Stress, the Microbiota and Visceral Pain

During the past several decades, recognition of the impact of gut microbiota on health is gathering increasing support.The gut microbiota comprises upwards of 10¹⁴ microorganisms, with an estimated 15,000 to 36,000 species.^1,2

Gut microbiota profiles are distinct between individuals, and evolve over one’s lifetime, particularly during periods of high stress.⁴ Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, ensuing in the subsequent release of corticotropin-releasing hormone, adrenocorticotopic hormone and cortisol.¹

HPA axis activation allows for an adaptive response alerting the organism of noxious stimuli. Its chronic activation however, results in maladaptive changes at the cellular, structural functional and microbial levels, the latter resulting in microbial dysbacteriosis-the imbalance and/or impairment of gut microbiota –and affecting the gut-brain axis.^1,3,5

The gut-brain-gut axis facilitates bidirectional communication between these organs via the sympathetic, parasympathetic, autonomic, and enteric nervous systems, using neuroendocrine and neuroimmune pathways. These feedback systems allow for modulation of gastrointestinal tract activity (motor, sensory and/or secretory).³

Stress-related disturbances to these finely-tuned pathways have been reported to increase sensitivity to pain,enhance pain perception and promote visceral pain disorders, including irritable bowel syndrome (IBS).^{1, 6}

Unlike other types of visceral pain disorders, IBS, which manifests with abdominal pain, bloating, nausea, urgency, and incomplete evacuation, is not associated with structural and/or histological abnormalities, or activation of mechanical nociceptive receptors in visceral organs, but with modifications in central pain neurocircuitry, leading to a top-down experience of visceral pain.^1,6,7

According to the Rome III diagnostic criteria for IBS, an IBS diagnosis can be reached when changes in bowel function (eg, urgency, incomplete evacuation) and consistency (eg, constipation-predominant IBS; diarrhea-predominant IBS; IBS mixed; and un-subtyped IBS) occur in conjunction with gastrointestinal pain and/or discomfort for at least 3 days per month over a minimum of 3 consecutive months.⁷

In the present study, 12 subjects were recruited (6 healthy controls and 6 patients with IBS) to participate in a positron emission tomography (PET) study.⁸ in order to assess whether affected cerebral blood flow.⁸

Anticipation and/or experience of noxious visceral events activated the anterior cingulate cortex involved in pain processing in control subjects and the left prefrontal cortex, a region associated with cognitive and affective responses to pain, as well as affective disorders in IBS patients.^8,10 An estimated 20-60% of patients with IBS have comorbid anxiety and/or depression.^1,11,12 

In another study, microbiota-deficient rats were transplanted with fecal microbiota from individuals with major depression (n=34) or healthy controls (n=33).¹³

Three days post-transplantation, microbiota from the depressed group had reduced diversity, and increased levels of proinflammatory markers (interleukin [Il]-6, P =.009; Il-8, P =.021; tumor necrosis factor-α, P =.022; C-reactive protein, P =.001), compared to those exposed those exposed to healthy subject microbiomes.

These results implicate the gut microbiota in the manifestation of depressive symptomatology (including anxiety and anhedonia), via the neuro-endocrine and immune systems of the gut-brain axis.

Based on these and other studies showing significant overlap between affective disorders and IBS, psychotropic treatments such as selective serotonin reuptake inhibitors and tricyclic antidepressants are indicated by the American College of Gastroenterology and the National Institute for Health and Care Excellence as a second-line therapy for IBS.⁷

Because of the heterogeneous nature of IBS, its treatment will likely be multimodal, and require lifestyle changes (eg, dietary modifications and physical activity), psychotherapy/psychopharmacology, as well as restoration of the gut microbiota’s balance.⁷

References 

1. Moloney RD, Johnson AC, O’Mahony SM, Dinan TG, Greenwood-Van MB, Cryan JF. Stress and the Microbiota-Gut-Brain Axis in Visceral Pain: Relevance to Irritable Bowel Syndrome. CNS Neurosci Ther 2016;22(2):102-117.
2. Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A 2007;104(34):13780-13785.
3. Kennedy PJ, Cryan JF, Dinan TG, Clarke G. Kynurenine pathway metabolism and the microbiota-gut-brain axis. Neuropharmacology 2016.
4. Knights D, Ward TL, McKinlay CE et al. Rethinking “enterotypes”. Cell Host Microbe 2014;16(4):433-437.
5. Burke NN, Finn DP, McGuire BE, Roche M. Psychological stress in early life as a predisposing factor for the development of chronic pain: Clinical and preclinical evidence and neurobiological mechanisms. J Neurosci Res 2016.
6. Greenwood-Van MB, Moloney RD, Johnson AC, Vicario M. Mechanisms of stress-induced visceral pain: implications in irritable bowel syndrome. J Neuroendocrinol 2016.
7. Foxx-Orenstein AE. New and emerging therapies for the treatment of irritable bowel syndrome: an update for gastroenterologists. Therap Adv Gastroenterol 2016;9(3):354-375.
8. Silverman DH, Munakata JA, Ennes H, Mandelkern MA, Hoh CK, Mayer EA. Regional cerebral activity in normal and pathological perception of visceral pain. Gastroenterology 1997;112(1):64-72.
9. Fuchs PN, Peng YB, Boyette-Davis JA, Uhelski ML. The anterior cingulate cortex and pain processing. Front Integr Neurosci 2014;8:35.
10. Mariano TY, Van’t Wout M, Garnaat SL, Rasmussen SA, Greenberg BD. Transcranial Direct Current Stimulation (tDCS) Targeting Left Dorsolateral Prefrontal Cortex Modulates Task-Induced Acute Pain in Healthy Volunteers. Pain Med 20
11. 16;17(4):737-745.
12. Lackner JM, Ma CX, Keefer L et al. Type, rather than number, of mental and physical comorbidities increases the severity of symptoms in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol 2013;11(9):1147-1157.
13. Folks DG. The interface of psychiatry and irritable bowel syndrome. Curr Psychiatry Rep 2004;6(3):210-215.
14. Kelly JR, Borre Y, O’ Brien C et al. Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res 2016;82:109-118.