Microbiome and Mental Health

From Wikiversity
Jump to navigation Jump to search

History of the gut microbiome[edit]

Before Antonie van Leeuwenhoek first discovered bacteria in a sample in 1676, though the connection between microbiome and mental health has recently come to the attention of public media with articles about it published in the New York Times[1], Scientific American[2], Huffington Post[3], and Nature[4], the history of research in this area has deep roots in the science field. Scientists have been pondering and writing on the connection between the brain and the body for centuries. For instance, in 1759, Laurence Sterne said in reference to “a man’s body and his mind" that if you "rumple the one, -you rumple the other" in his book The Life and Times of Tristan Sterne.

The human gastrointestinal tract alone contains a delicately balanced ecosystem of 100 trillion microorganisms, nearly ten times the number of cells in the entire human body. [5] These bacteria in our gut, which are collectively called the gut microbiome, play many physiological roles in the body, for instance synthesizing vitamins, developing the immune system, aiding digestion to name a few, and managing the stress response.[5] Beyond involvement in somatic processes, bacteria within the body are so interwoven in our systems that impact our behavior and cognition. One study even found that when the gut contents of two mice were swapped, including all of their gut microbiome, the mice's personalities switched; for example, stress-prone mice became calm and calm mice became stress-prone.[5]

Even without the context of disease, humans and animals alike have very diverse interpersonal compositions of their microbiomes. Thus, it has been difficult for researchers to discern the difference between unbalanced, or dysbiotic, microbiome and a healthy microbiome.[6] Over the past decades, researchers have found hundreds of bacteria strains in the human gut; however, only a handful amongst such are ubiquitous[6]. Some of these ubiquitous bacteria include: anaerobic cocci and Bacteroides--which are prevalent in high abundance--and Clostridium, Bifidobacterium, Eubacterium, Lactobacillus, Escherichia coli and Streptococcus--which are prevalent in lower abundance[6].

Acquisition and development in humans[edit]

Bacteria begin to form an inextricable link to us shortly before birth when they colonize our guts within the womb.[5] By the time people are 3-5 years old, people have developed a full adult microbiome and a gut-brain axis. Once the microbiome is established, it is relatively stable throughout life. [7]

The gut-brain axis[edit]

The gut-brain axis describes the connection between the gut in the brain via many different body systems, such as the immune system, nervous system, and endocrine system. In much the same way that proprioceptors help gauge the state of muscle tension and stress, provide feedback to the brain, which in turn changes the state of muscles to prevent damage, the gut and brain have similar systems of providing dual-direction feedback and change. Many factors throughout the body have a significant impact on the state of one's mental health[8]:

  • Excessive bodily inflammation
  • Poor absorption of nutrients and medication in the gut
  • Gut serotonin imbalance
  • Leaky gut syndrome, which causes nutrients to leach into the blood stream rather than being absorbed by the intestines
  • A dearth of brain serotonin, dopamine, and other neurotransmitters
  • Hormonal imbalance
  • Deficiencies in certain vitamins and minerals (A, B, C, D, E, K, Calcium, Iron, Magnesium, Phosphorus, Sodium, and Zinc, among others)

Although these varied systems may seem disparate, they are largely interconnected through the gut-brain axis. The gut-brain axis (GBA) is a set of mechanisms through which the gut and brain communicate bidirectionally. Three of the main communication routes are the immune system, the nervous system, and the endocrine system. Through these mechanisms, the information in the gut can affect behavior and cognition, although not necessarily in a negative way. For instance, one study found that when the gut bacteria from two different mice were swapped, the behavioral traits of those mice also swapped. stress-prone mice became calm and calm mice became stress-prone[5].

Immune system interaction[edit]

The first mechanism through which bacteria in the gut interact with our brain is through inflammation. The mechanisms thpersat cause the brain to convert typical chronic inflammation into depression and anxiety symptoms are a result of typical immune system function. During a regular immune response to an infection, there is an increase in pro-inflammatory cytokines, such as interleukin-1 and interleukin-2. In immune response, cells throughout the body release cytokines that mediate and regulate immunity, inflammation, and hematopoiesis (induced blood cell destruction in case of infection)[9]. Pro-inflammatory cytokines seek infected cells and signal other cells to destroy them, as well as induce other biological responses to infection like inflammation. Anti-inflammatory cytokines release signaling compounds that cause biological processes that inhibit further inflammation. In a mentally and physically healthy person, anti-inflammatory cytokines are in equilibrium with pro-inflammatory cytokines[9]. However, when someone becomes infected with deleterious bacteria, the body produces more pro-inflammatory cytokines, as inflammation will stop the bacteria from infecting the whole body. Research has found that increased levels of pro-inflammatory cytokine activity in the brain lowers metabolism of neurotransmitters, specifically that of GABA; GABA, when in lower levels, causes depressive symptoms[8].

Nervous system interaction[edit]

Through various mechanisms, including the vagus nerve and through the release of neurotransmitter precursors, the enteric nervous system is connected bidirectionally with the central nervous system. A second communication system the gut and brain have with one another is through the nervous system and the brain. As previously mentioned, bacteria become incorporated in the human gut before birth in the womb. Bacteria also become enmeshed within the nervous system in addition to the gut, strengthening specific neural pathways and lines of communication between the gut and brain and causing the development of signaling mechanisms in the central nervous system that irrevocably affect behavior and cognition[9]. Thus, our normal nervous system function is dependent upon the bacterial balance and correct functioning. Normally, information is sent from the heart, lungs, pancreas, liver, stomach, and intestines to the brain (including the cerebral cortex, medulla oblongata, limbic system, etc.) via sensory fibers in the vagus nerve[9]. From the medulla oblongata, the afferent inputs go to the locus ceruleus in the brain stem, from which the inputs send signals to widespread areas of the CNS that commence a stress response. If the locus ceruleus, an area responsible for coordinating stress response, is activated repeatedly, permanent changes occur in the way neurons activate and interact with one another that are in line with anxiety and depressive disorders[9]. This is also known as a hyperactive HPA axis, and it is activated similarly in the inflammatory aspect of the gut-brain axis, resulting in elevated stress response and anxiety. Elevated stress and anxiety has been shown to deplete ones microbiome of bacteria that produce anti-inflammatory cytokines, thus resulting in the biological effects inherent in inflammatory response and subsequent depression

Endocrine system interaction[edit]

Research has be conducted on the interactions between neuroendocrine hormones, and specifically on the relationships between hormones and the gut microbiota. Findings show that stress-induced neuroendocrine hormones can influence bacterial growth[10] and that gut microbiota may play an important role in hormone regulation such that endocrine effects of bacteria may influence host responses ranging from behavior to metabolism and appetite, and even immune responses.[11]

Microbiome in physical illness[edit]

For years, research has been underway to uncover the relationships between microbiome dysfunction and conditions such as colorectal cancer, inflammatory bowel disease, and immunologically mediated skin diseases. While associations have been established, causal relationships between the microbiome and these diseases have not been supported.[12]

Microbiome and mental illness[edit]

Anxiety and depression[edit]

Depression is known to be closely related to elevations in C-reactive proteins, inflammatory cytokines, and oxidative stress.[13] Current research is being done on the relationship between fecal bacteria (which served as a proxy to analyze the gut microbes) and depression, showing that the presence of certain bacteria are correlated to symptoms of depression.[14] One such study examined the role of switching the gut contents of two mice with distinct behavioral characteristics, with one very stress prone and the other not. Researchers found that when the gut contents were switched, the non-stressed mouse became stress prone and stressed mouse became more calm[5].

Schizophrenia and bipolar disorder[edit]

Schizophrenia is a neuropsychiatric disorder which can appear during adolescence and usually persists throughout an individuals' life. There are varying degrees of Schizophrenia, with characteristic symptoms such as hallucinations, delusions, apathy, and social withdrawal. Bipolar disorder (BD) is a complex and multifaceted disorder with a wide range of manifestations. Bipolar Disorder varies greatly and is defined by the presence of mania or depression in different regards. Previous studies have demonstrated that both schizophrenia and bipolar disorder are associated with alterations of the systemic immune system including low-grade chronic inflammation (increased plasma cytokines, soluble cytokine receptors, chemokines, acute phase reactants) and T-cell activation features.[15][16][17] In addition, elevated antibodies to S. cerevisiae were also found in increased levels in individuals with schizophrenia and bipolar disorder [18] The gut microbiome can influence brain function, thus playing a role in mental diseases such as Schizophrenia. Specifically, humoral immunity to food antigens, intestinal inflammation, exposure to the parasite Toxoplasma gondii, endothelial barrier defects and microbial dysbiosis consistent with a physiological model where gut-bases processes create a systematic state of immune dysregulation.[19][20] A variety of factors influence GI function and environment, and while no known medication exists to completely suppress GI trauma, practicing psychiatrists should consider complementing treatment with probiotics, herbal remedies, vitamins, and minerals that improve GI symptoms in individuals with schizophrenia and bipolar disorder.[21]

Autism spectrum disorder[edit]

Links between particular bacteria and phenotypes relevant to ASD raise the question of whether microbial dysbiosis (imbalances of the microbiome) plays a role in the development or presentation of ASD symptoms.[22] Studies of fecal DNA have found over represented clusters of Clostridium or Desulfovibrio in children with ASD and gastrointestinal complaints as compared to children with typical neuro-behavioral development and similar GI complaints.[23][24][25] A study found that children with autism have increased incidences of GI problems such as constipation and food selectivity, suggesting that neurobehavioral etiology may account for the higher incidences of the GI symptoms in children with autism.[26]

Anorexia and bulimia[edit]

Because of the growing evidence suggesting the importance of the microbiome in weight regulation and its relationship to anxiety and depression, research into gut-brain interactions may be important to the treatment of anorexia and bulimia. [27]

Clinical utility of the microbiome[edit]


The potential clinical utility of probiotics, or microorganisms that cause growth of beneficial bacteria when consumed, has become clearer in light of the accumulation of epical support. Research into the microbiome-gut-brain axis has not only revealed the potential anxiogenic affects of specific bacteria and parasites and gut dysbiosis, but also the anxiolytic (anxiety-reducing) effects of certain microbial species. Two bacterial genera, Lactobacillus and Bifidobacteria, are common anti-inflammatory probiotics that have been shown to reduce anxiety and behavioral signs of distress in both human and rodent studies.[28] Other genera, including Campylobacteria, Citrobacter, and Trichuris have also shown such anxiolytic affects. The following table compiles results of many different studies on the effects of certain microbiota on cognitive and behavioral dimensions.

Type of study Species/microbial compound Behavioral/cognitive affect Citation
Rodent study Campylobacter jejuni, Citrobacter rodentium, Trichuris muris, high-fat microbiota Increased anxiety symptoms/behavior Bruce-Keller et al. (2015)[29]; Lyte, Varcoe, and Bailey (1998)[30]; and Stilling, Dinan, and Cryan (2014)[31]
Rodent study Bifidobacterium spp., Lactobacillus spp. Decreased anxiety symptoms/behavior Bercik et al. (2011)[32], Bravo et al. (2011)[33], and Messaoudi et al. (2011)[34][35]
Rodent study Bifidobacterium spp., Lactobacillus spp. Decreased depressive symptoms/behavior Arseneault-Bréard et al. (2012)[36] and Bravo et al. (2011)[33]
Human study (Cross-sectional finding) Alistipes, Bacteroidales, Enterobacteriaceae Positive association with depression Jiang et al. (2015)[37] and Naseribafrouei et al. (2014)[38]
Human study (Cross-sectional finding) Faecalibacterium, Lachnospiraceae Negative association with depression Jiang et al. (2015)[37] and Naseribafrouei et al. (2014)[38]
Human study (Longitudinal finding) Bifidobacterium spp., Lactobacillus spp., Lactobacillus helveticus Decreased anxiety symptoms Messaoudi et al. (2011)[34][35], Mohammadi et al., 2015)[39], and Rao et al. (2009)[40]
Human study (Longitudinal finding) Bifidobacterium spp., Lactobacillus spp., Lactobacillus helveticus Decreased depressive symptoms Benton, Williams, and Brown (2007)[41], Messaoudi et al. (2011)[34][35], and Mohammadi et al., 2015)[39]
Human study (Longitudinal finding) Bifidobacterium longum, Lactobacillus helveticus Decreased anger/hostility Messaoudi et al. (2011)[34][35]
Human study (Longitudinal finding) Bifadobacterium spp., Lactobacillus spp., Lactococcus lactis Decreased cognitive reactivity to negative stimuli, mediated by reduction in rumination and aggressive thoughts Steenbergen, Sellaro, van Hemert, Bosch, & Colzato (2015)[42]
Human study (Longitudinal finding) Bifidobacterium animalis subsp. Lactis, Lactobacillus bulgaricus, Lactococcus lactis subsp. Lactis, Streptococcus thermophiles Decreased activity in emotional and sensory brain regions in response to negative stimuli Tillisch et al. (2013)[43]
Human study (Longitudinal finding) Bimuno-galacto-oligosaccharides Decreased attentional bias toward negative stimuli Schmidt et al. (2015)[44]

A recent study found that probiotics decrease ruminative, negative thoughts in humans, and that the introduction of prebiotics (or fibers that promote the growth of beneficial bacteria decrease anxiety[42].

"Crapsules" and fecal transplant[edit]

It is challenging to find ways to deliver desirable biota in a way where they can thrive in a new body. Eating or drinking them means that the bacteria need to survive exposure to stomach acid. Two solutions are currently being explored: fecal transplant, and enteric coating of pills to protect them until they move into the intestine. The enteric coated capsules have been nicknamed "crapsules." The delivery system appears effective. The remaining challenge is for the Food and Drug Administration and other regulatory agencies to decide how to monitor the quality, purity, and efficacy of the microbiome material.


  1. Smith, Peter Andrey (2015-06-23). "Can the Bacteria in Your Gut Explain Your Mood?". The New York Times. ISSN 0362-4331. Retrieved 2017-11-10.
  2. Schmidt, Charles. "Mental Health May Depend on Creatures in the Gut" (in en). Scientific American. doi:10.1038/scientificamerican0315-S12. https://www.scientificamerican.com/article/mental-health-may-depend-on-creatures-in-the-gut/. 
  3. Gregoire, Carolyn (2016-11-10). "How 'Psychobiotics' Use Gut Bacteria To Treat Mental Illness". Huffington Post. Retrieved 2017-11-10.
  4. Rogers, G B; Keating, D J; Young, R L; Wong, M-L; Licinio, J; Wesselingh, S (2016-04-19). "From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways" (in en). Molecular Psychiatry 21 (6): 738–748. doi:10.1038/mp.2016.50. ISSN 1476-5578. https://www.nature.com/articles/mp201650. 
  5. 5.0 5.1 5.2 5.3 5.4 5.5 Kramer, Peter; Bressan, Paola (2015-07-14). "Humans as Superorganisms". Perspectives on Psychological Science10 (4): 464–481. doi:10.1177/1745691615583131.
  6. 6.0 6.1 6.2 Lloyd-Price, Jason; Abu-Ali, Galeb; Huttenhower, Curtis (2016-04-27). "The healthy human microbiome". Genome Medicine8: 51. ISSN 1756-994X. doi:10.1186/s13073-016-0307-y.
  7. Rodríguez, Juan Miguel; Murphy, Kiera; Stanton, Catherine; Ross, R. Paul; Kober, Olivia I.; Juge, Nathalie; Avershina, Ekaterina; Rudi, Knut et al. (2015). "The composition of the gut microbiota throughout life, with an emphasis on early life" (in en). Microbial Ecology in Health & Disease 26 (0). doi:10.3402/mehd.v26.26050. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315782/. 
  8. 8.0 8.1 Dantzer, Robert; O'Connor, Jason C.; Freund, Gregory G.; Johnson, Rodney W.; Kelley, Keith W. (2008-01-01). "From inflammation to sickness and depression: when the immune system subjugates the brain" (in en). Nature Reviews Neuroscience 9 (1): 46–56. doi:10.1038/nrn2297. ISSN 1471-0048. http://www.nature.com/doifinder/10.1038/nrn2297. 
  9. 9.0 9.1 9.2 9.3 9.4 Forsythe, Paul; Bienestock, John (2008-01-01). Probiotics in Neurology and Psychiatry. American Society of Microbiology. pp. 285–298. doi:10.1128/9781555815462.ch22.
  10. Hegde, Manjunath; Wood, Thomas K.; Jayaraman, Arul (September 2009). "The neuroendocrine hormone norepinephrine increases Pseudomonas aeruginosa PA14 virulence through the las quorum-sensing pathway". Applied Microbiology and Biotechnology 84 (4): 763–776. doi:10.1007/s00253-009-2045-1. ISSN 1432-0614. PMID 19517106. https://www.ncbi.nlm.nih.gov/pubmed/19517106. 
  11. "Microbial endocrinology: the interplay between the microbiota and the endocrine system (PDF Download Available)". ResearchGate. Retrieved 2017-11-09.
  12. Cho, Ilseung; Blaser, Martin J. (2012-03-13). "The human microbiome: at the interface of health and disease" (in en). Nature Reviews Genetics 13 (4). doi:10.1038/nrg3182. ISSN 1471-0064. https://www.nature.com/articles/nrg3182. 
  13. Logan, Alan C.; Jacka, Felice N.; Craig, Jeffrey M.; Prescott, Susan L. (2016-05-31). "The Microbiome and Mental Health: Looking Back, Moving Forward with Lessons from Allergic Diseases". Clinical Psychopharmacology and Neuroscience14 (2): 131–147. ISSN 1738-1088. doi:10.9758/cpn.2016.14.2.131.
  14. Naseribafrouei, A.; Hestad, K.; Avershina, E.; Sekelja, M.; Linløkken, A.; Wilson, R.; Rudi, K. (2014-08-01). "Correlation between the human fecal microbiota and depression". Neurogastroenterology & Motility26 (8): 1155–1162. ISSN 1365-2982. doi:10.1111/nmo.12378.
  15. Rosenblat, Joshua D.; Cha, Danielle S.; Mansur, Rodrigo B.; McIntyre, Roger S.. "Inflamed moods: A review of the interactions between inflammation and mood disorders". Progress in Neuro-Psychopharmacology and Biological Psychiatry 53: 23–34. doi:10.1016/j.pnpbp.2014.01.013. http://linkinghub.elsevier.com/retrieve/pii/S0278584614000141. 
  16. Anderson, George; Maes, Michael (2015-02-01). "Bipolar Disorder: Role of Immune-Inflammatory Cytokines, Oxidative and Nitrosative Stress and Tryptophan Catabolites" (in en). Current Psychiatry Reports 17 (2): 8. doi:10.1007/s11920-014-0541-1. ISSN 1523-3812. https://link.springer.com/article/10.1007/s11920-014-0541-1. 
  17. Anderson, George; Maes, Michael (2015-02-01). "Bipolar Disorder: Role of Immune-Inflammatory Cytokines, Oxidative and Nitrosative Stress and Tryptophan Catabolites" (in en). Current Psychiatry Reports 17 (2): 8. doi:10.1007/s11920-014-0541-1. ISSN 1523-3812. https://link.springer.com/article/10.1007/s11920-014-0541-1. 
  18. Severance, Emily G.; Alaedini, Armin; Yang, Shuojia; Halling, Meredith; Gressitt, Kristin L.; Stallings, Cassie R.; Origoni, Andrea E.; Vaughan, Crystal et al.. "Gastrointestinal inflammation and associated immune activation in schizophrenia". Schizophrenia Research 138 (1): 48–53. doi:10.1016/j.schres.2012.02.025. http://linkinghub.elsevier.com/retrieve/pii/S0920996412001478. 
  19. Severance, Emily G.; Gressitt, Kristin L.; Buka, Stephen L.; Cannon, Tyrone D.; Yolken, Robert H.. "Maternal complement C1q and increased odds for psychosis in adult offspring". Schizophrenia Research 159 (1): 14–19. doi:10.1016/j.schres.2014.07.053. http://linkinghub.elsevier.com/retrieve/pii/S0920996414004137. 
  20. Severance, Emily G.; Gressitt, Kristin L.; Halling, Meredith; Stallings, Cassie R.; Origoni, Andrea E.; Vaughan, Crystal; Khushalani, Sunil; Alaedini, Armin et al.. "Complement C1q formation of immune complexes with milk caseins and wheat glutens in schizophrenia". Neurobiology of Disease 48 (3): 447–453. doi:10.1016/j.nbd.2012.07.005. http://linkinghub.elsevier.com/retrieve/pii/S096999611200246X. 
  21. Vitetta, Luis; Bambling, Matthew; Alford, Hollie (2014-12-01). "The gastrointestinal tract microbiome, probiotics, and mood" (in en). Inflammopharmacology 22 (6): 333–339. doi:10.1007/s10787-014-0216-x. ISSN 0925-4692. https://link.springer.com/article/10.1007/s10787-014-0216-x. 
  22. Vuong, Helen E.; Hsiao, Elaine Y. "Emerging Roles for the Gut Microbiome in Autism Spectrum Disorder". Biological Psychiatry81 (5): 411–423. doi:10.1016/j.biopsych.2016.08.024.
  23. Finegold, Sydney M.; Dowd, Scot E.; Gontcharova, Viktoria; Liu, Chengxu; Henley, Kathleen E.; Wolcott, Randall D.; Youn, Eunseog; Summanen, Paula H. et al.. "Pyrosequencing study of fecal microflora of autistic and control children". Anaerobe 16 (4): 444–453. doi:10.1016/j.anaerobe.2010.06.008. http://linkinghub.elsevier.com/retrieve/pii/S1075996410001010. 
  24. Parracho, Helena MRT; Bingham, Max O; Gibson, Glenn R; McCartney, Anne L (2005). "Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children". Journal of Medical Microbiology 54 (10): 987–991. doi:10.1099/jmm.0.46101-0. http://jmm.microbiologyresearch.org/content/journal/jmm/10.1099/jmm.0.46101-0. 
  25. Song, Yuli; Liu, Chengxu; Finegold, Sydney M. (2004-11-01). "Real-Time PCR Quantitation of Clostridia in Feces of Autistic Children" (in en). Applied and Environmental Microbiology 70 (11): 6459–6465. doi:10.1128/aem.70.11.6459-6465.2004. ISSN 0099-2240. PMID 15528506. http://aem.asm.org/content/70/11/6459. 
  26. Ibrahim, Samar H.; Voigt, Robert G.; Katusic, Slavica K.; Weaver, Amy L.; Barbaresi, William J. (2009-08-01). "Incidence of Gastrointestinal Symptoms in Children With Autism: A Population-Based Study" (in en). Pediatrics 124 (2): 680–686. doi:10.1542/peds.2008-2933. ISSN 0031-4005. PMID 19651585. http://pediatrics.aappublications.org/content/124/2/680. 
  27. Borgo, Francesca; Riva, Alessandra; Benetti, Alberto; Casiraghi, Maria Cristina; Bertelli, Sara; Garbossa, Stefania; Anselmetti, Simona; Scarone, Silvio et al. (2017-06-21). "Microbiota in anorexia nervosa: The triangle between bacterial species, metabolites and psychological tests". PLOS ONE 12 (6): e0179739. doi:10.1371/journal.pone.0179739. ISSN 1932-6203. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179739. 
  28. Deans, Emily (2016-06-27). "Microbiome and mental health in the modern environment". Journal of Physiological Anthropology36: 1. ISSN 1880-6805. doi:10.1186/s40101-016-0101-y.
  29. Bruce-Keller, Annadora J.; Salbaum, J. Michael; Luo, Meng; Blanchard, Eugene; Taylor, Christopher M.; Welsh, David A.; Berthoud, Hans-Rudolf (2015-04-01). "Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity". Biological Psychiatry 77 (7): 607–615. doi:10.1016/j.biopsych.2014.07.012. ISSN 1873-2402. PMID 25173628. PMC PMC4297748. https://www.ncbi.nlm.nih.gov/pubmed/25173628. 
  30. Lyte, M.; Varcoe, J. J.; Bailey, M. T. (August 1998). "Anxiogenic effect of subclinical bacterial infection in mice in the absence of overt immune activation". Physiology & Behavior 65 (1): 63–68. ISSN 0031-9384. PMID 9811366. https://www.ncbi.nlm.nih.gov/pubmed/9811366. 
  31. Stilling, R. M.; Dinan, T. G.; Cryan, J. F. (January 2014). "Microbial genes, brain & behaviour - epigenetic regulation of the gut-brain axis". Genes, Brain, and Behavior 13 (1): 69–86. doi:10.1111/gbb.12109. ISSN 1601-183X. PMID 24286462. https://www.ncbi.nlm.nih.gov/pubmed/24286462. 
  32. Bercik, Premysl; Denou, Emmanuel; Collins, Josh; Jackson, Wendy; Lu, Jun; Jury, Jennifer; Deng, Yikang; Blennerhassett, Patricia et al. (August 2011). "The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice". Gastroenterology 141 (2): 599–609, 609.e1–3. doi:10.1053/j.gastro.2011.04.052. ISSN 1528-0012. PMID 21683077. https://www.ncbi.nlm.nih.gov/pubmed/21683077. 
  33. 33.0 33.1 Bravo, Javier A.; Forsythe, Paul; Chew, Marianne V.; Escaravage, Emily; Savignac, Hélène M.; Dinan, Timothy G.; Bienenstock, John; Cryan, John F. (2011-09-20). "Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve". Proceedings of the National Academy of Sciences of the United States of America 108 (38): 16050–16055. doi:10.1073/pnas.1102999108. ISSN 1091-6490. PMID 21876150. PMC PMC3179073. https://www.ncbi.nlm.nih.gov/pubmed/21876150. 
  34. 34.0 34.1 34.2 34.3 Messaoudi, Michaël; Lalonde, Robert; Violle, Nicolas; Javelot, Hervé; Desor, Didier; Nejdi, Amine; Bisson, Jean-François; Rougeot, Catherine et al. (March 2011). "Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects". The British Journal of Nutrition 105 (5): 755–764. doi:10.1017/S0007114510004319. ISSN 1475-2662. PMID 20974015. https://www.ncbi.nlm.nih.gov/pubmed/20974015. 
  35. 35.0 35.1 35.2 35.3 Messaoudi, Michaël; Violle, Nicolas; Bisson, Jean-François; Desor, Didier; Javelot, Hervé; Rougeot, Catherine (July 2011). "Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers". Gut Microbes 2 (4): 256–261. doi:10.4161/gmic.2.4.16108. ISSN 1949-0984. PMID 21983070. https://www.ncbi.nlm.nih.gov/pubmed/21983070. 
  36. Arseneault-Bréard, Jessica; Rondeau, Isabelle; Gilbert, Kim; Girard, Stéphanie-Anne; Tompkins, Thomas A.; Godbout, Roger; Rousseau, Guy (June 2012). "Combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 reduces post-myocardial infarction depression symptoms and restores intestinal permeability in a rat model". The British Journal of Nutrition 107 (12): 1793–1799. doi:10.1017/S0007114511005137. ISSN 1475-2662. PMID 21933458. https://www.ncbi.nlm.nih.gov/pubmed/21933458. 
  37. 37.0 37.1 Jiang, Haiyin; Ling, Zongxin; Zhang, Yonghua; Mao, Hongjin; Ma, Zhanping; Yin, Yan; Wang, Weihong; Tang, Wenxin et al. (August 2015). "Altered fecal microbiota composition in patients with major depressive disorder". Brain, Behavior, and Immunity 48: 186–194. doi:10.1016/j.bbi.2015.03.016. ISSN 1090-2139. PMID 25882912. https://www.ncbi.nlm.nih.gov/pubmed/25882912. 
  38. 38.0 38.1 Naseribafrouei, A.; Hestad, K.; Avershina, E.; Sekelja, M.; Linløkken, A.; Wilson, R.; Rudi, K. (August 2014). "Correlation between the human fecal microbiota and depression". Neurogastroenterology and Motility: The Official Journal of the European Gastrointestinal Motility Society 26 (8): 1155–1162. doi:10.1111/nmo.12378. ISSN 1365-2982. PMID 24888394. https://www.ncbi.nlm.nih.gov/pubmed/24888394. 
  39. 39.0 39.1 Mohammadi, Ali Akbar; Jazayeri, Shima; Khosravi-Darani, Kianoush; Solati, Zahra; Mohammadpour, Nakisa; Asemi, Zatollah; Adab, Zohre; Djalali, Mahmoud et al. (November 2016). "The effects of probiotics on mental health and hypothalamic-pituitary-adrenal axis: A randomized, double-blind, placebo-controlled trial in petrochemical workers". Nutritional Neuroscience 19 (9): 387–395. doi:10.1179/1476830515Y.0000000023. ISSN 1476-8305. PMID 25879690. https://www.ncbi.nlm.nih.gov/pubmed/25879690. 
  40. Rao, A. Venket; Bested, Alison C.; Beaulne, Tracey M.; Katzman, Martin A.; Iorio, Christina; Berardi, John M.; Logan, Alan C. (2009-03-19). "A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome". Gut Pathogens 1 (1): 6. doi:10.1186/1757-4749-1-6. ISSN 1757-4749. PMID 19338686. PMC PMC2664325. https://www.ncbi.nlm.nih.gov/pubmed/19338686. 
  41. Benton, D.; Williams, C.; Brown, A. (March 2007). "Impact of consuming a milk drink containing a probiotic on mood and cognition". European Journal of Clinical Nutrition 61 (3): 355–361. doi:10.1038/sj.ejcn.1602546. ISSN 0954-3007. PMID 17151594. https://www.ncbi.nlm.nih.gov/pubmed/17151594. 
  42. 42.0 42.1 Steenbergen, Laura; Sellaro, Roberta; van Hemert, Saskia; Bosch, Jos A.; Colzato, Lorenza S. (August 2015). "A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood". Brain, Behavior, and Immunity 48: 258–264. doi:10.1016/j.bbi.2015.04.003. ISSN 1090-2139. PMID 25862297. https://www.ncbi.nlm.nih.gov/pubmed/25862297. 
  43. Tillisch, Kirsten; Labus, Jennifer; Kilpatrick, Lisa; Jiang, Zhiguo; Stains, Jean; Ebrat, Bahar; Guyonnet, Denis; Legrain-Raspaud, Sophie et al. (June 2013). "Consumption of fermented milk product with probiotic modulates brain activity". Gastroenterology 144 (7): 1394–1401, 1401.e1–4. doi:10.1053/j.gastro.2013.02.043. ISSN 1528-0012. PMID 23474283. PMC PMC3839572. https://www.ncbi.nlm.nih.gov/pubmed/23474283. 
  44. Schmidt, Charles (2015-02-26). "Mental health: thinking from the gut". Nature 518 (7540): S12–15. doi:10.1038/518S13a. ISSN 1476-4687. PMID 25715275. https://www.ncbi.nlm.nih.gov/pubmed/25715275.