Stress and the Microbiota-Gut-Brain Axis in Visceral Pain: Relevance to Irritable Bowel Syndrome

Abstract

Visceral pain is a global term used to describe pain originating from the internal organs of the body, which affects a significant proportion of the population and is a common feature of functional gastrointestinal disorders (FGIDs) such as irritable bowel syndrome (IBS). While IBS is multifactorial, with no single etiology to completely explain the disorder, many patients also experience comorbid behavioral disorders, such as anxiety or depression; thus, IBS is described as a disorder of the gut-brain axis. Stress is implicated in the development and exacerbation of visceral pain disorders. Chronic stress can modify central pain circuitry, as well as change motility and permeability throughout the gastrointestinal (GI) tract. More recently, the role of the gut microbiota in the bidirectional communication along the gut-brain axis, and subsequent changes in behavior, has emerged. Thus, stress and the gut microbiota can interact through complementary or opposing factors to influence visceral nociceptive behaviors. This review will highlight the evidence by which stress and the gut microbiota interact in the regulation of visceral nociception. We will focus on the influence of stress on the microbiota and the mechanisms by which microbiota can affect the stress response and behavioral outcomes with an emphasis on visceral pain.

Keywords: Brain-Gut axis; Gut microbiota; Stress; Visceral Pain.

Conflict of interest statement

The authors declare no conflict of interest.

© 2015 John Wiley & Sons Ltd.

Figures

Figure 1

Central and Peripheral Pain Sensitization. Heightened pain perception can occur due to a combination of both central sensitization and peripheral sensitization. The hypothalamic–pituitary–adrenal (HPA) axis is activated by stress. In brief, the hypothalamus secretes corticotropin‐releasing hormone (CRH) into the hypophyseal portal system for the activation of the anterior pituitary and subsequent release of adrenocorticotropic hormone (ACTH) into the systemic circulation. In response to ACTH, the adrenal cortex releases cortisol (corticosterone in rodents), which can directly activate resident immune cells and extrinsic primary afferents within the gastrointestinal tract to promote peripheral sensitization. While cortisol binding to the hypothalamus promotes feedback inhibition of the stress response, cortisol binding to the amygdala facilitates further stress‐induced secretion of CRH, promoting central sensitization of stress pathways. The amygdala also promotes CRH signaling in the brain stem to further promote central sensitization by altering descending inhibition within the spinal cord. Direct injury to the GI tract can lead to sensitization of spinal afferents (lower threshold for activation and/or longer lasting responses) that can persist following recovery from the injury.

Figure 2

Summary Figure. The mechanisms by which stress can lead to heightened pain perception are varied and primarily occur through 3 distinct routes: (1) hypothalamic–pituitary–adrenal (HPA) axis activation, (2) sensitized spinal afferents, and (3) altered descending pain pathways. Stress and the gut microbiota are also known to interact bidirectionally, with stress causing intestinal dysbiosis, which subsequently alters HPA axis functioning. Many systems and mediators are involved in this complex network including altered neurochemistry of the central, peripheral, and enteric nervous systems, altered immune system functioning, and perturbed local production of gut hormones and mediators. What remains to be fully investigated are the exact pathways by which the microbiota can exert direct effects on visceral pain processes and vice versa.