Over the past few decades, researchers have worked to unravel the delicate connections between the human gastrointestinal (GI) microbiota and the brain. The bidirectional communication along the gut-brain axis involves many organ systems, including the endocrine, immune, autonomic, central (CNS), and enteric nervous systems (ENS), with the intestinal microbiota influencing those interactions.1,2 The ENS is able to operate GI function independently of the CNS; however, many of the pathways and neurotransmitters are similar between the nervous systems in the brain and the gut.3 The connections between brain and gut abound, which can be seen in the dysfunctions that often unite them. Many neurological and mood disorders often have enteric manifestations,3,4 GI disorders may present neurological and psychiatric symptoms,5,6 and psychological stress may adversely impact microbiome balance and GI function.2,7
How can clinicians help patients create a healthy ecosystem within the gut to promote overall system balance, healthy immune function, and optimal wellness? In the following video, IFM educator David Rakel, MD, talks about the connection between stress and GI function:
Chronic Stress and GI Function: Bidirectional Considerations
Research suggests that stress not only alters intestinal mucosa permeability and cytokine secretion,7,8 but stress may also significantly change the community structure and activity of the commensal microbiota in the gut.9,10 In turn, considering the bidirectional interaction of the gut-brain axis, gut microbiota potentially influence stress-related physiologic responses.1,10,11
Life stress has multiple physiological impacts within the human body, and may be one causal factor in dysbiosis.10
Emerging research has suggested a close interaction between the gut microbiota and the hypothalamic-pituitary-adrenal (HPA) axis, the major neuroendocrine system that regulates responses to stress, and their communication may be closely interrelated with other systems.12
Communication: neurotransmitters & GUT HORMONES
Serotonin and catecholamines such as norepinephrine, epinephrine, and dopamine are active in the brain as well as in the gut.13 Research suggests that these neurotransmitters regulate not only blood flow, but influence gut motility, nutrient absorption, the GI innate immune system, and the microbiome.13 Studies suggest that stress-mediated changes, like changes in the level of catecholamines, may shift the microbial colonization patterns of the intestine and alter one’s susceptibility to infection.14 Conversely, changes in the microbiome may lead to a spectrum of other physiological changes, including HPA activation and altered autonomic nervous system (ANS) responses.11
In addition to neurotransmitters, peptide hormones released from the gut also contribute to the bidirectional gut-brain communication through binding receptors on immune cells and vagus nerve terminals.1 Research also suggests that gut peptide concentrations are modulated by enteric microbiota signals, and may actually vary according to the microbiota composition.1 In this communication context, research suggests that gut microbiota play a role in regulating stress-related conditions such as anxiety and depression.1 Other examples include the following:
- Major depressive disorder (MDD) is associated with changes in gut permeability and microbiota composition.4
- Episodes of anxiety and depression may be experienced more frequently in patients with GI disorders like irritable bowel syndrome (IBS).6
- Negative emotions, stressful life events, and personality traits like neuroticism have also been associated with colitis, Crohn’s disease, and dyspepsia.6
Clinical Applications: Stress Transformation & Treatment Strategies
A cornerstone of Functional Medicine is the development of personalized treatment strategies that address root causes of chronic conditions, and stress is one of the modifiable lifestyle factors that may be addressed in a patient’s intervention. Transforming the body’s response to stress may lead to more positive health outcomes, and research suggests that some techniques have the potential power to bolster immune function,15 strengthening overall resilience.
A recent review evaluated the effectiveness of stress management for inflammatory bowel disease (IBD), a chronic intestinal inflammatory condition associated with dysfunctional interactions between the gut and the brain.7 While there are inconsistencies among studies, many found that stress management techniques such as the following had beneficial effects on inflammatory activity, anxiety status, and quality of life in IBD patients:7
- Mindfulness meditation practice.
- Relaxation training that creates physiological and mental rest. The training may be given to patients by a therapist, or in a self-directed manner.
- Combined therapies of relaxation and guided imagery, which replaces stressful thoughts with mind-relaxing images.
- Multi-convergent therapy that combines mindfulness meditation and cognitive behavioral therapy.
Exercise is another lifestyle strategy that may mitigate the detrimental impact of stress,16 and in general, moderate exercise is considered a positive modulator of gut microbiota biodiversity.17 As a low-cost and effective stress reduction treatment, incorporating an appropriate exercise program into an intervention strategy may increase enteric microbial species and metabolites that have stress-protective properties.16
Prebiotics and Probiotics
Some smaller human studies have investigated the effect of prebiotic and probiotic interventions on stress-related conditions and found the following:
- Results from a 2016 double-blind, placebo-controlled study suggested that daily consumption of probiotics preserved gut microbiota diversity and may relieve stress-associated responses of abdominal dysfunction in healthy subjects exposed to stressful situations.18
- A 2015 triple-blind, placebo-controlled, randomized study suggested that probiotic supplementation may be effective to ameliorate or prevent depression.19
- Results from a 2015 randomized controlled study suggested that in healthy individuals, consumption of prebiotics may decrease the waking cortisol response and improve emotional response.20
Most recently, however, a 2019 meta-analysis of 34 controlled clinical trials that evaluated the effects of prebiotics and probiotics on depression and anxiety found that prebiotic interventions did not differ from placebo, yet probiotic interventions yielded small but significant antidepressant and anxiolytic effects.21 In addition, a 2019 systematic review found that more than half of 21 studies (1,503 individuals) concluded that regulating the intestinal microbiota is an effective treatment for anxiety symptoms.22 The review focused on two kinds of interventions: probiotic and non-probiotic interventions, and interestingly, it found that the non-probiotic interventions (such as adjusting daily diets) were more effective than the probiotic interventions.22
Consideration of the bidirectional relationship of the gut-brain axis may inform individual treatment strategies. Managing external stress-related factors while optimizing gut health may jointly address some chronic health conditions. Specifically, personalized therapeutic strategies that combine stress transformation approaches with gut health interventions, such as nutritional therapies, supplements, and nutraceuticals, may help to optimize gut function and bolster related body systems. Learn more about supporting the microbiome and its effect on overall health.
- Lach G, Schellekens H, Dinan TG, Cryan JF. Anxiety, depression, and the microbiome: a role for gut peptides. Neurotherapeutics. 2018;15(1):36-59. doi:10.1007/s13311-017-0585-0
- Cryan JF, O’Riordan KJ, Cowan CSM, et al. The microbiota-gut-brain axis. Physiol Rev. 2019;99(4):1877-2013. doi:10.1152/physrev.00018.2018
- Rao M, Gershon MD. The bowel and beyond: the enteric nervous system in neurological disorders. Nat Rev Gastroenterol Hepatol. 2016;13(9):517-528. doi:10.1038/nrgastro.2016.107
- Macedo D, Filho AJMC, Soares de Sousa CN, et al. Antidepressants, antimicrobials or both? Gut microbiota dysbiosis in depression and possible implications of the antimicrobial effects of antidepressant drugs for antidepressant effectiveness. J Affect Disord. 2017;208:22-32. doi:10.1016/j.jad.2016.09.012
- Ferro JM. Neurologic manifestations of inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2014;10(9):599-600.
- Panduro A, Rivera-Iñiguez I, Sepulveda-Villegas M, Roman S. Genes, emotions, and gut microbiota: the next frontier for the gastroenterologist. World J Gastroenterol. 2017;23(17):3030-3042. doi:10.3748/wjg.v23.i17.3030
- Oligschlaeger Y, Yadati T, Houben T, Condello Oliván CM, Shiri-Sverdlov R. Inflammatory bowel disease: a stressed “gut/feeling.” Cells. 2019;8(7):659. doi:10.3390/cells8070659
- Brzozowski B, Mazur-Bialy A, Pajdo R, et al. Mechanisms by which stress affects the experimental and clinical inflammatory bowel disease (IBD): role of brain-gut axis. Curr Neuropharmacol. 2016;14(8):892-900. doi:10.2174/1570159×14666160404124127
- Mackos AR, Maltz R, Bailey MT. The role of the commensal microbiota in adaptive and maladaptive stressor-induced immunomodulation. Horm Behav.2017;88:70-78. doi:10.1016/j.yhbeh.2016.10.006
- Karl JP, Hatch AM, Arcidiacono SM, et al. Effects of psychological, environmental and physical stressors on the gut microbiota. Front Microbiol. 2018;9:2013. doi:10.3389/fmicb.2018.02013
- Rea K, Dinan TG, Cryan JF. The microbiome: a key regulator of stress and neuroinflammation. Neurobiol Stress. 2016;4:23-33. doi:10.1016/j.ynstr.2016.03.001
- Farzi A, Fröhlich EE, Holzer P. Gut microbiota and the neuroendocrine system. Neurotherapeutics. 2018;15(1):5-22. doi:10.1007/s13311-017-0600-5
- Mittal R, Debs LH, Patel AP, et al. Neurotransmitters: the critical modulators regulating gut-brain axis. J Cell Physiol. 2017;232(9):2359-2372. doi:10.1002/jcp.25518
- Lyte M, Vulchanova L, Brown DR. Stress at the intestinal surface: catecholamines and mucosa—bacteria interactions. Cell Tissue Res. 2011;343(1):23-32. doi:10.1007/s00441-010-1050-0
- Schakel L, Veldhuijzen DS, Crompvoets PI, et al. Effectiveness of stress-reducing interventions on the response to challenges to the immune system: a meta-analytic review. Psychother Psychosom. 2019;88(5):274-286. doi:10.1159/000501645
- Mika A, Rumian N, Loughridge AB, Fleshner M. Exercise and prebiotics produce stress resistance: converging impacts on stress-protective and butyrate-producing gut bacteria. Int Rev Neurobiol. 2016;131:165-191. doi:10.1016/bs.irn.2016.08.004
- Ticinesi A, Lauretani F, Tana C, Nouvenne A, Ridolo E, Meschi T. Exercise and immune system as modulators of intestinal microbiome: implications for the gut-muscle axis hypothesis. Exerc Immunol Rev. 2019;25:84-95.
- Kato-Kataoka A, Nishida K, Takada M, et al. Fermented milk containing Lactobacillus casei strain Shirota preserves the diversity of the gut microbiota and relieves abdominal dysfunction in healthy medical students exposed to academic stress. Appl Environ Microbiol. 2016;82(12):3649-3658. doi:10.1128/AEM.04134-15
- Steenbergen L, Sellaro R, van Hemert S, Bosch JA, Colzato LS. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav Immun. 2015;48:258-264. doi:10.1016/j.bbi.2015.04.003
- Schmidt K, Cowen PJ, Harmer CJ, Tzortzis G, Errington S, Burnet PW. Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers. Psychopharmacology (Berl). 2015;232(10):1793-1801. doi:10.1007/s00213-014-3810-0
- 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;102:13-23. doi:10.1016/j.neubiorev.2019.03.023
- 22. Yang B, Wei J, Ju P, Chen J. Effects of regulating intestinal microbiota on anxiety symptoms: a systematic review. Gen Psychiatr. 2019;32(2):e100056. doi:10.1136/gpsych-2019-100056
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