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===Pathophysiology===
====Mucosal barrier====
*The gastric mucosa is protected from the acidic environment by mucus, bicarbonate, prostaglandins, and blood flow.
*This mucosal barrier consists of three protective components which include:
**Layer of epithelial cells lining. 
**Layer of mucus, secreted by surface epithelial cells and Foveolar cells. 
**Bicarbonate ions, secreted by the surface epithelial cells.
[[Image: Stomach mucosal layer labeled.svg.png|center|]]

===Mechanism of Action===
*The insoluble mucus forms a protective gel-like coating over the entire surface of the gastric mucosa.
*The mucus protects the gastric mucosa from autodigestion by e.g. pepsin and from erosion by acids and other caustic materials that are ingested.
*The bicarbonate ions act to neutralize harsh acids.
*If the balance of gastric acid secretion and mucosal defenses is disrupted, acid interacts with the epithelium to cause damage
===Pathogenesis===
*Regardless of etiology, if the balance of gastric acid secretion and mucosal defenses is disrupted, acid interacts with the epithelium to cause damage.
**Helicobacter pylori disrupts the mucosal barrier and causes inflammation of the mucosa of the stomach and duodenum.
**As the ulcer progresses beyond the mucosa to the submucosa the inflammation causes weakening and necrosis of arterial walls, leading to pseudoaneurysm formation followed by rupture and hemorrhage.
**NSAIDs inhibit cyclooxygenase, leading to impaired mucosal defenses by decreasing mucosal prostaglandin synthesis.
**During stress, there is acid hypersecretion; therefore, the breakdown of mucosal defenses leads to injury of the mucosa and subsequent bleeding.
**Mucosal defects along with dilated and tortuous vessels in dieulafoy lesion put them at risk for rupture because of necrosis of the arterial wall from exposure to gastric acid.
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==Pathogenesis of Crohn's disease==
*Genetic component
*Stress and environmental component
*Microbial component
*Inflammatory component
===Genetic Component===
====Genes involved====
*NOD2/CARD15 gene
*OCTN1 gene
*DLG5 gene
*TLR4 gene

{| class="wikitable"
!Genes
! colspan="2" |Chromosome
!Function
!Mutation
|-
|NOD2/CARD15 
|16
|16q12.1
|Encodes a scaffolding protein important for maintaining epithelial integrity
|Disrupts normal epithelial integrity
|-
|OCTN1
|05
|5q31
|Ecodes an ion channel
|Alters the function of cation transporters and cell-to-cell signaling
|-
|DLG5
|10
|10q22.3
|Interact additively with the NOD2/CARD15 gene
|Iincrease susceptibility to CD along with CARD15
|-
|TLR4 
|09
|9q33.1
|Lipopolysaccharide signaling, bacterial recognition, and subsequent immune response
|Altered immune response to pathogens and a subsequent increase in inflammation.
|}
===Stress and Environmental Component===
*Stress signals are perceived by the central nervous system (CNS), triggering the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal-medullary axis.
*Neuroendocrine mediators released in response to stress not only modulate secretory, absorptive, and barrier functions in the gut but also increase the gut permeability.
*Factors involved in the effects of stress on gut permeability include 
**Corticotropin-releasing factor
**Autonomic nervous system
**Enteric nervous system
===Microbial Component===
The possible mechanisms for a bacterial etiology in the development of CD include:
*Initial immune response to a specific pathogen resulting in intestinal infection
*Alterations in normal bacterial flora of the intestinal tract
*Defective mucosal barrier and overwhelming exposure to resident bacteria and their antigens and endotoxins
*Alterations to the intestinal immune response

{| class="wikitable"
!Infectious Pathogens Implicated in Crohn’s Disease
|-
|Escherichia coli
Listeria monocytogenes

Yersinia enterocolitica

Mycobacterium avium subspecies paratuberculosis

Measles virus
|}

=== Immune Component ===
*'''<u>Altered immune response</u>''':
** An abnormal antibody response to an unspecified bacterial antigen is mainly responsible for inflammation in Crohn's disease. 
** The inflammatory response is believed to be triggered when elimination of specified microbial antigen was unsuccessful leading to altered immune response
** Dysregulation of normal mucosal immune response results in failure of phagocytosis leading to antigen persistence. 
** Antigen persistance leads to antibodies production against all the normal gut flora.
** Activation resulted in secretion of tumor necrosis factor-alpha (TNF-alpha) and subsequent epithelial changes.
*'''<u>Cytokine response</u>''':
**The primary precipitating event in Crohn's disease is T-cell  mediated immune response.
**Activated T cells are responsible for the release of cytokines.
**The production of inflammatory cytokines results in ulceration and increased intestinal permeability.
**The characteristic granulomatous lesion seen in Crohn’s disease is evidence of a cell-mediated immune response.
**The early lesions of Crohn's disease are characterized by elevations in interleukin-4 (IL-4) and decrease in IFN-gamma, a pattern more consistent with an overactive Th2 immune response.
**Chronic lesions are associated with high levels of interleukin-2 (IL-2), interferon gamma (IFN-gamma), TNF-alpha, and interleukin-12 and -18 (IL-12 and IL-18) consistent with an Th1 immune response.
**Tumor necrosis factor appears to play a significant role in the pathogenesis of CD.
***TNF-alpha induces expression of adhesion factors that allow for inflammatory cells to infiltrate and activates macrophages to promote release of other pro-inflammatory mediators such as IFN-gamma.
***Neutralization of TNF resulted in significant decrease in inflammation.
***TNF-alpha concentrations in the stool can be used to monitor disease activity in both CD and UC.