Probiotics together with the supporting bacteria, prebiotics (1), are named psychobiotics because they can influence gut-brain relations.
Some bacterial species are being studied to further investigate their role in mental health recovery from cases of depression, anxiety to more severe disorders and to evaluate their use in formulating psychobiotics to support or replace current drug therapy.
Introduction
In the 4th century BC. Hippocrates argued that diseases originated in the intestines. Nowadays, studies highlight the key role of this organ and its microbiota for human, extra-intestinal health. Alterations in the microbiota caused by inflammation or dysbiosis, in addition to being able to cause chronic diseases (2) are involved in dysfunction of central nervous system activity.
The intestinal microbiota includes all the microorganisms that inhabit the intestinal tract. If you include their genomes within it, this is called the microbiome, a key node in the gut-brain axis.
The microbiome-gut-brain relationship
The importance of the gut-brain axis as a two-way communication pathway between the gut and the cognitive and emotional centers of the central nervous system (CNS) is now recognized.
The pathways the axis uses to connect mind, gut, and microbiome are multiple and include nervous (vagal and nonvagal), endocrine, immune, and metabolic mechanisms, showing a dense network of relationships that converge into a single system, our organism. Therefore, mental disorders are closely related to the microbiome and consequently to gut health.
The role of the gut microbiome in nervous system activity
A demonstration was provided by a study (3) showing that mice raised in sterile environments so as not to develop indigenous bacteria show exaggerated physiological reactions to stress compared with the control group.
The abnormal reactions were reversible through probiotic-induced bacterial recolonization. This finding revealed the causal involvement of the microbiome in the development of the hypothalamic-pituitary-adrenal (HPA) axis.
This discovery reconsidered the role of gut bacteria as an integral part in the regulation of various important physiological processes, including immunomodulation, adiposity and energy balance, and electrophysiological activity of the central nervous system.
Regulatory mechanism between gut and nervous system
The regulatory mechanisms between the microbiome and the nervous system can be altered by inflammation and dysbiosis that make the gut permeable to various metabolites, such as substances produced by the gut flora and/or bacteria themselves (bacterial translocation).
Psychophysiological effects were mainly studied in mice to evaluate their stress-induced and behavioral reactions for anxiety and depression.
More recent studies have also focused on humans showing that the effects of altering the microbiome fall into the following three categories.
1- Psychological effects on emotional and cognitive processes.
Bacterial metabolites, such as short-chain fatty acids, act as modulators of gene expression (epigenetic factors) and can influence cognitive and behavioral/emotional functions.
2- Systemic effects on HPA axis and stress response.
The gut microbiota has been shown to develop parallel to the HPA (hypothalamic-pituitary-adrenal) axis, one of the most important components of the gut-brain axis that provides the primary biological response to stressful stimuli.
The effects on the HPA axis primarily impact glucocorticoid levels as well as inflammation, which is often characterized by elevated cytokine concentrations. Pro-inflammatory cytokines have a strong positive association with psychiatric conditions such as depression.
3- Neural effects on neurotransmitters and proteins.
Gut inflammation alters the metabolism of tryptophan, the precursor to serotonin (the happiness hormone), resulting in a brain deficit of the neurotransmitter.
Relevant neurotransmitters include γ-aminobutyric acid (GABA) and glutamate, which control the neural excitation-inhibition balance. The proteins include Brain Derived Neutropic Factor (BDNF- BDNF), which plays a crucial role in learning and memory processes. BDNF is reduced in anxiety and depression, a reversible reduction through the action of antidepressants.
Negative effects of antidepressants
Traditional antidepressant drugs commonly used to treat some psychiatric disorders can alter the gut microbiome as a side effect by prolonging and/or making the disease condition more severe.
Among the drugs tested on mice in the CopenhagenEuropean College of Neuropsychopharmacology (ECNP) study (4) appear lithium or valproate or antidepressant drugs such as fluoxetine (Prozac) and escitalopram.
After four weeks, the researchers examined the gut microbiomes and found that the drugs, in some cases, had steadily increased the number of certain species of bacteria in the gut. Valproate and lithium, which are usually given to treat bipolar disorder, caused the increase in the number of Clostridium; other antidepressant drugs, however, inhibited the growth of Escherichia coli strains.
The need to find alternatives to drug treatment used for mental disorders is becoming increasingly urgent in light of the side effects induced.
Psychobiotics
Psychobiotics are beneficial bacteria (probiotics) or supportive bacteria (prebiotics) that influence the relationship between bacteria and the brain. They exert anxiolytic and antidepressant effects, characterized by changes in emotional, cognitive, systemic, and neural (3). The communication channels between bacteria and the brain include the enteric nervous system and the immune system.
The bacteria most commonly used as probiotics are the Bifidobacterium and Lactobacillus families (5,6). These do not possess pro-inflammatory lipopolysaccharide chains, so their propagation in the gut does not trigger true immunological reactions.
The immune system learns to distinguish between pro- and anti-inflammatory entities and develops appropriate immunogenic responses by identifying pro-inflammatory elements as antigenic.
Lactic acid bacteria to alleviate depression
Several researches have investigated the association between gut microbiota and major depression.
A study by Cheung et al. (7) conducted a review of six research cases comparing the gut microbiota of patients with major depression and healthy controls by analyzing strains of Bacteroidetes, Firmicutes, Actinobacteria, Fusobacteria and Protobacteria.
The researchers found that nine genera had higher abundance (including Clostridium, Klebsiella and Streptococcus), six genera had lower abundance (including Bifidobacterium, Dialister and Escherichia/Shigella) while six were more divergent(Alistipes, Bacteroides, Megamonas, Oscillibacter, Prevotella and Roseburia) in patients with depression. Probiotics, but not prebiotics, have been shown to exert small but significant antidepressant and anxiolytic effects. (8)
..and improve the living conditions of patients
Studies on mice with induced anxiety and depression have shown that the bacterium Lactobacillus rhamnosus appears to improve mood by reducing the effects of the alteration.
This beneficial effect, however, is lost when signals traveling along the vagus nerve are blocked, suggesting that bacteria may be using it as a communication pathway.
Administration of Lactobacillus plantarum in patients with major depression also improves cognitive performance in terms of attention and verbal learning.
Bifidobacterium to reduce stress and promote memory
Stress is an important influence on the structural and functional aspects of the microbiome.
The stress condition increases the production of glucocorticoids that dysregulate intestinal barrier function, triggering inflammatory immune responses. As a consequence of barrier disruption, there is bacterial migration that increases concentrations of pro-inflammatory elements such as lipopolysaccharide, a process also associated with human depression.
Probiotic supplementation with Bifidobacterium or Lactobacillus can restore intestinal barrier integrity and reduce stress-induced intestinal leakage in mice and rats.
Another clinical study showed that administration of the Bifidobacterium longum strain not only reduced stress level but also improved memory in healthy volunteers (9).
Maternal stress
In one study (10), maternal stress and cortisol concentrations during late pregnancy were also shown to be associated with changes in the intestinal microbiota of infants. Effects persisting until the end of the follow-up period at 16 weeks.
Infants of mothers with high stress levels and high cortisol concentrations had much higher relative abundances of proteobacterial groups and lower relative abundances of lactic acid bacteria.
The microbiome in severe psychiatric disorders
More severe mental disorders such as bipolar disorder and schizophrenia have also been shown to be caused by HPA axis dysfunction. Patients observed in the reported studies had major alterations in the microbiome.
Bipolar disorder
Some studies (11,12) have investigated the gut microbiota in patients with bipolar disorder. The results of one such study imply that patients with bipolar disorder, compared with controls, show higher abundance of Actinobacteria, Choriobacteria and Choriobacteriacease and lower abundance of Faecalibacterium and Ruminococcaceae.
Flavonifractor
was significantly more prevalent in patients with bipolar disorder, but not in their unaffected first-degree relatives, than in healthy controls. However, this difference was limited to cigarette smoking patients.
Schizophrenia
The study by Yuan et al. (13) found that patients who were unresponsive to medication with first-episode schizophrenia psychosis had lower numbers of Bifidobacterium spp., E. coli and Lactobacillus spp. compared with healthy controls.
Another study revealed a higher number of Lactobacillus group bacteria in patients with first-episode psychosis than in controls. In addition, higher numbers of Lactobacillus group bacteria were seen to be associated with greater severity of positive symptoms and worse overall functioning.
Interim conclusions
The diversity of species and the many bacterial interactions that occur in the gut influence the messages that are sent to the brain through nerve pathways and the signal molecules that originate from the digestive tract. Therefore, any nutritional deficit or imbalance can reduce the biodiversity of the microbiota and adversely affect the patient’s psychophysical state.
While waiting for the medical applications of psychobiotics to be confirmed by clinical trials, it is certainly possible to take preventive action by implementing a diet that improves the health of the gut and its microbiota.
Giulia Pietrollini
Notes
(1) Dario Dongo and Carlotta Suardi. Prebiotics and probiotics, microbiome and immune system. GIFT (Great Italian Food Trade). 28.4.20
(2) Giulia Pietrollini, Probiotics, a solution for chronic inflammation. GIFT (Great Italian Food Trade). 6.12.22
(3) Sarkar A, Lehto SM, Harty S, et al. Psychobiotics and the Manipulation of Bacteria-Gut-Brain Signals. Trends Neuroscience, 2016 ;39(11):763-781. doi: 10.1016/j.tins.2016.09.002.
(4) European College of Neuropsychopharmacology (Ecnp). Scientists find psychiatric drugs affect gut contents, 8.09.2019, https://www.eurekalert.org/news-releases/900535
(5) Mayer EA, Knight R, Mazmanian SK, Cryan JF, Tillisch K. Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci. 2014 Nov 12;34(46):15490-6. doi: 10.1523/JNEUROSCI.3299-14.2014. PMID: 25392516; PMCID: PMC4228144.
(6) Burnet PW, Cowen PJ. Psychobiotics highlight the pathways to happiness. Biol Psychiatry. 2013 Nov 15;74(10):708-9. doi: 10.1016/j.biopsych.2013.08.002. PMID: 24144322.
(7) Cheung, S., & Tangmatitham, M. (2019). A preliminary study of the impact of high school astronomy research-based learning in Thailand. Proceedings of the International Astronomical Union, 15(S367), 34-37. doi:10.1017/S1743921321001113
(8) Liu RT, Walsh RFL, Sheehan AE. Prebiotics and probiotics for depression and anxiety: A systematic review and meta-analysis of controlled clinical trials. Neurosci Biobehav Rev. 2019 Jul;102:13-23. doi: 10.1016/j.neubiorev.2019.03.023. Epub 2019 Apr 17. PMID: 31004628; PMCID: PMC6584030.
(9) Allen, A., Hutch, W., Borre, Y. et al. Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers. Transl Psychiatry 6, e939 (2016). https://doi.org/10.1038/tp.2016.191
(10) Zijlmans MA, Korpela K, Riksen-Walraven , et al. Maternal prenatal stress is associated with the infant intestinal microbiota. Psychoneuroendocrinology. 2015 Mar;53:233-45. doi: 10.1016/j.psyneuen.2015.01.006. Epub 2015 Jan 19. PMID: 25638481.
(11) Aizawa E, Tsuji H, Asahara T, et al. Possible association of Bifidobacterium and Lactobacillus in the gut microbiota of patients with major depressive disorder. J Affect Disord. 2016 Sep 15;202:254-7. doi: 10.1016/j.jad.2016.05.038. Epub 2016 May 24. PMID: 27288567.
(12) K. Coello, T.H. Hansen, N. Sørensen, et al.,Gut microbiota composition in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives Brain Behav. Immun., 75 (2019), pp. 112-118
(13) X. Yuan, P. Zhang, Y. Wang, et al. Changes in metabolism and microbiota after 24-week risperidone treatment in drug-naïve, normal weight patients with first episode schizophrenia. Schizophr. Res., 201 (2018), pp. 299-30
Graduated in industrial biotechnology and passionate about sustainable development.
