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The Microbiome, Stress Hormones, & Gut Function

Over the past few decades, researchers have worked to unravel the delicate connections between the human gastrointestinal microbiota and the brain, and mounting evidence suggests that psychological stress affects gastrointestinal function. Studies suggest that stress-mediated changes, like changes in the level of catecholamines, including norepinephrine, may shift the microbial colonization patterns on the mucosal surface of the intestine and alter one’s susceptibility to infection.1 Conversely, changes in the microbiome may lead to a spectrum of other physiological changes, including hypothalamic-pituitary-adrenal (HPA) axis activation and altered autonomic nervous system (ANS) responses.2

Research suggests that irritable bowel syndrome (IBS) may be a stress-sensitive disorder.3 A 2013 study showed that IBS patients had ANS dysregulation prior to, during, and after a visceral stressor; this autonomic dysregulation was more pronounced in patients who had the disease for a greater period of time.3 The principal effectors of the stress system are corticotropin-releasing hormone, arginine vasopressin, proopiomelanocortin-derived peptides, alpha-melanocyte-stimulating hormone and beta-endorphin, glucocorticoids, and the catecholamine hormones norepinephrine and epinephrine.4

Some research suggests that episodes of anxiety and depression may be experienced more frequently in patients with gastrointestinal disorders like IBS.5 Negative emotions, stressful life events, and personality traits like neuroticism have also been associated with colitis and Crohn’s disease.5 In one study, patients experiencing intense and prolonged stressful life events had a 90% recurrence rate of their colitis as compared to a 40% recurrence rate in low-stress patients.6 Early life stress and trauma, in the form of abuse, neglect, or loss, contribute to the development of gastrointestinal disorders.2,4,5 Acute life-threatening stress episodes in adult life (e.g., rape) are also important risk factors for gastrointestinal disorders.2

How can clinicians help patients create a healthy ecosystem within the gut? In the following video, IFM educator David Rakel, MD, talks about the connection between stress and gastrointestinal function:

David Rakel, MD, is the founder and director of the University of Wisconsin (UW) Integrative Medicine Program and associate professor with tenure in the Department on Family Medicine at the UW School of Medicine and Public Health.

Stress also plays a central role in another common gastrointestinal disorder: functional dyspepsia (FD).7 Utilizing the Buspirone Neuroendocrine challenge test, researchers have shown that FD patients have hypersensitive central 5-HT (serotonin) receptors.5 5-HT serves multiple functions in the human brain and is involved in the control of emotions, endocrine responses, stress coping, and aggression,8 and also plays an important role in the control of gastrointestinal function, both peripherally and centrally. Research suggests that hypersensitivity of the central 5-HT receptors is highly correlated with delayed gastric emptying.5

Peripheral outputs of the stress response, in particular glucocorticoids and catecholamines, have an effect on cytokine networks, including those in the gut mucosa.2 Stress influences the production of key regulatory type 1 and type 2 cytokines, T helper Th1 and Th2 functions, and components of cellular and humoral immunity. In healthy individuals, both glucocorticoids and catecholamines suppress Th1 responses and cellular immunity and shift the immune response toward Th2 responses and humoral immunity. In contrast, in Crohn’s disease, the response pattern is shifted toward Th1 responses. Based on these observations, researchers speculate that the different patterns of the stress response in chronic functional and inflammatory conditions of the gut may have opposite effects on the Th1/Th2 balance in the gut mucosa.2

Several studies have investigated the effect of prebiotic and probiotic intervention on emotional dysregulation.2 Using cortisol as an index of the stress response, the probiotics Lactobacillus helveticus and Bifidobacterium longum as well as galactooligosaccharide prebiotic were effective in boosting the subjects’ resilience to stress and improved emotional responses.2 A 2015 study suggests that prebiotic administration of bimuno-galactooligosaccharides reduces the salivary cortisol awakening response in healthy people.8 Ingestion of a specific probiotic cocktail was shown to alter brain activity and informational processing of emotional material in a functional magnetic resonance imaging study, as well as to reduce negative thoughts associated with a sad mood, further suggesting a role for gastrointestinal microbiota in stress and emotional responses.2 

A 2016 double-blind, placebo-controlled study found that the daily consumption of probiotics such as the Lactobacillus casei strain Shirota preserves the diversity of the gut microbiota and may relieve stress-associated responses of abdominal dysfunction in healthy subjects exposed to stressful situations.9

A 2019 systematic review found that more than half of 21 studies (1,503 individuals) concluded it was effective to treat anxiety symptoms by regulating the intestinal microbiota.10 The review focused on two kinds of interventions: probiotic and non-probiotic interventions, and interestingly, found that the non-probiotic interventions (such as adjusting daily diets) were more effective than the probiotic interventions.10

Exercise is another non-pharmacological strategy that may mitigate the detrimental impact of stress.11 New evidence suggests that both prebiotic diets and exercise interventions are most effective if given early in life when the gut and brain are more plastic.11 In adults, replacing a Western diet with one high in fiber, protein, and vegetarian dietary patterns has been shown to be beneficial for healthy gastrointestinal function.12

What other dietary and lifestyle interventions can help to diminish the effects of stress within the body and affect gastrointestinal function? Learn more in the GI Advanced Practice Module.

References 
  1. 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
  2. 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
  3. Cheng P, Shih W, Alberto M, et al. Autonomic response to a visceral stressor is dysregulated in irritable bowel syndrome and correlates with duration of disease. Neurogastroenterol Motil. 2013;25(10):e650-e659. doi:10.1111/nmo.12177
  4. Charmandari E, Kino T, Souvatzoglou E, Chorousos GP. Pediatric stress: hormonal mediators and human development. Horm Res. 2003;59(4):161-179. doi:10.1159/000069325
  5. Panduro A, Rivera-Iniguez 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
  6. Hollander D. Inflammatory bowel diseases and brain-gut axis. J Physiol Pharmacol. 2003;54(Suppl 4):183-190. 
  7. Chua ASB, Keeling PWN. Cholecystokinin hyperresponsiveness in functional dyspepsia. World J Gastroenterol. 2006;12(17):2688-2693. doi:10.3748/wjg.v12.i17.2688
  8. Puglisi-Allegra S, Andolina D. Serotonin and stress coping. Behav Brain Res. 2015;277:58-67. doi:10.1016/j.bbr.2014.07.052
  9. 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
  10. 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 
  11. 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
  12. Conlon MA, Bird AR. The impact of diet and lifestyle on gut microbiota and human health. Nutrients. 2014;7(1):17-44. doi:10.3390/nu7010017

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