Mechano-Regulation of Gene Expression in the Gut: Implications in Pathophysiology and Therapeutic Approaches in Obstructive, Inflammatory, and Functional Bowel Disorders

The gastrointestinal (GI) tract is composed of a series of hollow organs, subject to transient or persistent mechanical stress. Recent studies have revealed that persistent mechanical stress is present in obstructive and inflammatory conditions and alters gene transcription in the GI tract. Mechanical stress-induced gene expression (mechano-transcription) of inflammatory molecules, pain mediators, pro-fibrotic and growth factors has been shown to play a critical role in pathogenesis of motility dysfunction, visceral hypersensitivity, inflammation, and fibrosis in the gut. Specifically, mechanical stress-induced cyclo-oxygenase-2 (COX-2) and other pro-inflammatory mediators in gut smooth muscle cells account for motility dysfunction and inflammatory process. Mechano-transcription of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and other pain mediators may lead to visceral hypersensitivity. Emerging evidence suggests that mechanical stress in the gut also leads to up-regulation of certain pro-fibrotic and proliferative mediators such as connective tissue growth factor (CTGF) and osteopontin (OPN), which may contribute to fibrostenotic Crohn’s disease. In this chapter, we will discuss the pathophysiological significance of mechano-transcription of pro-inflammatory molecules, pain mediators, pro-fibrotic and growth factors in obstructive, inflammatory, and functional bowel disorders. We will also evaluate potential therapeutic targets of mechano-transcription process for the management of these disorders.