Table 1. Summary of studies performed in animal models evaluating the effect of the gut microbiota and/or changes induced by probiotic and prebiotic interventions.

Animal model	Test	GI microbiota	Effects	Notes	Effect	Reference
NMRI mice	EPM Dark/light box	GF vs SPF	GF mice have increased motor activity and reduced anxiety compared with SPF with a normal microbiota. GF mice exposed to gut microbiota early in life display similar characteristics as SPF mice	Commensal microbiota can affect the postnatal development of the HPA stress response in mice.	CNS	28
Balb/c male mice	Restraint stress	GF vs SPF vs gnotobiotic mice (with B. infantis; with enteropathogenic E. coli with/without intimin receptor gene)	GF male mice have a decrease in brain derived neurotrophic factor (BDNF)- a key neurotrophin involved in neuronal growth and survival -compared with SPF mice. They also have decreased expression of the glutamate NMDA receptor subunit 2a in the cortex and hippocampus. Effect was reversed in gnotobiotic animals colonized with B. infantis, but not with E. coli	Measured by polymerase chain reaction and Western Blotting. Commensal microbiota can affect the postnatal development of the HPA stress response in mice.	CNS	29
Swiss Webster female mice	EPM	GF vs SPF mice	GF mice have a more pronounced anxiolytic behavior and increased expression of BDNF mRNA in the dentate gyrus of the hippocampus compared with SPF mice. They have reduced serotonin 1A receptor mRNA expression in the dentate gyrus of the hippocampus	Measured by in situ hybridization	CNS	27
Recombinase activating gene (RAG) Ko mice	EPM		Reduced inflammation is linked to reduced anxiety		Brain-gut communication	30
Male Balb/c mice or AKH mice infected with T. muris.	Light/dark test	L. rhamnosus NCC4007 and B. longum NCC3001	Infection with T. muris induced anxiety like behavior and decreased level of BNDF. Treatment with B. longum reverses the effect and normalizes BDNF level.	Vagatomy did not have an effect on the probiotic treatment		86
Male Wistar rats (gnotobiotic model)	Conditioned defensive burying test	L. helveticus R0052 + B. longum RO07 Vs. placebo vs. diazepam	Probiotics have anxiolytic effect compared with placebo	Same probiotics were also administered in 75 healthy volunteers with stress symptoms in another study		35
Sprawley rats	Colorectal distension,tail flick and paw pressure tests	L. reuteri ATCC 23272	Live, killed probiotic bacteria or conditioned medium inhibited the constitutive cardioautonomic response to colorectal distension in rats through effects on enteric nerves.			16
Balb/c mice	EPM Swim test	L. rhamnosus (JBI)	Increase of corticosterone Increase of GABA	Alter mRNA expression of GABA receptor Vagotomy prevented these effects	ENS/CNS	31
Balb/c mice and NIH mice		SPF + antibiotic vs. GF mice	Antibiotic decreased anxiety behaviors, Interspecies gut microbiota transplantation changed species specific associated phenotype			87
CF1 mice		Citrobacter rodentidum infection	Increase anxiety like in pathogen infected mice		CNS	36
C57BL/6 mice		Citrobacter rodentidum infection	Increase memory dysfunction in pathogen infected mice		CNS	37
Maternal deprivation in offspring’s rats		L. paracasei NCC 2461	Probiotic reverse rectal hyperalgesia	Animal model for IBS	CNS and brain-gut axis	21
Maternal deprivation in male offspring’s rats			Plasma PUFA different in maternally separated animal vs controls	Animal model for IBS	CNS and brain-gut axis	88
Maternal deprivation in male offspring’s rats		Lipopolysaccharide challenge	Plasma corticosterone increase in maternally separated animals. Increase in immune response after LPS challenge Alteration in fecal microbiota vs control group	Animal model for IBS	CNS and brain-gut axis	89
Maternal deprivation in offspring’s rats	Swim test	B. infantis	Probiotic treatment resulted in normalization of the immune response, reversal of behavioral deficits peripheral interleukin (IL)-6 release and amygdala corticotrophin-releasing factor mRNA level) and restoration of basal noradrenaline concentrations in the brainstem	Animal model for IBS	CNS and brain-gut axis	24

Abbreviations: ANS, autonomous nervous system; CNS, central nervous system; ENS, enteric nervous system; EPM, Elevated plus maze; GF, germ-free; HPA, hypothalamic-pituitary-adrenal; IBS, irritable bowel syndrome; SPF, specific pathogen free.