Abstract
Ulcerative colitis (UC) is the result of an inappropriate colonic inflammatory response triggered by environmental and genetic factors. We have recently shown that mucus from UC patients has a decreased phosphatidylcholine (PC) content, while clinical trials revealed that therapeutic addition of PC to the colonic mucus alleviated the inflammatory activity. The mechanisms behind this are still unclear. We hypothesized that PC has at least two possible functions in the intestine: First, it establishes the surface hydrophobicity of the mucus and therefore protects the underlying tissue against intraluminal aggressors; recent experiments on surgical specimens revealed reduced surface tension and hydrophobicity in UC patients. Second, mucus phospholipids might also be integrated into the plasma membranes of enterocytes and thereby influence the signaling state of the mucosa. PC has been shown to inhibit TNF-α induced pro-inflammatory responses including: (1) assembly of plasma membrane actin; (2) activation of MAP kinases ERK and p38; and (3) activation of NF-κB and synthesis of pro-inflammatory gene products. Other phospholipids like phosphatidylethanolamine or sphingomyelin had no effect. PC also inhibited latex bead phagosome actin assembly, killing of M. tuberculosis in macrophages, and sphingosine-1-phosphate induced actin assembly in macrophages. Collectively, these results provide a molecular foundation that shows PC, firstly, as an anti-inflammatory, and secondly, as a surface hydrophobicity increasing compound with promising therapeutic potential in the treatment of inflammatory bowel disease.
Highlights
A potential positive impact of phosphatidylcholine (PC) on impaired medical conditions was already shown in rat about 80 years ago, when Best et al demonstrated that the supplementation of a fat enriched diet with PC prevented the accumulation of triglycerides in the liver of healthy rats [1]
Quite a number of studies have concentrated on the role of PC in gastrointestinal damage and disease, such as the development of ulcers, bleeding and chronic inflammatory conditions like ulcerative colitis
The first evidence that PC might play a role in the pathogenesis of human Ulcerative colitis (UC) came from lipid analysis of mucus gained by gentle scraping of the rectal wall with a cotton wool sponge during rectoscopy
Summary
A potential positive impact of phosphatidylcholine (PC) on impaired medical conditions was already shown in rat about 80 years ago, when Best et al demonstrated that the supplementation of a fat enriched diet with PC prevented the accumulation of triglycerides in the liver of healthy rats [1]. Already in 1983, Lichtenberger et al described a rat model of acid induced gastric bleeding and ulcer development in which the intraluminal application of a liposomal surfactant suspension acted in a positive manner [4] From this experimental outcome emerged the hypothesis of a protective hydrophobic and PC enriched monolayer between epithelial cells and noxious luminal compounds in the gastrointestinal tract (Figure 1). Indomethacin treatment is able to alter the structure of lipid membranes This has two potential effects in the GI-tract: Firstly, it reduces the mucosal hydrophobicity; and secondly, it most likely interacts with enterocyte membranes, which, in turn, leads to impairment in the function of membrane proteins and downstream signaling pathways. How this concept of the protective effects of PC in the GI-tract plays a role in the pathogenesis and treatment of ulcerative colitis is discussed in this review
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