Lipid Based Therapy for Ulcerative Colitis—Modulation of Intestinal Mucus Membrane Phospholipids as a Tool to Influence Inflammation

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.

Relevance of dietary glycerophospholipids and sphingolipids to human health

“…Treede et al [136] and Taylor et al [36] explained the anti-inflammatory effects of PC with inhibition of TNF alpha and TNF beta , whose reduced levels might also play positive roles on weight control. In addition, PC administration improves colitis mostly because it restores the appropriate gastrointestinal concentrations of this PL, which decrease with inflammation [137][138][139][140]. PC also improves the effects of NSAIDs [141] and reduces their gastric side effects via PGE-mediated gastric juice production [142].…”

Oral drug delivery with polymeric nanoparticles: The gastrointestinal mucus barriers

“…The overall thickness of the adherent mucus layer in the colorectum is reduced due to overall depletion of goblet cells [115, 116], accompanied by reduced expression of the protective trefoil peptides [117]. Additionally, altered lipid composition [118, 119] may be responsible for the observed decrease in surface tension and hydrophobicity in clinical specimens obtained from UC patients [120]. Although it is not clear which factor contributes most to UC pathogenesis, it was recently found in a phase IIa/b studies that lipid supplementation in the colon led to mucosal healing in 60% of patients [121].…”

The Impact of Lipid Types and Liposomal Formulations on Osteoblast Adiposity and Mineralization

“…In consistent with our previous studies, we found PC containing liposomes show good anti-inflammatory activities [6]. In the human intestinal epithelial cell line Caco-2, PC down-regulated TNF-α-induced gene expressions of pro-inflammatory cytokines such as ICAM-1, MCP-1, IL-8 and IP-10 through the inhibition of NFκB activation and hence lipid based therapy with PC may have benefits for ulcerative colitis, through anti-inflammatory effect [41,42]. Taken together, the behavior of osteoblasts under the stimuli of different liposomal formulations can be arranged in the following rank order PC liposomes > DC-Chol/DOPE liposomes > PC/DOTAP liposomes = Chol/DOTAP liposomes.…”