Animal models show gut microflora (bacteria, viruses, fungi, archaea and eukaryotes such as helminths) influence various aspects of physiology including brain function. Though data on their effect on human physiology is sparse, gut-associated pathologies and mental health issues such as depression () are strongly linked. Reverse also applies. For example, strong correlations between autism severity and gastrointestinal (GI) symptoms ( , ).
Physicians have for long recognized the link between ‘melancholia’ and constipation and other GI tract disturbances, and attempted to treat their symptoms with GI tract interventions (4). Though ideas such as autointoxication, the notion that psychiatric symptoms owed their genesis to GI tract disturbances (), faded over the 20th century, renewed research interest in gut-microbiota-brain link is helping move an idea that relied more on pseudoscience onto a firmer scientific footing.
Recently the term psychobiotic was coined for, ‘a live organism that, when ingested in adequate amounts, produces a health benefit in patients suffering from psychiatric illness‘ (5). Could such outcomes be engineered reproducibly and if yes, exactly how do they work? Here the story gets much murkier because so far little can be stated unequivocally and even less claimed as a replicable therapeutic approach capable of manipulating human neuropsychiatric outcomes at will ().
This answer briefly explores
- Physical and neurochemical links between gut, gut bacteria and brain: Vagus nerve, Serotonin, other neurochemicals.
- Human studies on gut bacteria and brain: too few, poorly done, contradictory results.
- Antibiotics could affect brain function: Could harm (insomnia, mood alterations, psychosis, mania, depression, autism) or help (treatment-resistant depression, schizophrenia).
1. Physical & Neurochemical Links Between Gut, Gut Bacteria & Brain
Major nerve of the parasympathetic division of the autonomic nervous system, the vagus nerve physically connects the ~100 million neurons of the enteric (gut) nervous system to the base of the brain at the medulla () with projections into many other parts of the brain including the thalamus, hypothalamus, amygdala ( ). Gut inflammation and brain are theorized to connect via the vagus nerve, i.e., ( ).
- Enteric nerves could directly sense bacteria ( ).
- Vagus expresses receptors for many gastrointestinal hormones such as , which regulate food intake ( ), which may explain why blocking it can cause drastic weight loss ( , 13).
- is a procedure that increases parasympathetic tone. Its utility for and strengthens the link between gut-associated inflammation and brain function.
- Influencing brain states from appetite to circadian rhythms to moods, Serotonin is one of the clearest tangible links between gut microflora and brain function. Major target of antidepressants, it’s also the most studied neurotransmitter in psychiatric illnesses. Rather than the brain, the in the gut are the body’s major source of serotonin ( ), and mouse gut microbiota were found to play a role in its synthesis ( ). Gut being abundant in both microflora and serotonin, the latter in turn playing a major role in brain states, makes this a credible link though how serotonin, densely packed inside platelet granules, makes its way into the brain is still a mystery.
Bacteria As Source Of Other Neurochemicals
Many microbes can not only abundantly secrete neurochemicals such as Acetylcholine, Dopamine, Epinephrine, GABA, Norpeinephrine, Serotonin in culture () but also respond to them ( ). Sheer quantity of such neurochemicals suggests they may be of physiologic importance.
- For example, fermented foods such as Japanese funa-sushi (18) and Chinese paocai (19) use lactobacilli in their making and have millimolar levels of GABA in the final product.
- Bacteria that contaminate fish or shellfish products can secrete such large amounts of the neurotransmitter, histamine, testing is necessary to ensure levels don’t exceed government guidelines for food poisoning (20).
- Gut bacteria are also an important source of vitamins important for CNS ( ) function. For example, Lactobacillus reuteri, a normal human gut inhabitant, is a rich source of ( ), whose deficiency is implicated in in fetuses ( , ).
2. Human Studies On Gut Bacteria & Brain
Too many fundamentals yet lack answers. No consensus definition of what constitutes a healthy human gut microbiota. Gut bacteria alone are estimated to be >1000 species. Add how confounding variables such as age, diet, ethnicity, gender, location influence gut microbiota composition and the picture gets fuzzier rather than clearer. While proper understanding of gut microbiota-brain link requires an ecological approach, many studies assess gut microbiota-brain link in reductionist inbred rodent models whose results are hard if not impossible to extrapolate to human brain function.
- Often studies on effect of probiotics on brain function are poorly done, have few subjects and use questionnaires or scale-based assessments plagued by subjective bias.
- There are few RCT ( ).
- No wonder a 2015 systematic review found ‘very limited evidence for the efficacy of probiotic interventions in psychological outcomes‘ ( ) while a 2016 meta-analysis of RCTs could only provisionally conclude probiotics might improve CNS function but couldn’t rule out towards positive results ( ).
- No surprise that studies so far ( , , 28, , 30) comparing gut microbiota between MDD ( ) patients and healthy controls yield contradictory data.
- OTOH, a small study when well-designed and controlled can yield useful pointers for future studies. In one such ( ), healthy women were given fermented milk product with probiotic (n=12), non-fermented milk product (n=11), or nothing (n=13) twice daily for 4 weeks. The probiotics included Bifidobacterium animalis subsp lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, Lactobacillus lactis subsp lactis. fMRI ( ) suggested such probiotics might reduce stress responses and enhance cognition in healthy subjects.
3. Antibiotics Could Affect Brain Function
Do antibiotics influence neuropsychiatric symptoms? Since antibiotics wipe out gut bacteria, this offers another avenue to explore gut bacteria-brain link. Case-reports, epidemiological studies, clinical trials, a variety of such studies suggest antibiotics could either harm or help brain function, distinction depending on the antibiotic and kinds of bacteria it targets.
- One of the clearest examples is from case reports of antibiotics inducing insomnia, mood alteration (32), psychosis (33, 34, 35), even mania, antibiomania, especially in the elderly (36). Antibiotics most commonly implicated in these unusual behavior changes are clarithromycin, ciprofloxacin and ofloxacin.
- A retrospective medical records-based study (37) of 202974 patients with depression, 14570 with anxiety, 2690 with psychosis with 803961, 57862 and 10644 matched controls, respectively, concluded recurrent antibiotic Rx increased risk for depression and anxiety but not psychosis.
- Link between prior heavy antibiotic use and autism is quite strong (38, , ), especially use of trimethoprim/sulfamethoxazole ( ).
, a semi-synthetic , is usually used to treat acne and other skin conditions. It’s been suggested as a possibility for treatment-resistant depression ( ) and schizophrenia ( ).
- A small, open-label study found minocycline effective and well-tolerated in treatment-resistant depression (44).
- A pilot study by King’s College, London, is completed but no results posted yet ( , ).
- A couple of clinical trials are underway, one a phase II in Germany ( ) and another in Thailand/Australia ( ).
Thus, accumulating circumstantial data suggests gut microbiota influence human brain function but little of it is as yet tangible and reproducible.
1. Foster, Jane A., and Karen-Anne McVey Neufeld. “Gut–brain axis: how the microbiome influences anxiety and depression.” Trends in neurosciences 36.5 (2013): 305-312.
2. Adams, James B., et al. “Gastrointestinal flora and gastrointestinal status in children with autism–comparisons to typical children and correlation with autism severity.” BMC gastroenterology 11.1 (2011): 22.
3. de Theije, Caroline GM, et al. “Pathways underlying the gut-to-brain connection in autism spectrum disorders as future targets for disease management.” European journal of pharmacology 668 (2011): S70-S80.
4. Phillips, J. George Porter. “The treatment of melancholia by the lactic acid bacillus.” The British Journal of Psychiatry 56.234 (1910): 422-NP.
5. Dinan, Timothy G., Catherine Stanton, and John F. Cryan. “Psychobiotics: a novel class of psychotropic.” Biological psychiatry 74.10 (2013): 720-726.
6. MacQueen, Glenda, Michael Surette, and Paul Moayyedi. “The gut microbiota and psychiatric illness.” J Psychiatry Neurosci 42.2 (2017): 75.
7. Alcock, Joe, Carlo C. Maley, and C. Aktipis. “Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms.” Bioessays 36.10 (2014): 940-949.
8. Kennedy, Paul J., et al. “Microbiome in brain function and mental health.” Trends in Food Science & Technology 57 (2016): 289-301.
9. Tracey, Kevin J. “The inflammatory reflex.” Nature 420.6917 (2002): 853-859.
10. Raybould, Helen E. “Gut chemosensing: interactions between gut endocrine cells and visceral afferents.” Autonomic Neuroscience 153.1 (2010): 41-46.
11. Strader, April D., and Stephen C. Woods. “Gastrointestinal hormones and food intake.” Gastroenterology 128.1 (2005): 175-191.
12. Camilleri, Michael, et al. “Intra-abdominal vagal blocking (VBLOC therapy): clinical results with a new implantable medical device.” Surgery 143.6 (2008): 723-731.
13. Sarr, Michael G., et al. “The EMPOWER study: randomized, prospective, double-blind, multicenter trial of vagal blockade to induce weight loss in morbid obesity.” Obesity surgery 22.11 (2012): 1771-1782.
15. Wikoff, William R., et al. “Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites.” Proceedings of the national academy of sciences 106.10 (2009): 3698-3703.
16. Lyte, Mark. “Probiotics function mechanistically as delivery vehicles for neuroactive compounds: microbial endocrinology in the design and use of probiotics.” Bioessays 33.8 (2011): 574-581.
17. Iyer, Lakshminarayan M., et al. “Evolution of cell–cell signaling in animals: did late horizontal gene transfer from bacteria have a role?.” TRENDS in Genetics 20.7 (2004): 292-299.
18. Komatsuzaki, Noriko, et al. “Production of γ-aminobutyric acid (GABA) by Lactobacillus paracasei isolated from traditional fermented foods.” Food microbiology 22.6 (2005): 497-504.
19. Li, Haixing, et al. “A high γ-aminobutyric acid-producing Lactobacillus brevis isolated from Chinese traditional paocai.” Annals of Microbiology 58.4 (2008): 649-653.
20. Ieniştea, C. “Bacterial production and destruction of histamine in foods, and food poisoning caused by histamine.” Molecular Nutrition & Food Research 15.1 (1971): 109-113.
21. Santos, Filipe, et al. “High-level folate production in fermented foods by the B12 producer Lactobacillus reuteri JCM1112.” Applied and environmental microbiology 74.10 (2008): 3291-3294.
22. Smithells, R. W., S. Sheppard, and C. J. Schorah. “Vitamin dificiencies and neural tube defects.” Archives of Disease in Childhood 51.12 (1976): 944-950.
23. Dror, Daphna K., and Lindsay H. Allen. “Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms.” Nutrition reviews 66.5 (2008): 250-255.
24. Romijn, Amy R., and Julia J. Rucklidge. “Systematic review of evidence to support the theory of psychobiotics.” Nutrition reviews 73.10 (2015): 675-693.
25. Wang, Huiying, et al. “Effect of probiotics on central nervous system functions in animals and humans: A systematic review.” Journal of Neurogastroenterology and Motility 22.4 (2016): 589-605.
26. Naseribafrouei, A., et al. “Correlation between the human fecal microbiota and depression.” Neurogastroenterology & Motility 26.8 (2014): 1155-1162.
27. Jiang, Haiyin, et al. “Altered fecal microbiota composition in patients with major depressive disorder.” Brain, behavior, and immunity 48 (2015): 186-194.
28. Zheng, P., et al. “Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism.” Molecular psychiatry 21.6 (2016): 786-796.
29. Aizawa, Emiko, et al. “Possible association of Bifidobacterium and Lactobacillus in the gut microbiota of patients with major depressive disorder.” Journal of affective disorders 202 (2016): 254-257.
30. Kelly, John R., et al. “Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat.” Journal of Psychiatric Research 82 (2016): 109-118.
31. Tillisch, Kirsten, et al. “Consumption of fermented milk product with probiotic modulates brain activity.” Gastroenterology 144.7 (2013): 1394-1401.
32. Sternbach H & State R. (1997). Antibiotics: neuropsychiatric effects and psychotropic interactions. HarvRevPsychiatry 5, 214-226.
33. Mehdi S. (2010). Antibiotic-induced psychosis: a link to D-alanine?. MedHypotheses 75, 676- 677.
34. Bercik, Premysl, and Stephen M. Collins. “The effects of inflammation, infection and antibiotics on the microbiota-gut-brain axis.” microbial endocrinology: the microbiota-gut-brain axis in health and disease. Springer New York, 2014. 279-289.
35. Ly, Duy, and Lynn E. DeLisi. “Can antibiotics cause a psychosis?: Case report and review of the literature.” Schizophrenia Research (2017).
36. Abouesh, A., Stone, C. & Hobbs, W. R. Antimicrobial‐ induced mania (antibiomania): a review of spontaneous reports. J. Clin. Psychopharmacol. 22, 71–81 (2002).
37. Lurie, Ido, et al. “Antibiotic exposure and the risk for depression, anxiety, or psychosis: a nested case-control study.” The Journal of clinical psychiatry 76.11 (2015): 1522.
38. Niehus, Rebecca, and Catherine Lord. “Early medical history of children with autism spectrum disorders.” Journal of Developmental & Behavioral Pediatrics 27.2 (2006): S120-S127.
39. Atladóttir, Hjördis Ósk, et al. “Autism after infection, febrile episodes, and antibiotic use during pregnancy: an exploratory study.” Pediatrics 130.6 (2012): e1447-e1454.;
40. Mezzelani, Alessandra, et al. “Environment, dysbiosis, immunity and sex-specific susceptibility: a translational hypothesis for regressive autism pathogenesis.” Nutritional neuroscience 18.4 (2015): 145-161.
41. Finegold, Sydney M., et al. “Gastrointestinal microflora studies in late-onset autism.” Clinical Infectious Diseases 35.Supplement 1 (2002): S6-S16.
42. Soczynska, Joanna K., et al. “Novel therapeutic targets in depression: minocycline as a candidate treatment.” Behavioural brain research 235.2 (2012): 302-317.
43. Chaudhry, Imran B., et al. “Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment.” Journal of psychopharmacology 26.9 (2012): 1185-1193.
44. Miyaoka, Tsuyoshi, et al. “Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study.” Progress in Neuro-Psychopharmacology and Biological Psychiatry 37.2 (2012): 222-226.
46. Husain, Muhammad I., et al. “Minocycline as an adjunct for treatment-resistant depressive symptoms: study protocol for a pilot randomised controlled trial.” Trials 16.1 (2015): 410.
48. Dean, Olivia May, et al. “Protocol and rationale-the efficacy of minocycline as an adjunctive treatment for major depressive disorder: a double blind, randomised, placebo controlled trial.” Clinical psychopharmacology and neuroscience 12.3 (2014): 180-188.