Fig. 1. Schematic illustration of the candidate mechanisms of irritable bowel syndrome (IBS) with a focus on corticotropin-releasing factor (CRF), Toll-like receptor 4 (TLR4), and proinflammatory cytokine signaling. Hypothalamus−pituitary−adrenal (HPA) axis is activated by stress, which is triggered by CRF. Cortisol is produced from the adrenals to alter microbiota, and impairs gut barrier via modifying tight junction protein (TJP). Bacterial metabolites including short-chain fatty acids (SCFAs) also modify gut barrier integrity, and modulate brain and behavior via the vagus and/or directly acting brain through circulation, thereby possibly causing psychiatric comorbidities, which frequently occurs in IBS. CRF is also released from peripheral tissue including gastrointestinal (GI) tract triggered by stress, and acts peripheral CRF receptors. Peripheral CRF secretion is controlled by the brain possibly via the autonomic nerve. Activation of peripheral CRF receptors modifies TJP via TLR4 to increase colonic permeability. Then, bacterial translocation occurs leading to dysbiosis, and increases lipopolysaccharide (LPS). In turn, LPS activates TLR4 in immune cells to trigger the production of proinflammatory cytokines, which induce visceral hypersensitivity through the activation of visceral afferents, and impair gut barrier via modifying TJP. At the same time, mast cells having CRF receptors and TLR4, release chemical mediators including proinflammatory cytokines triggered by CRF and LPS, which can also induce these GI changes. LPS and proinflammatory cytokines can enter the circulation to act brain to alter emotion and cognition, which possibly contribute to psychiatric comorbidities in IBS. Moreover, proinflammatory cytokine also stimulates the secretion of CRF from hypothalamus leading to the activation of HPA axis. Additionally, LPS activates peripheral CRF receptors to further increase colonic permeability. Thus, CRF and TLR4−proinflammatory cytokine signaling create a vicious cycle resulting in leaky gut and dysbiosis to cause the symptoms of IBS. ACTH, adrenocorticotropic hormone.
© J Neurogastroenterol Motil
