Table 1.
Animal studies showing effect of gut microbiome/probiotics on the central nervous system (CNS).
| Reference | Study characteristics |
|---|---|
| 1. Sudo et al. (86) | Participants: mice study, in vivo. Germ-free (GF) at 9 weeks of age |
| Intervention: stress protocol | |
| Controls: specific pathogen-free (SPF) BALBc mice, gnotobiotic mice | |
| Primary outcome: plasma ACTH, corticosterone levels, fecal microflora analysis, plasma cytokine assays | |
| Conclusion: plasma ACTH and corticosterone responses of GF mice were more susceptible to stress than those of SPF mice. Gut flora regulates the development of the HPA stress response | |
| 2. Bravo et al. (87) | Participants: adult male BALB/c mice, in vivo (n = 36) |
| Intervention: Lactobacillus rhamnosus 109 cfu gavaged for 28 days | |
| Control: control broth | |
| Type of probiotic: L. rhamnosus (JB-1) | |
| Primary outcome: corticosterone level, behavioral analysis, GABA B1b mRNA expression in hippocampus, amygdala, and locus coeruleus | |
| Conclusion: L. rhamnosus supplementation reduced corticosterone response to stress and modulated the GABAergic system in mice. Vagotomized mice did not show the neurochemical effects of this bacterium | |
| 3. Desbonnet et al. (88) | Participants: adult Sprauge-Dawley rats (n = 20) |
| Intervention: Bifidobacterium infantis 35624 gavaged for 14 days (n = 12) | |
| Controls: n = 8 | |
| Type of probiotic: B. infantis 35624 | |
| Primary outcome: corticosterone level, tryptophan and IFN-g, TNF-alpha and IL-6, brain monoamines analysis | |
| Conclusion: attenuation of pro-inflammatory immune responses and the elevation of the serotonergic precursor, tryptophan, in probiotic-treated group | |
| 4. Alenina et al. (89) | Participants: Tph2-deficient (Tph2−/−) mice, in vivo study |
| Intervention: gene targeting leading to mice with absent TPH2, n = 4 | |
| Type of probiotic: none | |
| Controls: n = 6 | |
| Primary outcome: serotonin in the brain of Tph2−/− mice | |
| Conclusion: the lack of central serotonin in these mice leads to impaired early postnatal growth and altered autonomic control of sleep, thermoregulation, and cardiorespiratory reflexes | |
| 5. Lyte et al. (84) | Participants: 9-week-old CF-1 male mice, in vivo study |
| Intervention: in an animal model of IBD, infection with Citrobacter rodentium, to determine whether the infection could lead to anxiety-like behavior | |
| Controls: saline | |
| Type of probiotic: none | |
| Primary outcome: tested for anxiety-like behavior measurement, immune cytokine analysis, and colon for histological analysis | |
| Conclusion: C. rodentium infection could induce anxiety-like symptoms that are likely mediated via vagus | |
| 6. Gareau et al. (90) | Participants: mouse in vivo study |
| Intervention: behavior was assessed following infection with the non-invasive enteric pathogen, C. rodentium in both C57BL/6 mice and GF Swiss-Webster mice | |
| Primary outcome: whether daily treatment with probiotics normalized behavior was assessed | |
| Conclusion: memory dysfunction occurred in infected mice exposed to acute stress, while in the GF setting, memory was altered at baseline | |
| 7. McVey Neufeld et al. (91) | Participants: mouse ex vivo study |
| Intervention: segments of jejunum from 8- to 12-week old GF, SPF, and CONV-GF mice dissected to expose myenteric plexus. Intracellular recordings by impaling cells with sharp microelectrodes | |
| Type of probiotic: none | |
| Primary outcome: action potential shapes, firing thresholds, the number of APs fired at 2× threshold, and passive membrane characteristics were measured | |
| Conclusion: commensal intestinal microbiota are essential for normal excitability of gut sensory neurons. When the vagus nerve is severed, effects of gut bacteria on brain biochemistry, stress response, and behavior disappear | |
| 8. Heijtz et al. (92) | Participants: mouse in vivo study GF versus SPF mice with normal microbiological gut flora |
| Intervention: motor activity and anxiety-like behavior measured | |
| Conclusion: unstressed GF mice were more active and willing to explore exposed areas of a maze than mice that had normal gut microbiota. Transplanting normal gut bacteria into the GF mice erased those behavioral differences only in early life, suggesting that there is a critical window for gut bacteria to establish normal patterns of behavior | |
| 9. Clarke et al. (52) | Participants: male GF animals compared with conventionally colonized control animals |
| Intervention: measurement of 5-HT in hippocampus | |
| Male GF animals have a sex-specific significant elevation in hippocampal 5-HT and 5-HIAA compared with conventionally colonized control animals. Concentrations of tryptophan, the precursor of serotonin, are increased in the plasma of male GF animals, suggesting a humoral route through which the microbiota can influence CNS serotonergic neurotransmission | |
| Conclusion: microbiome–gut–brain axis in early life modulate hippocampal serotonin levels in a gender-dependent manner |