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One of the important coordinators of the endocrine,behavioural and immune response to stress is corticotrophinreleasing factor (CRF). The CRF family of peptides areexpressed in the CNS and within the gut and displays potentbiologic actions. CRF has a potent effects on gut viamodulationof inflammation, increase of gut permeability, contribution tovisceral hypersensitivity (increased perception to pain) andmodulation of the gut motility. CRF release in the hypothalamusis the first step in activation of HPAinvolved in stress response.This represents the major endocrine response system to stress.The pituitary gland responds to CRF by releasing ofadrenocorticotropic hormone (ACTH) to stimulate adrenalglands secretion of the stress hormone cortisol (12).
The topic of the brain-gut axis has recently received evenmore attention due to the discovery of the bidirectionalinteraction between the brain-gut axis and gut microbiota. Thecross talk between gut microbiota, the immune system and thebrain-gut axis plays an important role in the modulation of thestress response of the gut in the context of the development ofdifferent gut disorders (13).
There is also an evidence that gut bacteria helps to keep thebidirectional contact between the components of the brain andgut axis. In other words exposure to stress modifies the bacterialflora, but also the opposite is true that the gut bacteria, whichmay have a profound effect on the BGAand may modulatemotility, permeability and visceral sensitivity. Microbiotacommunicate with the BGAthrough different mechanisms: 1)direct interaction with mucosal cells (endocrine message), 2) viaimmune cells (immune message) and finally 3) viacontact toneural endings (neuronal message) (13).
Stress causes changes in the composition of the microbiota;induces changes in neurotransmitter and proinflammatorycytokine levels, which could affect directly or indirectly themicrobiota. For example, norepinephrine increases the virulenceof some, bacteria like E. colior C. jejuni. Gut microbiota maymodulate the sensation to pain and some probiotics may inhibitthe hypersensitivity and perhaps the intestinal permeabilitycaused by the body's exposure to stress. Multiple lines ofevidence illustrate the impressive cross talk between stress,immune system and the gut microbiota (14).
Our own studies documented that a probiotic bacterialstrain of E. coliNissle (EcN) may significantly reduce thestress-induced gastric lesions, however this effect wasattenuated, at least in part, due to the blockade of the sensory
nerves with capsaicin. The role of sensory afferent nerves issupported by the fact that the addition of exogenous CGRPtorats with sensitive inactivated by capsaicin sensory nerves, theimportant neuromediator of these nerve endings restores theprotective effect of probiotics. This observation supports aclose link between the enteric nervous system (ENS) andmicrobiota in the mechanism of protection of the gastricmucosa (15).
Concerning the translation of the stress signals to the gut,mast cells play an important role. Interestingly, these cellssecrete a number of important mediators and have on theirsurface the receptors for the CRF indicating an important linkbetween stress and these cells (16, 17).
Finally, the exposure to chronic stress is associated withprolonged and excessive activation of stress response areaswithin the CNS. This exposure may cause even irreversiblechanges in the brain areas responsible for the perception of painin the gut. These changes can be shown using so calledfunctional magnetic resonance imaging (MRI) techniques (18).CLINICALCONSEQUENCES OF THE DYSREGULATIONOF BRAIN-GUT-MICROBIOTAAXIS IN THE UPPER
GASTROINTESTINALTRACTAconsequence of the dysregulation of BGAinduced byexposure to stress may lead to the development of a broad arrayof gastrointestinal diseases such as gastroesophageal refluxdisease (GERD), peptic ulcer disease (PUD), IBD, IBS and evenfood allergy (20, 21) (Fig. 3).
Gastroesophageal reflux disease (GERD) represents one of themost important manifestations of stress exposure to GI tract. It hasbeen shown that stress causes the aggravation of GERD symptomsdue to inhibition of the lower esophageal sphincter and increasedsensitivity to acid i.e.an increased perception of acid refluxate. Onthe other side the reduction of stress may lead to an improvementof GERD symptoms (22). Interestingly, during stress exposure theamount of reflux does not always increases, but the probability ofa feeling of reflux as heartburn increase. Generally, the treatmentfor GERD, especially in those who are not responsive to anti-refluxtherapy (PPI), requires further evaluation of potential effect ofstress on patients subjected to PPI therapy (23).
Concerning the link between stress and GERD, Li et al.(24)and Perlman et al.(25) have demonstrated in their recent studies
Fig. 3. Pathophysiologicalconsequences of thedisruption of brain-gut-microbiota axis by stress.The exposure to stress leadsto disturbance of brain-gutaxis (BGA) resulting in thedevelopment of differentdiseases of gastrointestinaltract includinggastroesophageal refluxdisease, peptic ulcer disease,irritable bowel disease,inflammatory bowel disease