Table 2.
Non-Human Animal Probiotic Trial Designs and Outcomes.
| Probiotic Treatment |
Blinding Status and Study Design |
Sex/Age, days |
Anxiety/ Depression Phenotypes |
Cognition /Social Phenotypes |
Other Probiotic Associated Outcomes |
Reference |
|---|---|---|---|---|---|---|
| Rat (Rattus) | ||||||
| L. plantarum MTCC1325 1.2 × 109 CFU/mL P.O. Q.D. for 60 days | Blinding status not reported Wistar control (n = 6), D-GAL (n = 6), D-GAL + L. plantarum (n = 6), L. plantarum (n = 6) | Male (n = 24) Age 90 days |
#PROT ↑ D-GAL induced ↓ gross behavior | #PROT ↓ D-GAL induced ↑ escape latency (MWM) |
#PROT ↑ D-GAL induced ↓ acetylcholine (HIP, cortex), organ and body weight #PROT ↓ D-GAL induced ↑ acetylcholinesterase |
(Nimgampall e and Kuna, 2017) |
| L. rhamnosus plus B. longum Ningxia Medical University 2 × 109 CFU/mL in 1 × PBS P.O. Q.D. for 12 days | Experimenter blinded behavior SPF Sprague Dawley No treatment (n = 8), 1× PBS control (n = 8), ampicillin (n = 8), ampicillin + PROT (n = 8), ampicillin + clonazepam (n = 8) for 12 days | Male (n = 40) Age 10 days |
#PROT ↓ ampicillin induced ↑ immobility (TST and FST) | #PROT ↓ ampicillin induced ↑ escape latency (MWM) |
#PROT ↑ ampicillin induced ↓ HIP GABA-A receptors *NSE #PROT on ampicillin induced change in gut microbial composition |
(Liang et al., 2017) |
| Ecologic® Barrier 3.8 × 108CFU/mL in water or vehicle Q.D. for 84 days | Experimenter blinded to #PROT and behavior FSL, FRL, & SD FSL CLD + vehicle (n = 11), FSL CLD + #PROT (n= 11), FSL HFD (60%) + #PROT (n= 12), FSL HFD + vehicle (n = 12), FRL CLD + vehicle (n = 12), SD CLD + vehicle (n = 8), SD HFD + vehicle (n = 8) | Male (n = 74) Age 35 days |
#PROT ↓ HFD ↑ depression (FST) in FSL *NSE #PROT depression CLD, locomotion (OFT) |
§NA |
#PROT ↓ CD4/CD8 for CD3+ cells in blood for FSL (*NSE brain) *NSE #PROT body weight, caloric intake, blood glucose, ghrelin, insulin, leptin, MCP, cytokines, WBC |
(Abildgaard et al., 2017a) |
| Ecologic® Barrier 2.5 × 109 CFU/g in water for 35 days during diet (began 35 days prior to #PROT) | Experimenter blinded to #PROT and behavior Sprague-Dawley SD (n= 10), HFD (n = 10), #PROT + SD (n = 10) #PROT + HFD (n = 10) | Male (n = 40) Adult |
#PROT ↓ immobility (FST) *NSE anxiety (OFT) |
*NSE memory (Barnes) | *NSE LPS | (Abildgaard et al., 2017b) |
| L. helveticus R0052 plus B. longum R0175 109 (n = 7) 1010 (n = 8) CFU/day in vehicle with water P.O. Q.D. for 70 days | Experimenter blinded behavior FLR vehicle only (n = 8) FSL (n = 22) 109 #PROT (n = 7), 1010 #PROT (n = 8), or vehicle (n = 7) | Male (n = 30) Adult |
*NSE immobility (FST)*NSE anxiety (OFT) |
*NSE memory (Y-maze, NOR) *NSE social interaction |
#PROT ↓ plasma betaine, NE, DA #PROT ↑ liver SAM *NSE betaine, norepinephrine, dopamine or SAM in PFC or HIP |
(Tillmann et al., 2018) |
| L. helveticus R0052 plus B. longum R0175 3 × 109 CFU P.O. Q.D. for 14 days | Experimenter blinded behavior Wistar #PROT (n = 12), diazepam (n = 12), and placebo (n = 12) | Male (n = 36) Adult |
#PROT and diazepam ↓ burying | §NA | Human trial outcomes are reported in Table 1 | (Messaoudi et al., 2011a) |
| B. infantis 356241 × 1010 CFU/100 mL or vehicle in drinking water Q.D. for 14 days | Experimenter blinded behavior Sprague Dawley #PROT (n = 12) or vehicle (n = 8) | Male (n = 20) Adult |
*NSE FST | §NA |
#PROT ↓ 5-HI A A (frontal cortex), DOPAC (amygdala), body weight #PROT ↓ serum IFN-γ, TNF-α, IL-6 after mitogen stimulation ↓ TNF-α after LPS stimulation #PROT ↓ IFN-γ, IL-6 after CON A stimulation #PROT ↓ plasma tryptophan and kynurenic acid |
(Desbonnet et al., 2008) |
| L. helveticus NS8 109CFU/mL Q.D. for 21 days | Blinding status not reported SPF Sprague Dawley CON (n = 8), chronic RS (n = 8), L. helveticus NS8 during chronic RS (n = 8), citalopram hydrobromide 30 mg/kg during chronic RS (n = 8) | Male (n = 32) Adult |
#PROT ↓anxiety (EPM & OFT) | #PROT ↑ memory (NOR & OPT) |
#PROT ↑ HIP 5-HT, NE, BDNF, IL-10 #PROT ↓ serum CORT, ACTH |
(Liang et al., 2015) |
| VSL#3 (low - 2.5 × 109 CFU or high - 2.5 × 1010 CFU) in maple syrup for 14 days before diet and 26 days during diet modification | Experimenter blinded behavior Sprague Dawley CFD, CFD + VSL#3 low, CFD + VSL#3 high, SD, SD + VSL#3 low, SD + VSL#3 high, (n = 10/group) | Male (n = 60) Adult |
*NSE anxiety (EPM) | VSL#3 high ↑ diet induced memory ↓ (NPR) VSL#3 low and high ↓ memory (NOR) for CFD and SD | CFD + VSL#3 high had ↑ Streptococcus Lactobacillus, Butyrivibrio than CFD alone *NSE overall microbial diversity |
(Beilharz et al., 2017) |
| L. acidophilus ATCC4356, B. lactis DSM 10140, plus L. fermentum ATCC9338 1010 CFU/g B.I.D. for 56 days | Blinding status not reported Wistar diabetic (Streptozotocin 65 mg/kg; n = 10), diabetic + #PROT (n = 10), CON (n= 10), CON + #PROT (n = 10) | Male (n = 40) Age 45 days |
§NA |
#PROT ↑ spatial memory (MWM) in control and diabetic rats #PROT ↑ HIP baseline EPSP and LTP in diabetic rats |
#PROT ↓ serum glucose ↑ insulin and SOD levels in diabetic rats | (Davari et al., 2013) |
| L. plantarum or B. B94 (industrial enzymes company, representative of DSM Company) 1.5 × 108 CFU/mL P.O. Q.D. for 28 days | Blinding status not reported Wistar HIP demyelination model EB (n = 8), EB + L. plantarum (n = 8), EB + B.B94 (n = 8), or saline (n = 8) | Male (n = 32) Age 56-80 days |
§NA | *NSE spatial memory (MWM) | §NA | (Goudarzvand et al., 2016) |
| L. plantarum KY 1032 and L. curvatus HY7601 1 × 1010 CFU Q.D. 48 days (6 days/week) | Blinding status not reported Fischer 344 young, older, older + #PROT, older + rapamycin (n = 6/group) | Male (n = 24) young age not reported older 540 days | §NA | #PROT ↑ memory (Y-maze) | #PROT ↑ HIP doublecortin and ↓ BDNF | (Jeong et al., 2015) |
| ampicillin + L. fermentum NS9 109 CFU/mL (n = 10) for 41 days | Blinding status not reported Sprague Dawley CON (n = 10), ampicillin (n = 10) ampicillin + L. fermenlum NS9 109 CFU/mL (n = 10) | Male (n = 30) Adult |
#PROT ↓ anxiety (EPM) *NSE locomotor activity |
§NA | #PROT ampicillin induced MPO activity | (Wang et al., 2015) |
| VSL#3 1.2 × 1010 CFU/kg in maple syrup Q.D. for 42 days | Blinding status not reported Wistar young, young +#PROT, aged, aged + PROT sample sizes not reported | Male young (90 days) aged (600 – 660 days) | §NA | #PROT ↑ HIP LTP in aged rats ≈ young rats |
#PROT ↓ microglia and ↑ Bacteroidetes in aged rats #PROT up and down regulates cortical gene expression |
(Distrutti et al., 2014) |
| L. paracasei HII01 1 × 108 CFU/mL P.O. in PBS Q.D. for 84 days with diet modification (84 days pre- L. paracasei and 84 days during L. paracasei trial) | Double-blind Wistar (n = 6 per group) Standard diet, HFD, Standard diet +#PROT, HFD +#PROT, Standard diet +#PROT + XOS, HFD + #PROT + XOS, Standard diet + XOS, HFD + XOS | Male (n = 48) Adult |
§NA | #PROT ↑ HFD induced ↓ HIP LTP (fEPSP) | #PROT ↓ HFD induced ↑ in serum LPS, plasma glucose, total cholesterol, LDL cholesterol, serum and brain MDA, insulin, HOMA | (Chunchai et al., 2018) |
| L. helveticus R0052 plus B. longum R0175 1 × 109 CFU in drinking water 7 days pre-MI/sham to 7 days post-MI/sham (14 days) | Experimenter blinded behavior Sprague Dawley MI (n = 9), MI + PROT (n = 9), sham (n = 9), sham + PROT (n = 9) | Male (n = 36) Age 84 days |
#PROT ↓ depression (FST) and anxiety (SDT) in MI not sham | #PROT ↑ social interaction in MI not sham | #PROT ↓ intestinal permeability in MI treated groups | (Arseneault-Breard et al., 2012) |
| L. helveticus NS8 1 × 109 CFU/mL Q.D. in drinking water for 14 days post HA neuroinflammatio n (28 days) | Blinding status not reported SPF Sprague Dawley saline (n = 6), HA (n = 6), HA + #PROT (n = 6) | Male (n = 18) Adult |
#PROT ↓ HA induced anxiety (EPM) | #PROT ↓ HA induced spatial memory deficits (MWM) |
#PROT ↑ 5-HIAA CBM, ↑ 5-HIAA HIP, ↓ 5-HT in HA rats #PROT ↓ HA induced IL-1β, iNOS, and PGE2 in CBM, HIP and PFC |
(Luo et al., 2014) |
| Lacidofil® 1 × 109 CFU/mL for 14 days | Blinding status not reported Sprague Dawley MS model: MS fathers, MS fathers + #PROT (prevention), MS fathers no treatment pups no treatment, MS fathers no treatment pups #PROT (active treatment), MS fathers #PROT (prevention) pups no treatment | Male Female P2-P14 (n = 398 all experiments) | §NA | Preventative and active #PROT ↓ cued fear conditioning and infantile amnesia in pups from MS fathers | §NA | (Callaghan et al., 2016) |
| Lacidofil® 1 × 109 CFU/mL in drinking water for 12 days (P2 to P14) | Double-blind Sprague Dawley #PROT during MS model MS + #PROT (n = 13), MS + vehicle (n = 14), no MS + vehicle (n = 10; n = 9) | Male Pups (n = 37) Age P2-P14 then experiments at P17 Female Mothers (n = 9) |
*NSE MS +#PROT anxiety (EPM) in male pups or female mothers | MS +#PROT ↑ infantile amnesia (7 days post-fear conditioning)*NSE MS + #PROT context dependent freezing in male pups | *NSE MS + #PROT for maternal behavior (pup retrieval) | (Cowan et al., 2016) |
| B. infantis 35624 1 × 1010 CFU/100 mL Q.D. for 45 days | Experimenter blinded behavior Sprague Dawley MS model CON (n = 11), MS (n = 7), MS + citalopram 30 mg/kg (n = 7), and MS + B. infantis (n = 8) | Male (n = 33) Age P2-P14 #PROT P50 to P95 |
#PROT ↓ MS induced depression (immobility, swimming - FST) | §NA |
*NSE stimulated or unstimulated IFN-γ, TNF-α, IL-6, (IL-10 #PROT ↓ MS induced NE and CRF expression in amygdaloid cortex |
(Desbonnet et al., 2010) |
| L. helveticus R0052 and B. longum R0175 109 CFU in 200 mL water Q.D. for 14 days post-MI | Blinding status not reported Sprague Dawley low or high ω-3 PUFA diet w/ or w/out #PROT after MI (n = 16/group) | Male (n = 64) Age 90 days |
#PROT x diet interaction depression (FST) |
#PROT reversed post-MI social interaction deficits in low-PUFA group *NSE post-MI social interaction in high PUFA group #PROT ↑ memory (↓ time and number of trials PAT) |
#PROT ↑ plasma IL-4 in high PUFA group | (Gilbert et al., 2013) |
| B. infantis 35624, B. breve UCC2003, or L. salivcirius UCC118 5 × 109 CFU/mL or vehicle P.O. Q.D. for 14 days | Experimenter blinded behavior Sprague Dawley (n = 40) Wistar-Kyoto (n = 40) PBS, B. infantis, B. breve, L. salivarius (n = 10/group/strain) | Sex not reported (n = 80) Age 63 days |
*NSE anxiety (OFT) | §NA | *NSE plasma corticosterone B. infantis ↓ pain behavior Wistar-Kyoto only | (McKernan et al., 2010) |
| L. fermentum CECT 5716 109 CFU/100g body weight P.O. Q.D. for 3 days pre-MS (age 10 days) or 15 days pre-WAS (age 21 days) | Blinding status not reported Sprague Dawley MS, WAS 8 groups (n = 6/group behavior experiments) | Sex not reported Age 10 and 21 days | *NSE anxiety (OFT) | #PROT ↑ exploratory behavior (OFT) |
#PROT ↓ WAS and MS induced ↑ plasma corticosterone, intestinal permeability #PROT ↑ IFN-γ and ↓ IL-4 after CD3/CD28 stimulation #PROT normalized WAS induced intestinal ZO-1 reorganization |
(Vanhaecke et al., 2017) |
| L. acidophilus (1688FL431-16LA02), L. fermentum (ME3), B. lactis (1195SL609-16BS01) and B. longum (1152SL593-16BL03) 1010 CFU Q.D. in drinking water for 28 days pre- β-amyloid injection and 28 days post-injection | Blinding status not reported Wistar control, control + #PROT, sham surgery, β-amyloid intra-hippocampal injection, β-amyloid intra-hippocampal injection + #PROT (n = 12/group) | Male (n = 60) Age 56 days |
§NA | #PROT ↓ β-amyloid injection induced ↑ in escape latency |
*NSE weight, catalase activity #PROT ↓ β-amyloid injection induced ↑ MDA, SOD, plaques, cell morphology |
(Athari Nik Azm et al., 2018) |
| L. rhamnosus GG 108 CFU/mL in drinking water for approximately 80 days | Blinding status not reported Sprague-Dawley 10 day MS or no MS control diet (n = 5), control diet + #PROT (n = 9), diet + PDX + GOS (n = 5), diet + PDX + GOS +#PROT (n = 9), followed by acute RS | Male only behavior (n = 56) MS Age 2-12 days Behavior Experiments Age 49-100 days |
#PROT + PDX + GOS ↓ MS induced ↑ anxiety (OFT) | #PROT + PDX + GOS ↑ MS induced ↓ spatial memory (MWM) |
#PROT ↓ Nr3c1, Nr3c2, Crhrl in MS group only #PROT + PDX + GOS delayed return of acute stress induced ↑ of corticosterone to baseline |
(McVey Neufeld et al., 2017) |
| Mouse (Mus) | ||||||
| L. fermentum LAB9 109 CFU/200μL or L. casei LABPC 109 CFU/200μL in cow’s milk P.O Q.D. for 28 days pre- LPS induced inflammation (4 days) | Blinding status not reported ICR/HaJ Saline (n = 6) LPS (n = 6) LPS + unfermented milk (n = 6) LPS + L. fermentum, (n = 6) LPS + L. casei (n = 6) |
Male (n = 30) Age 63 days |
§NA | L. fermentum and L. casei ↓ LPS induced spatial memory deficit – escape latency and distance (MWM) |
L. fermentum and L. casei ↑ LPS induced ↓ catalase, SOD, GSH, GPx, MDA, NO, MCP-1 L. fermentum and L. casei ↓ LPS induced ↑ AChE, IL-6, L. fermentum ↓ LPS induced ↑ IL-1β |
(Musa et al., 2017) |
| L. casei DG 109 CFU in saline P.O. for 7 days | Experimenter blinded behavior C57BL/6J (n = 8-9/group) CON, ABX, ABX + #PROT, ABX + saline for 14 days in water | Male (n = 36) Age 64 days |
#PROT ↓ ABX induced immobility (TST, FST) | *NSE social novelty |
*NSE muscle strength, motor coordination #PROT normalized ABX induced changes in BDNF, HIP firing rate, HIP TRN1 phosphorylation, astrocyte and microglia morphology, intestinal 5-HT and OA-5-HT |
(Guida et al., 2017) |
| L. brevis OW38 1 × 109 CFU P.O. for 56 days | Blinding status not reported C57BL/6J young+ vehicle (n = 6), young+ PROT (n = 6), older + vehicle (n = 6), older + PROT (n = 6) | Male (n = 24) Age 120 or 540 days |
§NA | #PROT ↑ memory (Y-maze) in aged mice |
#PROT ↓ age ↑ colonic p-F0X03a, p-mTor, fecal and plasma LPS #PROT ↑ age ↓ HIP BDNF, butyric acid, IL-1β, IL-6, TNF, COX-2, iNOS, NF-κB, claudin-1, ZO-1 |
(Eun et al., 2016) |
| L. plantarum C29 1 × 109 CFU P.O. Q.D. for 5 days post-TNBS induced memory deficit | Blinding status not reported SPF C57BL/6J (n = 6/group) Methods based on (Jeong et al., 2016) | Male (n = 24 - behavior)(n = 42 – colitis) Age 42 days |
§NA | #PROT ↑ TNBS induced ↓ memory (NOR, Y-maze, PAT) |
#PROT ↑ TNBS induced ↓ BDNF #PROT ↑ TNBS induced ↓ Bifidobacteria, Lactobacilli, Clostridia #PROT ↓ TNBS induced ↑ in Enterobacteriacae |
(Lee et al., 2018) |
| L. plantarum MTCC 9510 2 × 1010 CFU/300μl in PBS P.O. for 21 days during sleep deprivation and 28 days during chronic unpredictable stress | Experimenter blinded behavior Swiss Webster LACA chronic unpredictable stress for 28 d (n = 8), chronic unpredictable stress + #PROT (n = 8), naïve (n = 8), naïve +#PROT (n = 8), naïve (n = 6), 72h sleep deprivation (n = 8),72h sleep deprivation + #PROT (n = 8), naïve + #PROT (n = 6) | Male (n = 68) Age not reported |
#PROT ↓ chronic stress and sleep deprivation induced ↓ anxiety and depression behavior (FST, TST, OFT, EPM) | #PROT ↑ chronic stress induced ↓ spatial (MWM) and chronic stress and sleep deprivation induced ↓ working memory (PAT) |
#PROT ↓ stress and sleep deprivation induced ↑ NF-κB, LPS, TNF-α, MAO-A, MAO-B, MDA, GSH, corticosterone #PROT ↑ stress and sleep deprivation induced ↓ HIP BDNF #PROT ↑ cecal Lactobacilli and ↓ Enterobacteriaceae |
(Dhaliwal et al., 2018) |
| E. faceium CFR3003 104 CFU (n = 6), E. faceium CFR3003 108 CFU (n = 6), L. rhanmosus GG MTCC1408 108 CFU (n = 6), or saline (n = 6) P.O. for 28 days | Blinding status not reported CFT-Swiss LPS model of inflammation | Male (n = 24) Age 42 days |
E. faceium - 108 CFU and L. rhanmosus ↓ anxiety (OFT) | §NA |
E. faceium and L. rhanmosus reversed LPS induced ↑ TNF-α and ↓ IL-10 E. faceium -108 CFU and L. rhanmosus ↓ cecum weight and ↑ lactobacilli E. faceium - 104 CFU ↑ GST in HIP ↓ AchE in CTX and STR E. faceium - 108 CFU ↑ cytosolic GABA in CTX, HIP, STR, ↑ cytosolic DA in CTX, ↑ GST in CTX, HIP, STR, ↓ ROS in CTX L. rhanmosus ↓ ROS in HIP, ↑ cytosolic GABA in HIP and DA in STR, ↑ CAT in CTX, HIP ↑ GST in HIP, STR *NSE ROS STR |
(Divyashri et al., 2015) |
| B. fragilis NCTC9343 1 × 1010 CFU in food every other day for 6 days | Blinding status not reported SPF, germ-free and conventional C57BL/6J MIA model pregnant (E12.5) mice injected with saline or 20 mg/kg poly I:C n animals varied ranging from 10-75/group | Male Female Treatment Age approximately 28 days Behavior testing 42 days |
#PROT ↓ anxiety (OFT, burying) in MIA |
#PROT ↑ sensorimoto r gating (PPI) in MIA mice *NSE social interaction |
§NA | (Hsiao et al., 2013) |
| L. rhamnosus JB-1 1.6 × 109 CFU/200ul or saline P.O. Q.D. for 28 days | Blinding status not reported C57BL/6J Chronic social defeat stress began at day 18 of #PROT vehicle (n = 10),#PROT (n = 8), stress (n = 15), stress + #PROT (n= 10) | Male (n = 43) Age 63 days |
#PROT ↓ stress induced anxiety (OFT, light/dark) | #PROT prevented ↓ social interaction with conspecifics |
#PROT ↑ stress induced ↓ in fecal tyramine #PROT ↓ stress induced ↑ in MHCII+, CD11c+, CD80, CD86, #PROT ↓ IL-10+ Treg *NSE stress induced kynurenine, 4- hydroxybutyrate, or 1-methylnicoinamide |
(Bharwani et al., 2017) |
| Lacidofil® 1× 1010 CFU/mL P.O. Q.D. 7 days pre-DSS and 8 days during DSS | Blinding status not reported SPF C57BL/6J DSS model control, #PROT, DSS, DSS + #PROT (n = 9-12/group) | Male (n = 40) Female (n = 40) Age 42-56 days |
#PROT ↓ anxiety (light/dark box) | #PROT ↑ memory in DSS (NOR) |
#PROT ↑ DSS induced loss of cFos in CA1 HIP #PROT ↓ DSS induced dysbiosis |
(Emge et al., 2016) |
| L. rhamnosus NC4007 1010 CFU/100uL (n = 10), B. longum NCC3001 1010 CFU/100uL (n = 16), etanercept, budesonide, or placebo (n = 16) for 10 days after 30 days T. minis infection | Experimenter blinded behavior SPF BALB/c and AKR/J Vagotomy (n = 24) or sham vagotomy (n = 15) before infection | Male (n = 39) Age 42-56 days |
B. longum ↓ T. muris induced anxiety (light/dark box and SDT) *NSE L. rhamnosus on T. muris induced anxiety |
§NA |
B. longum ↑ T. muris induced ↓ brain BDNF *NSE B. longum circulating TNF-alpha *NSE B. longum kynurenine |
(Bercik et al., 2010) |
| B. longum NCC3001 1 × 1010 CFU/mL or vehicle P.O. Q.D. for 14 days (7 days during DSS and 7 days post-DSS) | Experimenter blinded histology SPF AKR/J naïve (n = 13), B. longum (n = 6), DSS (n = 12), sham surgery (n = 11), vagotomy (n = 15), Vagotomy + B. longum (n = 14), vagotomy + DSS (n = 15), vagotomy + DSS + B. longum (n = 15), sham surgery + B. longum (n = 9), B. longum + DSS (n = 11) | Male (n = 151) Age 42-56 days |
#PROT ↓ anxiety (SDT) in control and DSS w/out vagotomy | §NA |
#PROT ↓ excitability of enteric neurons and colonized intestine for sham and vagotomy, *NSE BDNF expression SH-SY5Y cells or colon histology |
(Bercik et al., 2011) |
| B. longum 1714 or B. breve 1205 1 × 109 CFU/mL P.O. Q.D. for 77 days | Experimenter blinded behavior BALB/c B. longum (n = 12), B. breve (n = 12), or vehicle (n = 12) | Male (n = 48) Age 49-56 days |
B. breve ↓ locomotion *NSE B. longum |
B. breve and B. longum ↑ memory (NOR) B. longum ↑ memory (Barnes, cued, and contextual fear conditioning) | *NSE CORT, body weight, colorectal distention | (Savignac et al., 2015) |
| VSL#3 1 × 107 CFU P.O. Q.D. for 10 days | Experimenter blinded behavior C57BL/6J SPF naïve (n = 10), SPF + #PROT (n = 10), SPF + exercise (n = 10), ABX (n = 10), ABX + #PROT (n = 10), ABX + exercise (n = 10), ABX + SPF fecal transplant (n = 10) | Female (n = 70) Age 42-56 days |
§NA | #PROT or exercise ↑ ABX induced memory deficit (NOR) | #PROT or exercise ↑ ABX induced brain monocyte or HIP neurogenesis reduction | (Mohle et al., 2016) |
| Lacidofil® 6 × 109 CFU/mL in water Q.D. for 7 days pre- C. rodentium infection P.O. and 7 days post-infection | Experimenter blinded immunohistochemistry C57BL/6J and Swiss-Webster SPF, germ-free, and conventional #PROT with and without C. rodentium infection or WAS (n = 10-14/group) | Female Age 35-42 days | §NA | #PROT ↑ working memory (T-maze) in C. rodentium infected and WAS mice |
#PROT ↓ serum CORT in C. rodentium infected and WAS mice #PROT ↓ IFNγ in C. rodentium not WAS mice *NSE on TNF-α in C. rodentium or WAS mice |
(Gareau et al., 2011) |
| Lacidofil® 6 × 109 CFU/day or placebo in water for 28 days before WAS | Experimenter blinded immunohistochemistr y C57BL/6JRcigl−/− (n = 4-6/group behavior experiments) no WAS, WAS 1hr for 1 day | Male Female Age 42 to 56 days |
#PROT ↓ anxiety (light/dark) in Rag−/− WAS and no WAS |
#PROT ↓ memory (NOR) in Rag1−/− WAS mice #PROT ↑ memory (NOR) in Rag1−/− naïve mice |
*NSE corticosterone #PROT normalized intestinal ion absorption in no WAS mice only #PROT ↓ abundance of Bacteroides, Enterobacteriaceae, Firmicutes, Lactobacilli |
(Smith et al., 2014) |
| L. pentosus ssp. plantarum C29 1 × 1010 CFU/mouse, P.O. Q.D. for 35 days during D-GAL (D-GAL induced aging 35 days pre-#PROT and 35 days during #PROT) | Blinding status not reported C57BL/6J Naïve (n = 6), D-GAL (n = 6), #PROT (n = 6) | Male (n = 18) Age 140 days (D-GAL) Age 182 days (#PROT) |
§NA | #PROT reversed D-GAL induced ↓ in memory (MWM, Y-maze, PAT) | #PROT reversed D-GAL induced ↓ in BDNF, DCX, and CREB | (Woo et al., 2014) |
| L. johnsonii ATCC33200 or L. renteri MM4-1A ATCC-PTA-6475 1 × 108 CFU in water for 28 days | Double-blind Germ-free C57BL/6J MRD (13.4% FAT, 30% PRO, and 57% CARB), MHFD (60% FAT, 20% PRO, 20% CARB), live #PROT, heat killed #PROT | Male (behavior) Age 49-84 days |
*NSE anxiety (OFT) | L. reuteri ↑ LTP in VTA DA neurons for MHFD L. reuteri ↑ sociability, social novelty, reciprocal social interaction in MHFD | §NA | (Buffington et al., 2016) |
| VSL#3: 1.7 × 1010 CFU P.O. Q.D. 10 days pre- and 10 days post-surgery | Blinding status not reported C57BL/6 SPF BDL model liver inflammation + #PROT (n = 10), BDL no #PROT (n = 10), sham + #PROT (n = 10), sham no #PROT (n = 10) | Males (n = 40) Age 42-56 days |
#PROT ↓ depression (immobility) in BDL model | #PROT ↑ social behavior in BDL model |
#PROT ↓ monocyte infiltration to brain in BDL model #PROT ↓ microglial activation in brain in BDL model #PROT ↓ TNF-α in BDL model *NSE gut permeability or liver injury |
(D'Mello et al., 2015) |
| B. longum 1714 or B. breve 1205 1 × 1010 CFU/mL Q.D. for 42 days | Experimenters blinded behavior BALB/c SIH vehicle (n ≈ 20), escitalopram 20mg/kg (n ≈ 20), B. longum (n ≈ 20), B. breve (n ≈ 20) | Male (n ≈ 80) Age 49 days |
B. longum ↓ SIH escitalopram, B. longum and B. breve ↓ marble burying B. breve ↓ anxiety (EPM) B. longum ↓ anxiety (OFT) B. longum ↓ depression TST *NSE depression (FST) |
§NA |
B. breve ↓ bodyweight gain B. breve ↑ spleen weight *NSE corticosterone |
(Savignac et al., 2014) |
| L. rhanmosus JB-1 109 CFU/mL or control broth P.O. Q.D. for 28 days | Blinding status not reported BALB/c CON (n = 20) CON naïve (n = 8), CON + SIH (n = 8), #PROT (n = 8), or #PROT with stress (n = 8) Vagotomy (n = not reported), vagotomy + #PROT (n = not reported) | Male Age 70-77 days |
#PROT ↓ depression (FST) #PROT ↓ anxiety (EPM, OFT) |
#PROT ↑ cued and contextual memory fear conditioning |
#PROT ↓ stress-induced CORT levels #PROT ↑ GABAB1b mRNA in cingulate of sham not vagotomized mice *NSE on FST or OFT after vagotomy *NSE on SIH |
(Bravo et al., 2011) |
| L. rhanmosus GG 1 × 109 CFU P.O. Q.D. for 14 days | Single-blind behavior BALB/c 5-HT1A/1B receptor agonist model of OCD (RU 24969) primed by social experience and then pretreatment with saline (n = 6), fluoxetine 10 mg/kg for 28 days (n = 12) or #PROT for 14 days (n = 12) before inducing OCD model | Male (n = 36) Age 56 days |
#PROT pretreatment ↓ anxiety (burying) fluoxetine had greater effect than #PROT #PROT and fluoxetine ↓ locomotion (OFT) *NSE aggression |
§NA | §NA | (Kantak et al., 2014) |
| L. casei-01 109 CFU/kg P.O. Q.D. for 20 days | Blinding status not reported Kunming (n = 10/ group) control, SCOP (3mg/kg), SCOP + piracetam (400mg/kg), SCOP + #PROT, SCOP + LSPC (60mg/kg), SCOP + LSPC (90mg/kg), SCOP + #PROT + LSPC (60mg/kg), SCOP + #PROT + LSPC (90mg/kg) | Male (n = 80) Age not reported |
§NA |
#PROT ↑ memory (Y-maze) in SCOP induced amnesia #PROT enhances effect of LSPC on SCOP induced amnesia at both dosages |
#PROT enhances LSPC ability to reduce MDA and increase antioxidant levels *NSE on brain NOS levels |
(Xiao et al., 2014) |
| L. plantarum CCFM639 5 × 109 CFU/mL P.O. Q.D. in milk for 84 days after 28 days aluminum toxicity | Experimenter blinded histology SPF C57BL6/J (n = 10/group) control, aluminum toxicity, aluminum toxicity + live #PROT, aluminum toxicity + heat killed #PROT | Male (n = 40) Age 42 days |
§NA | Live and heat killed #PROT ↑ aluminum induced ↓ spatial memory (MWM) |
Live #PROT ↓ aluminum induced ↑ brain Aβ1-40 & Aβ1-42 Live and heat killed #PROT ↓ aluminum induced ↑ ALT, AST, CRE, BUN, and live aluminum Live and heat killed #PROT ↑ fecal aluminum (day 14 #PROT) Live and heat killed #PROT ↓ aluminum induced ↓ SOD, CAT, GPx, GSH, MDA in liver and brain *NSE brain aluminum |
(Tian et al., 2017) |
| L. helveticus R0052 109 CFU P.O. or no treatment Q.D. for 21 days | Experimenter blinded histology SPF 129/SvEv wild type and IL-10 −/− fed SD (29% PRO, 55% CARB,13% FAT) (n = 5-6), SD + #PROT (n = 5-6), Western-style diet (28% PRO, 49% refined CARB, 33% FAT) (n = 5-6), Western diet plus #PROT (n = 5-6) | Sex not reported Age PD29 |
#PROT ↓ anxiety with western diet wild type and IL-10 −/− *NSE anxiety for IL-10 −/− fed standard chow |
#PROT ↓ memory that ↓ with western diet in IL-10 −/− *NSE anxiety for IL-10 −/− fed standard chow |
#PROT ↑ brain corticosterone, fecal corticosterone, Firmicutes/Bacteroidete s, IL-1B in IL-10 −/− mice | (Ohland et al., 2013) |
| L. plantarum PS128 5 × 109 CFU/mL P.O. Q.D. for 16 days | Blinding status not reported germ-free C57BL/6J live #PROT (n = 10), heat -killed #PROT (n = 10) or pre-warmed saline (n = 10) for 16 days | Male (n = 30) Age 42 days |
#PROT ↓ anxiety (EPM) Live #PROT ↑ locomotion | §NA | Live #PROT ↓ cecum weight Live #PROT ↓ DA, HVA, 5-HT, 5-HIAA in striatum *NSE #PROT in PFC or HIP *NSE #PROT organ histology and serum CORT |
(Liu et al., 2016a) |
| L. plantarum PS128 5 × 109 CFU P.O. Q.D. for 28 days | Blinding status not reported SPF C57BL/6J MS (n = 12), MS + #PROT (n = 10) from PD29, naïve adult mice (n = 10), and naïve adult + #PROT (n = not reported) from 8 weeks | Male Age PD29 and 56 days |
#PROT restores sucrose preference and FST in MS mice but *NSE #PROT for naïve mice #PROT ↓ anxiety (OFT, EPM) naïve mice *NSE anxiety in MS mice #PROT ↑ locomotor activities in MS and naïve mice |
§NA |
#PROT reverses MS ↑ IL-6 and ↓ IL-10 #PROT ↑ PFC dopamine in MS and naïve mice #PROT ↑ 5-HT in naïve #PROT ↓ serum CORT during basal & stressed states for MS not naïve mice #PROT ↑ levels of 5-HT in PFC in MS |
(Liu et al., 2016b) |
| C. butyricum WZMC1016 (CGMCC9831)1 × 108 CFU/200μl saline P.O. Q.D. for 42 days | Blinding status not reported SPF C57BL/6J Streptozotocin sham operation (n = 12), cerebral I/R injury (n = 12), cerebral I/R injury + C. butyricum (n = 12) | Male (n = 36) Age 87 days |
§NA | #PROT ↑ cerebral injury induced ↓ in spatial memory (MWM) | #PROT ↓ cerebral injury induced ↓ p-Akt | (Sun et al., 2016) |
| Zebrafish (Danio rerio) | ||||||
| L. plantarum (USDA-ARS) 2 × 107 CFU/mL single exposure for 2 days | Blinding status not reported Wild-type CV, CV + stress, CR, CR + stress, CR + stress + #PROT, GF, GF + stress, GF + stress + #PROT | Sex not reported Age 4 days post fertilization (#PROT) |
#PROT ↓ anxiety (thigmotaxis) *NSE locomotor activity |
§NA | #PROT ↓ stress induced cortisol level in CR not GF | (Davis et al., 2016a) |
| L. plantarum (USDA-ARS) 1 × 106 CFU/mL B.I.D for 30 days | Blinding status not reported Wild-type chronic unpredictable stress #PROT (n = 5-7), CON (n = 5-7) | Male Female Adult |
#PROT ↓ anxiety (novel tank diving) | §NA |
#PROT restores stress induced dysbiosis *NSE cortisol, lymphocytes, monocytes, neutrophils, eosinophils |
(Davis et al., 2016b) |
| L. rhanmosus GG in feed (CFU not reported) for 14 days | Blinding status not reported Wild-type #PROT (n= 15), #PROT + 0.5% EtOH (n = 15), 0.5% EtOH (n = 15), CON (n = 15) | Male Female Adult |
*NSE anxiety (novel tank diving) for #PROT or #PROT + ethanol groups |
§NA | §NA | (Schneider et al., 2016) |
| L. rhanmosus IMC501 1 × 106 CFU B.I.D. for 28 days | Blinding status not reported Wild-type - heterozygous #PROT (n = 12), CON (n = 12) | Male Female Age 120-180 days |
§NA | #PROT ↑ social (shoaling) and exploratory behavior |
#PROT ↓ Bacteroidetes ↑ BDNF and serotonergic gene expression in brain *NSE gut BDNF |
(Borrelli et al., 2016) |
| P. acidilactici JN039350 and L. plantarum JN039358 109 CFU/g in control and HCD feed (3% of total body weight) B.I.D. for 49 days | Blinding status not reported Wild-type control diet group (n = 6), HCD (n = 6), HCD + P. acidilactici JN039350 (n = 8) and the HCD + L. plantarum JN039358 (n = 8) | Male (n = 28) Adult |
§NA | P. acidilactici JN039350 or L. plantarum JN039358 ↑ HCD ↓ in spatial memory |
#PROT ↑ diet induced ↑ increase in cholesterol #PROT ↓ brain abba, liver abcal and ↓ liver and intestine npc111 expression |
(Lim et al., 2017) |
| Ouail (Coturnix japonica) | ||||||
| P. acidilactici R001 (MA 18/5M) ~ 1.9 × 107 CFU/day for 36 days with unpredictable stress during day 17-21 | Blinding status not reported #PROT (LTI n = 18 and STI n = 16) Control (LTI n = 19 and STI n = 16) |
Female #PROT Age 0-36 days Age 6-7 days for STI & LTI |
*NSE anxiety (OFT) #PROT ↓ emotional reactivity (STI & LTI) |
#PROT ↑ memory day 2 and 3 | *NSE emotional reactivity and memory interaction | (Parois et al., 2017) |
Abbreviations:
§
NA = Not Assessed,
*
NSE = No Significant Effect,
#
PROT = Probiotic Treatment, 5-HT = 5-hydroxytryptamine or Serotonin, abcal = ATP-binding cassette family transporter group Al, appa = amyloid precursor protein type a, ABX = Antibiotics, AchE = Acetylcholinesterase, ACTH = Adrenocorticotropic Hormone, ALT = Alanine Transaminase, AST = Aspartate Transaminase, ATCC = American Tissue Culture Collection, B.I.D. = twice a day, BDL = Bile Duct Ligation, BDNF = Brain Derived Neurotrophic Factor, BNR = Blinding Not Reported, BUN = Blood Urea Nitrogen, CAT = Catalase, CFD = Cafeteria Diet, CLD = Control Diet, CON = Control, CON-A = Concanavalin A, CORT = Corticosterone, CR = Conventionally Raised, CRE = Creatinine, RS = Restraint Stress, CTX = Cortex, CV = Conventionalized, D-GAL = D-galactose, DNBS = Dinitro-Benzene Sulfonic Acid, DSS = Dextran Sodium Sulfate, EB = Ethidium Bromide, Ecologic® Barrier = B. bifidum W23, B. lactis W52, L. acidophilus W37, L. brevis W63, L. casei W56, L. salivarius W24, be. Lactis W19, be. Lactis W58, EPM = Elevated Plus Maze, EPSP = Excitatory Post Synaptic Potentials, EtOH = Ethanol, FRL = Flinders Resistant Line, FSL = Flinders Sensitive Line, FST = Forced Swim Test, GF = Raised in Germ Free Environment, GPx = glutathione peroxidase, GSH = Glutathione, HA = Hyperammonemia (hepatic encephalopathy model), HCD = High Cholesterol Diet, HFD = High Fat Diet, HIP = Hippocampus, HYP = Hypothalamus, LACA = Laboratory Animal Center Albino, Lacidofil® = 95% b. rhamnosus R0011 & 5% b. helveticus R0052, Lc. = Lactococcus, LPS = Lipopolysaccharide, LSPC = Lotus Seedpod Proanthocyanidins, LTI = Long Tonic Immobility, LTP = Long Term Potentiation, MDA = Maiondialdehyde, MHFD = Maternal High Fat Diet, MI = Myocardial Infarction, MI = Myocardial Infarction, MIA = Maternal Immune Activation, ML-7 = myosin light chain kinase inhibitor, MS = Maternal Separation, MTCC = Microbial Type Culture Collection, MWM = Morris Water Maze, NE = Norepinephrine, and npclll = Neimann-Pick Cl-like 1, NOR = Novel Object Recognition, NOS = Nitric Oxide Synthase, OCD = Obsessive-Compulsive Disorder, OFT = Open Field Test, OPT = Object Placement Test, P.O. = PAT = Passive Avoidance Test, Per Oral, PD = Postnatal Day, PFC = Prefrontal Cortex, PGE2 = prostaglandin E2, PPI = Prepulse Inhibition, PRO = Protein, PUFA = Polyunsaturated Fatty Acids, PVN = Paraventricular Nucleus, Q.D. = Once a day, ROS = Reactive Oxygen Species, SAM = S-adenosylmethionine, SCOP = Scopolamine, SD = Standard Diet, STI, SDT = Step Down Test, SIH = Stress Induced Hyperthermia, SOD = Super Oxide Dismutase, SPF = Specific Pathogen Free, = Short Tonic Immobility, STR = Striatum, TNBS = 2,4,6-trinitrobenzenesulfonic acid, TST = Tail Suspension Test, VSL#3 = S. salivarius ssp. thermophilus, B. breve, B. infantis, B. longum, L. acidophilus, b. plantarum, b. casei, b. delbrueckii subsp. Bulgarians, VTA = Ventral Tegmental Area, WAS = Water Avoidance Stress, XOS = Xylooligosaccharide, ZO-1 = Zonula Occludens-1