sucrose-preference test, forced-swimming test)	L. plantarum PS128 109 28 days	Locomotor activity ↑ Anxiety (only in naïve mice) ↓ Depression (only in ELS mice) ↓	Corticosteroids (CORT) ↓ Cytokine: inflammatory cytokine TNF-α, IL-6 ↓, anti-inflammatory cytokine IL-10 ↑ Brain monoamines and metabolites: 5-HT ↑, 5-HIAA ↓, DA ↑, DOPAC ↓, HVA ↓
Liu et al,21 2016	GF mice	Locomotor activity (open-field test) Anxiety (elevated-plus maze) Depression (forced-swimming test)	L. plantarum PS128 109 16 days	Locomotor activity ↑ Anxiety ↓ Depression (−)	CORT: NA Brain monoamines and metabolites: DA ↑, HVA ↑, 5-HT ↑ and 5-HIAA ↑
Liang et al,38 2015	SPF CRS rats	Stress (chronic-restraint stress) Depression (sucrose-preference test) Anxiety (elevated-plus maze, open-field test) Non-spatial memory (object-recognition test, object-placement test)	L. helveticus NS8 109 Initial 21 days	Anxiety ↓ Depression ↓ Non-spatial memory ↑	CORT and ACTH ↓ Cytokines: IL-10 ↑ Brain monoamines: 5-HT ↑ and NE ↑ BDNF expression ↑
Wang et al,30 2015	Ampicillin-treated rats	Anxiety (elevate-plus maze) Spatial memory (Morris water maze)	L. fermentum N93 109 Initial 30 days	Anxiety ↓ Spatial memory ↑	CORT and ACTH ↓ Brain monoamines: MR ↑, NMDA ↑, GR: NA Brain BDNF: NA Colon inflammation: myeloperoxidase activity ↓ Fecal microbiota: Bacteroides ↑, C. coccoides ↓, Firmicutes ↓, Lactobacillus ↑
Smith et al,29 2014	RagI−/− mice	Stress response (water-avoidance stress) Anxiety (light/dark box test) Non-spatial memory (novel-object test)	L. rhamnosus R0011 + L. helveticus R0052 6 × 109 28 days	Anxiety ↓ Non-spatial memory ↑	CORT: NA Brain c-Fos expression ↑ Intestinal permeability ↓ Fecal microbiota: Bacteroides ↑, Enterobacteriaceae ↑, Firmicutes ↑
Luo et al,42 2014	Hyperammonemia rats	Anxiety (elevate-plus maze) Spatial memory (Morris water maze)	L. helveticus NS8 109 14 days	Anxiety ↓ Spatial memory ↑	Neuroinflammation: PGE2 ↓, IL-1β ↓ Brain monoamines: 5-HT ↓ Plasma kynurenine pathway: KYN/TRP ↑, KA/KYN ↓
Savignac et al,36 2014	Mice	Anxiety (defensive marble burying, elevated-plus maze, open field) depression (tail-suspension test, forced-swim test)	B. longum 1714/B. breve 1205 109 Initial 21 days	B. longum:  Anxiety ↓  Depression ↓ B. breve:  Anxiety ↓	CORT: NA
Ohland et al,37 2013	Il-10 deficient mice	Anxiety (elevated Barnes Maze) Spatial memory (elevated Barnes maze)	L. helveticus R0052 109 21 days	Anxiety ↓ Spatial memory ↑	Colon inflammation ↓ Cytokines: NA CORT ↓ SCFA metabolites: NA
Messaoudi et al,39 2011	Rats	Anxiety (conditioned defensive burying)	B. longum R0175 + L. helveticus R0052 109 14 days	Anxiety ↓	NA
Bravo et al,23 2011	Mice	Anxiety (open arms, elevated-plus maze, fear conditioning) Depression (forced-swim test)	L. rhamnosus JB-1 109 28 days	Anxiety ↓ Depression ↓	CORT ↓ GABA receptor expression influence depending on brain areas Probiotic effect via vagus nerve
Bercik et al,22 2011	Chronic colitis mice	Anxiety (step-down test)	B. longum NCC3001 1010 14 days	Anxiety ↓	Colon inflammation: NA Brain BDNF expression: NA Enteric neurons excitability ↓ Probiotic effect via vagus nerve
Bercik et al,35 2010	T-muris infected mice	Anxiety (light/dark behavior, step-down test)	B. longum NCC3001/L. rhamnosus NCC4007 1010 10 days	Anxiety ↓ (B. longum only)	Colon inflammation ↓ Plasma cytokines: NA BDNF expression ↑ (only by B. longum) Tryptophan and kynurenine: NA No effect of vagotomy
Singh et al,40 2012	Rats	CFS and depression induced by forced-swim test (immobility period, post-swim fatigue time)	L. acidophilus as LAB or LAB FB 107 7 days	Depression ↓ (larger effect of LAB FB than LAB);	Brain oxido-nitrosative stress biomarker ↓ Cytokines: TNF-α ↓
Arseneautl-Bread et al,41 2012	MI rats	Post-MI depression (forced-swim test); social behavior (social interaction test); emotional memory (passive avoidance step-down test)	B. longum R0175 + L. helveticus R0052 109 14 days	Depression ↓ Social interaction ↑ Non-spatial memory ↑	Cytokines: pro-inflammatory cytokine IL-1β ↓ Intestinal barrier permeability ↓
Desbonnet et al,27 2010	MS rats	Depression (forced-swim test)	B. infantis 35624 1010 Initial 40 days	Depression ↓	CORT: NA Cytokines: IL-10 ↓ Tryptophan: NA Brain monoamines (−) Noradrenaline ↑
Desbonnet et al,26 2008	Rats	Depression (forced-swim test)	B. infantis 35624 1010 14 days	No behavioral change	Cytokines: pro-inflammatory cytokines IL-6, IFN-γ ↓; anti-inflammatory cytokines IL-10 ↓ Tryptophan ↑ Brain monoamines and metabolites – 5-HIAA ↓, DOPAC ↓ Neuroendocrine: NA, CORT: NA, AVP: NA, CRF: NA
Liu etal,44 2015	VaD (vascular dementia) mice	Locomotor activity (open-field test) Spatial memory (Morris water maze)	C. butyricum WZMC1016 (CGMCC 9831) 106/107/108 42 days	Locomotor activity ↑ Spatial memory ↑	Morphological change of hippocampus ↓ BDNF expression ↑ Butyrate in feces and brain ↑ Fecal bacteria diversity ↑
Jeong et al,47 2015	Aged rats	Spatial memory (Y-maze, Morris water maze)	L. plantarum KY1032 + L. curvatus HY7601 1010 48 days	Spatial memory ↑	Cytokines: pro-inflammatory cytokines NF-κB, ↓ BDNF ↑ Lipidemia ↓
Savignac et al,43 2015	Mice	Non-spatial memory (object recognition, fear conditioning) Spatial memory (Barnes Maze)	B. longum 1714/B. breve 1205 109 initial 21 days	B. longum:  Non-spatial memory ↑  Spatial memory ↑ B. breve:  Non-spatial memory ↑	Visceral sensitivity -colon distension: NA CORT: NA
Gareau et al,45 2011	C. rodentium infected mice	Memory dysfunction induced by water avoidance (novel-object test, T-maze);	L. rhamnosus R0011 + L. helveticus R0052 6 × 109 17 days	Non-spatial memory ↑	CORT ↓ Colon epithelial cell hyperplasia ↓ Cytokine: pro-inflammatory cytokines IFN γ ↓ Brain BDNF and c-Fos expression ↑ Microbiota: Firmicutes ↓, Enterobacteriaceae ↓, Eubacteria rectale ↓, Lactobacillus ↑
Davari et al,46 2013	Diabetic rats	Spatial memory (Morris water maze)	L. acidophilus 4356 + B. lactis 10140 + L. fermentum ATCC9338 2 × 1010 56 days	Spatial memory ↑	Hippocampal long-term potentiation ↑ Serum glucose ↓ and insulin ↑ Oxidative stress biomarkers: SOD ↑, 8-OHdG ↓
Hsiao et al,31 2013	MIA mice	Autism spectrum disorder: Anxiety (open field, marble burying); Sensory gating (prepulse inhibition); Communicative behavior (ultrasonic vocalizations); Social interaction (3-chamber social test)	B. fragilis NCTC9343 1010 6 days	Anxiety ↓ Sensory gating ↑ Communicative behavior ↑ Social interaction (−)	Intestinal permeability ↓ Tryptophan metabolites: indolepyruvate ↓ Microbiota: Lachnospiraceae ↓, Bacteroidales ↓
Kantak et al,48 2014	Male mice	obsessive-compulsive-disorder-like behavior (open field, marble burying, ultrasonic vocalizations, intermale aggression)	L. rhamnosus GG (ATCC 53103) 109 14, 28 days	Locomotor behavior ↓ Marble burying ↓ Ultrasonic vocalizations (−) Intermale aggression (−)	NA
D’Mello et al,49 2015	Male mice	Inflammation associated sickness behavior (social exploratory)	VSL#3 1.7 × 109 10 days	Social exploratory behavior in bile duct ligation treated mice ↑	Intestinal permeability: NA Cytokine: pro-inflammatory cytokine TNF-α ↓ Monocyte infiltration ↓ Microglial activation ↓ Fecal Microbiota (−)
Takada et al,50 2016	Male rats	Stress response to water avoidance stress	L. casei Shirota YIT 9029 3 × 109 14 days	NA	CORT ↓ c-Fos expression in the paraventricular nucleus ↓ Gastric vagal afferent activity ↑ Neuronal excitability of NTS ↑

ELS, early life stress; CORT, corticosterone; 5-HT, 5-hydroxytryptamine; 5-HIAA, 5-Hydroxyindoleacetic acid; DA, dopamine; DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanillic acid; GF, germ free; NA, not applicable; SPF, specific pathogen free; CRS, chronic restraint stress; ACTH, adrenocorticotropic hormone; NE, norepinephrine; BDNF, brain-derived neurotrophic factor; MR, mineralocorticoid; NMDA, N-methyl-D-aspertate; GR, glucocorticoid; RagI−/−, RagI knockout; PGE2, prostaglandin E2; KYN, L-kynurenine; TRP, tryptophan; KA, kynurenic acid; SCFA, short-chain fatty acid; GABA, gamma-Aminobutyric acid; CFS, chronic fatigue syndrome; LAB, Lactobacillus acidophilus; FB, floating bead; MI, myocardial infarction; MS, maternal separation; AVP, arginine vasopressin; CRF, corticotrophin-releasing factor; VaD, vascular dementia; NF-κB, nuclear factor-kappa B; SOD, superoxide dismutase; 8-OHdG, 8-hydroxy-2’deoxyguanosine; MIA, maternal immune activation; VSL#3, a high-concentration probiotic preparation of 8 live freeze-dried bacterial (Lactobacillus casei, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus bulgaricus, Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium infantis, and Streptococcus thermophiles); NTS, nucleus tractus solitary; B. breve, Bifidobacterium breve; B. fragilis, Bifidobacterium fragilis; B. infantis, Bifidobacterium infantis; B. lactis, Bifidobacterium lactis; B. longum, Bifidobacterium longum; C. butyricum, Clostridium butyricum; C. coccoides, Clostridium coccoides; C. rodentium, Citrobacter rodentium; L. acidophilus, Lactobacillus acidophilus; L. casei, Lactobacillus casei; L. curvatus, Lactobacillus curvatus; L. fermentum, Lactobacillus fermentum; L. helveticus, Lactobacillus helveticus; L. plantarum, Lactobacillus plantarum; L. rhamnosus, Lactobacillus rhamnosus.