One Giant Leap from Mouse to Man: The Microbiota–Gut–Brain Axis in Mood Disorders and Translational Challenges Moving towards Human Clinical Trials
Abstract
:1. Introduction
2. Pathways of Communication along the Microbiota–Gut–Brain Axis
2.1. The Autonomic Nervous System and the Enteric Nervous System
2.2. The Vagus Nerve
2.3. Immune Signaling
2.4. Enteroendocrine Regulation
2.5. Neurotransmitters
3. The Microbiota–Gut–Brain Axis in Stress and Related Disorders, and Opportunities by Probiotics to Relieve or Prevent Symptoms
3.1. Stress, Anxiety and Probiotics
3.2. Depression and Probiotics
4. From Preclinical to Clinical—Translational Challenges in Microbiota–Gut–Brain Axis Studies
4.1. Germ-Free Models
4.2. Antibiotic Models
4.3. Humanized (Gut) Models
Model | Changes | Effects | References | ||
---|---|---|---|---|---|
Germ-free | Brain physiology and function | Increase of neurogenesis in adult GF mice | Important role in learning and memory | [117] | |
Increased hippocampal and amygdalar volume, altered dendrite and neuronal morphology within these brain regions | Structural integrity and signaling pathways within brain regions involved in stress response, anxiety behavior, and social interactions are dependent on the presence of the gut microbiota | [118,119] | |||
Increased neuronal activity within the amygdala is associated with upregulated genes | GF mice have significantly lower BDNF mRNA expression compared to specific pathogen-free (SPF) mice | [119] | |||
Lack of gut microbiota | Significant effect on serotonergic neurotransmission within CNS | [100] | |||
Hippocampal concentrations of serotonin and 5-hydroxyindoleacetic acid, 5-HIAA (main metabolite of serotonin) are increased in male GF mice, and plasma concentrations of tryptophan are also increased | [100] | ||||
Decreased expression of the serotonin receptor 1A (5HT1A) in the hippocampus | [120] | ||||
Both increase and decrease of hippocampal BDNF mRNA expression reported in different studies | [100,120,121] | ||||
Upregulation of genes linked to myelination and myelin plasticity in prefrontal cortex of adult GF mice | Presence of hyper-myelinated axons within prefrontal cortex | Significant impact on the future development of treatment strategies for myelination diseases, such as multiple sclerosis | [122] | ||
Absence of gut microbiota | Microglia of GF mice are defective and display an immature phenotype and an impaired innate immune response to infection with a bacterial-associated inflammatory mediator—lipopolysaccharide (LPS) | The immune response is also defective within the periphery | [24,100,123] | ||
Increase in BBB permeability | The CNS of GF mice is particularly vulnerable to brain damage and infection | [124] | |||
Behavioral profiles, cognitive function and stress responses | Absence of gut microbiota | Increased pain response and visceral sensitivity | [125,126,127,128] | ||
Impairment in sociability and social cognition, although one study has shown the opposite | i.e., the gut microbiome is essential for normal social behavior | [126,127,128,129] | |||
Impaired short-term recognition and working memory | [130] | ||||
Hyperactivity of the HPA axis response to stress | Varied effect of anxiety-like behavior, depending on the experimental design, species, strain, and sex | [100,101,116,120,121,126,130,131] | |||
Antibiotic | During critical windows | Alterations or depletion of microbiota through administration of antibiotics (single/cocktail, absorbable/non-absorbable) to dams either during the periconception period, and/or during pregnancy, and/or during weaning or to the offspring in early life | Effect on neurodevelopment and behavior | [132,133,134,135] | |
Reduced anxiety-like behavior Increased aggressive behavior Increased resilience to stress Reduction of social behavior and preference for social novelty Altered cytokine expression in the brain Altered BBB integrity | [136] | ||||
Increased visceral hypersensitivity | [137,138] | ||||
Reduced anxiety-like behavior, cognitive deficits, altered tryptophan metabolism and gene expression | [139] | ||||
Expression of BDNF and its receptor in both ENS and CNS | [140] | ||||
Expression of genes involved in immune function, neurotransmission, and neuroplasticity in the amygdala | Long-lasting effects on gut microbiota composition into adulthood | [141] | |||
In mood disorders and neurodegenerative disorders | Alterations in gut microbiota | Attenuated inflammation, and β-amyloid (Aβ) and other pathologies associated with disease progression Delay disease related memory deficits | [142,143,144,145] | ||
Depletion of gut microbiota | Decreased microglia activation, reduced | Indication that gut microbiome is important for enhancing Parkinson’s disease-like symptoms | [146] | ||
Administration of an antibiotic cocktail from adolescence to adulthood to mice with experimental autoimmune encephalomyelitis (EAE)t | Depletion of the gut microbiota significantly delayed the onset of EAE symptoms and altered several immunological and neurobehavioral responses | [147] | |||
Administration of antibiotics prior to exposure to chronic social defeat stress (CSDS) | No development of anhedonic-like behavior in adulthood when compared to mice administered water only | [148] | |||
Administration of antibiotic cocktail | Depleted serotonin levels in the intestine coupled with an altered sleep/wake cycle | [149] | |||
Humanized gut models | Generation of a humanized mouse with a gut microbiota resembling that of the human donor | GF recipient mice are already markedly altered and depending on the dose, duration, and composition of the antibiotic cocktail, antibiotic-treated recipient mice may have experienced other CNS effects or incomplete microbiome depletion | FTM from human donors with, e.g., depression, alcoholism, anorexia nervosa, IBS, and schizophrenia; rodents later presented abnormalities in behavior, indicating at least partial transfer of the clinical psychiatric phenotype | [81,82,109,110,111,112,113,114] | |
Transplantation of the gut microbiota from patients with PD | Worsening of the motor symptoms in genetically susceptible mice compared with those in receipt of the gut microbiota from healthy controls | Highlight the gut microbiome as a significant contributing factor towards progression of PD symptoms in genetically susceptible hosts | [146] | ||
Recipient rats developed behavioral and physiological features characteristic of the donors with depressive disorder such as increased anhedonic- and anxiety-like behaviors, as well as alterations in tryptophan metabolism and an increased inflammatory profile | [113,114] |
5. Psychobiotics—Selected Case Studies of Translational Results from Preclinical to Clinical
5.1. Bifidobacterium longum 1714®
5.2. Lacticaseibacillus paracasei Lpc-37®
5.3. Lactobacillus helveticus Rosell®-52 + Bifidobacterium longum Rosell®-175
5.4. Lacticaseibacillus rhamnosus JB-1™
6. Future Perspectives and Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Neurotransmitter | Endogenous Production | Exogenous Production | Function | Remarks | References |
---|---|---|---|---|---|
Nitric oxide (NO) | Enteric inhibitory neurons | Enterobacteria, some lactobacilli and bifidobacteria, and some oral anaerobes | Gut motility, brain development, memory, and anti-anxiety | Enteric-produced NO does not play a role in anxiety | [38,39,40] |
γ-aminobutyric acid (GABA) | GABA-ergic neurons | Some lactic acid bacteria and bifidobacteria | Neuroprotection, anti-diabetic, antioxidant, anti-inflammatory, anti-allergic, hepatoprotection, renoprotection, anti-depression, and anti-insomnia | Does not cross blood–brain barrier | [41,42,43] |
Norepinephrine | Enteric nerve cells | E. coli, Bacillus, Saccharomyces spp., S. marcescens and P. vulgaris | Anti-inflammatory, anti-stress, and anti-anxiety | Does not cross blood–brain barrier | [44,45,46,47,48,49] |
Dopamine | Central nervous system, various other tissues | Bacillus spp. | Locomotion, learning, working memory, cognition, and emotion | Does not cross blood–brain barrier | [46,49,50] |
Acetylcholine | Cholinergic neurons | L. plantarum | Cognitive function and intestinal motility | Does not cross blood–brain barrier | [51,52,53] |
Serotonin (5-hydroxytryptamine; 5-HT) | Serotonergic neurons mainly in the gut | Candida, E. coli, Lc. lactis, L. plantarum, S. thermophilus, M. morganii, K. pneumoniae, H. alvei and Enterococcus spp. | Regulation of mood, appetite, sleep, and cognitive function | Does not cross blood–brain barrier | [49,54,55,56,57] |
Melatonin | Enterochromaffin cells in the gut | - | Regulation of circadian rhythm | Intestinal microbiota may be involved in breakdown | [57,58,59] |
Indole | - | Actinobacteria, Firmicutes, Bacteroidetes, Proteobacteria, Fusobacteria, Clostridium, Burkholderia, Streptomyces, Pseudomonas and Bacillus | May influence emotional behavior | Crosses blood–brain barrier | [57,60] |
Kynurenine and/kynurenic acid | Central nervous system, various other tissues | B. infantis | Associated with depression and schizophrenia | Increased kynurenic acid: kynurenine is neuroprotective. Both can cross blood–brain barrier | [57,61,62] |
Quinolinic acid | Epithelial cells and intestinal immune cells | - | Associated with depression | Neurotoxic. Does not cross blood–brain barrier. May be blocked by L. helveticus and B. longum | [57,61,63,64] |
Histamine | Mast cells and other immune cells | Certain lactic acid bacteria fermented foods | Mediates arousal, attention, and reactivity | Does not cross blood–brain barrier | [56,65,66,67] |
Short chain fatty acids (SCFA) * | Muscle tissue | Most anaerobes in the gut | Regulate inflammation, appetite, depression, and gut motility | Crosses blood–brain barrier | [68,69,70,71,72,73,74,75,76,77,78,79,80,81] |
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Forssten, S.D.; Ouwehand, A.C.; Griffin, S.M.; Patterson, E. One Giant Leap from Mouse to Man: The Microbiota–Gut–Brain Axis in Mood Disorders and Translational Challenges Moving towards Human Clinical Trials. Nutrients 2022, 14, 568. https://doi.org/10.3390/nu14030568
Forssten SD, Ouwehand AC, Griffin SM, Patterson E. One Giant Leap from Mouse to Man: The Microbiota–Gut–Brain Axis in Mood Disorders and Translational Challenges Moving towards Human Clinical Trials. Nutrients. 2022; 14(3):568. https://doi.org/10.3390/nu14030568
Chicago/Turabian StyleForssten, Sofia D., Arthur C. Ouwehand, Síle M. Griffin, and Elaine Patterson. 2022. "One Giant Leap from Mouse to Man: The Microbiota–Gut–Brain Axis in Mood Disorders and Translational Challenges Moving towards Human Clinical Trials" Nutrients 14, no. 3: 568. https://doi.org/10.3390/nu14030568