The Gut-Brain Axis & Systems Biology

Gut-Brain Axis

Neurogastroenterology, a subspecialty of gastroenterology that overlaps with neurology, encompasses the study of the brain, the gut, and their interactions. It is a particularly fascinating area of research with a rapidly evolving knowledge base. Specifically, neurogastroenterology focuses on the functions, malfunctions, and the malformations of the sympathetic, parasympathetic, and enteric divisions of the digestive tract.

In 2017, for the first time in humans, UCLA researchers established an association between gut microbiota and brain regions involved in processing sensory information.1 The study showed that differences in gut microbial composition correlate with regional brain volumes in patients with irritable bowel syndrome (IBS). It also shed light on the connections between childhood trauma, brain development, and gut microbiome composition.1  

The study found a trend for a greater history of childhood emotional trauma in IBS, and the study’s authors speculated that “brain driven disturbances of the gut microbial environment in early life may have a long lasting effect on gut microbial composition persisting throughout life, which in turn may lead to further changes in brain structure/function.”1 The correlation of microbial taxa with early adverse life events, and with distinct brain structural changes, suggests a possible role of gut microbes and their metabolites in the development and shaping of the gut-microbiota-brain axis early in life.1

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Bidirectional Communication Between the Gut & the Brain

The gut-brain axis is the bidirectional communication between the gut and the brain, which occurs through multiple pathways that include hormonal, neural, and immune mediators.2 Interestingly, the signals along this axis can originate in the gut, the brain, or both, with the objective of maintaining normal gut function and appropriate behavior.2

However, scientists struggle to uncover whether brain and behavioral alterations precede gut dysfunction and dysbiosis, or vice-versa.2 Nonetheless, some researchers like De Palma et al postulate that “in the future, the manipulation of gut microbiota, through probiotics or symbiotics, might be a valuable adjuvant to traditional medicine in the treatment of irritable bowel syndrome patients with co-morbid anxiety or depression.”2

“It’s important to recognize that many times when there’s inflammation in other areas of the body, it could be coming from the digestive system,” says IFM educator Elizabeth Boham, MD, MS, RD.

All of the systems of the body are intertwined.”

In the following video, Dr. Boham talks about how she uses the Functional Medicine DIGIN mnemonic to assess and heal her patient’s digestive and system-wide disorders:

IFM educator Elizabeth Boham, MD, MS, RD, is board certified in family medicine and a registered dietitian.

In addition to IBS,3 studies suggest that alterations in the gut-brain axis may be involved in the pathogenesis of an array of disorders, including Parkinson’s disease4 and disorders of mood and affect such as major depressive disorder, chronic pain,5 schizophrenia,6 and even dementia.7 However, there continues to be controversy over the magnitude of these effects, as well as the sites, pathways, and molecular mechanisms within the gut-brain axis that may be responsible for these alterations.5 While it has been well established that probiotics have therapeutic effects on many GI diorders,8 their ability to improve mood and cognitive function in humans has been disputed.

Probiotics & Mood Disorders

Clinical studies have shown a connection between supplementation with probiotics containing specific species and strains of bacteria and the regulation of the body’s response to stress as well as with the exacerbation of depressive and anxiety symptoms in humans.9 A 2015 study found that fermented foods that contain probiotics may have a protective effect against social anxiety for those at higher genetic risk, as indexed by trait neuroticism.10 Researchers have also studied the potential of manipulating the GI microbiota to alleviate depressive symptoms.8 A 2017 systematic review of the effects of probiotics on depressive symptoms in humans concluded that the evidence for probiotics alleviating depressive symptoms is compelling.8 That same year, a systematic review and meta-analysis found that probiotic consumption may have a positive effect on psychological symptoms of depression, anxiety, and perceived stress in healthy human volunteers.11

In a 2018 randomized clinical trial, eight weeks of probiotic supplements for patients with major depressive disorder (MDD) resulted in an improved Beck Depression Inventory score.12 However, to date, studies on the use of probiotics in the prophylaxis and treatment of depressive and anxiety disorders included too few subjects, especially in groups of patients diagnosed with depression, to be able to clearly determine the effectiveness of probiotics in prevention and, in particular, treatment of these disorders in humans.9

A 2017 double-blind, randomized trial found no evidence that Lactobacillus helveticus and Bifidobacterium longum were effective in treating low mood, or in moderating levels of inflammatory and other biomarkers.13 The study involved 79 patients (with 10 dropouts) not taking psychotropic medications with at least moderate scores on self-reported mood measures.13 Another study—a double-blind, placebo-controlled trial of probiotic supplementation conducted in patients with schizophrenia—failed to show superiority over placebo.13,14

To be sure, future research in the area of neurogastroenterology will cast more light onto the conflicting nature of these studies, giving clinicians a firmer foundation for informing patient care. A better understanding of the microbiome could revolutionize the possibility of therapies, like diet and eating habits, for many diseases.15

Learn more about GI function and dysfunction, and download a free IFM Toolkit resource

What is the gut-brain connection in IBS?

Learn More About gut Dysfunction and Chronic Conditions


  1. Labus JS, Hollister EB, Jacobs J, et al. Differences in gut microbial composition correlate with regional brain volumes in irritable bowel syndrome. Microbiome. 2017;5(1):49. doi:10.1186/s40168-017-0260-z. 
  2. De Palma G, Collins SMBercik P, Verdu EF. The microbiotagutbrain axis in gastrointestinal disorders: stressed bugs, stressed brain or both? J Physiol. 2014;592(14):29892997. doi:10.1113/jphysiol.2014.273995. 
  3. Lee CY, Abizaid A. The gut-brain-axis as a target to treat stress-induced obesity. Front Endocrinol. 2014;5:117doi:10.3389/fendo.2014.00117. 
  4. Matheoud D, Cannon T, Voisin A. Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1 mice. Nature. 2019. doi 10.1038/s41586-019-1405-y. 
  5. Mayer EA, Tillisch K, Gupta A. Gut/brain axis and the microbiota. Clin Invest. 2015;125(3):926-938. doi:10.1172/JCI76304. 
  6. Xu R, Wu B, Liang J, et al. Altered gut microbiota and mucosal immunity in patients with schizophrenia. Brain Behav Immun. 2019. doi  
  7. Saji N., Niida S., Murotani K., Hisada T., Tsuduki T., Sugimoto T., et al. . (2019). Analysis of the relationship between the gut microbiome and dementia: a cross-sectional study conducted in Japan. Sci. Rep. 9:1008.  
  8. Wallace CJK, Milev R. The effects of probiotics on depressive symptoms in humans: a systematic review. Ann Gen Psychiatry. 2017;16:14doi:10.1186/s12991-017-0138-2. 
  9. Herman A. Probiotics supplementation in prophylaxis and treatment of depressive and anxiety disorders – a review of current research. Psychiatr Pol. 2019;53(2):459-473. doi:12740/PP/92392
  10. Hilimire MR, DeVylder JE, Forestell CA. Fermented foods, neuroticism, and social anxiety: an interaction model. Psychiatry Res. 2015;228(2):203-208. doi:10.1016/j.psychres.2015.04.023. 
  11. McKean J, Naug H, Nikbakht E, Amiet B, Colson N. Probiotics and subclinical psychological symptoms in healthy participants: a systematic review and meta-analysis. Altern Complement Med. 2017;23(4):249-258. doi:10.1089/acm.2016.0023. 
  12. Kazemi A, Noorbala AA, Azam K, Eskandari MH, Djafarian K. Effect of probiotic and prebiotic vs placebo on psychological outcomes in patients with major depressive disorder: a randomized clinical trial [published online April 24, 2018]Clin Nutrdoi:10.1016/j.clnu.2018.04.010. 
  13. Romijn AR, Rucklidge JJ, Kuijer RG, Frampton C, et al. A double-blind, randomized, placebo-controlled trial of Lactobacillus helveticus and Bifidobacterium longum for the symptoms of depression. Aust N Z J Psychiatry. 2017;51(8):810821. doi:10.1177/0004867416686694. 
  14. Dickerson FB, Stallings C, Origoni A, et al. Effect of probiotic supplementation on schizophrenia symptoms and association with gastrointestinal functioning: a randomized, placebo-controlled trial. Prim Care Companion CNS Disord. 2014;16(1):PCC.13m01579. doi:10.4088/PCC.13m01579. 
  15. Novotný M, Klimova B, Valis M. Microbiome and cognitive impairment: can any diets influence learning processes in a positive way? Front Aging Neurosci. 2019;11:170. doi:10.3389/fnagi.2019.00170


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