Z Gastroenterol 2011; 49 - A11
DOI: 10.1055/s-0031-1304771

The Role of Phospholipids Within the Intestinal Mucosal Barrier

Annika Braun 1, Wolfgang Stremmel 1, Robert Ehehalt 1
  • 1Department of Gastroenterology, University Hospital Heidelberg, INF 410, 69120 Heidelberg, Germany

Phospholipids are an important functional constituent of the intestinal mucosal barrier. They are not only essential for the cell membranes of intestinal epithelial cells, but are also abundant within the intestinal mucus layer which coats the gastrointestinal tract continually with a thickness of up to about 800 µm [1]. This layer is the very first line of defense of the host against potential luminal aggressors like the trillions of bacteria inhabiting the colon [2,3]. Apart from water, it is predominantly composed of glycoproteins, lipids, other proteins and nucleic acids [1,4].

The integrity of the intestinal mucus barrier is maintained through the interactions of its principal glycoproteins, the mucins, with lipids [5,6]. By mass, phospholipids constitute only a minor part of gastrointestinal mucus. So far, phospholipids in gastrointestinal mucus have been systematically analysed in different animal species and humans [7–9,19,20]. The main phospholipid class present there is phosphatidylcholine (PC) with 35 to 72%.

By electron microscopy, phospholipids, especially PC, could be demonstrated to form a monolayer between the mucus layer and the intestinal lumen [9]. It is suggested that the polar head groups of these amphiphilic molecules are adjusted to the negatively charged mucin network whereas the non-polar fatty acid tails extend luminally [10,11]. In addition, phospholipids can be detected in small vesicles as well as lamellar structures within the mucus layer throughout the gastrointestinal tract. They have been addressed as surfactant like particles (SLPs) [9]. Even though these structures could also be found within intestinal epithelial cells, it is yet unclear whether the mechanism of secretion corresponds to the one of surfactant-containing lamellar bodies by type II pneumocytes in the lung.

Which physiological functions do phospholipids exert within the intestinal mucosal barrier? We have two main hypotheses on it, and they probably both play a role in the maintenance of the integrity of the barrier. First, by forming a monolayer between the intestinal lumen and the mucus, phospholipids render the mucus surface hydrophobic. The hydrophobicity of the mucus surface seems to help to prevent adherence and invasion of bacteria and to repel the luminal contents by acting like a closing seal [10]. Second, there seems to be a substantial exchange of phospholipids between the mucus and the cell membranes of enterocytes. Lipids can modulate cellular responses by different mechanisms. For PC, it is likely that if added to the cell, it is integrated into the plasma membrane and changes the binding and signalling processes embedded [10]. This will alter the inflammatory response. For example, it could be shown that PC inhibits membrane-dependent actin assembly as well as TNFα-induced MAP-kinase and subsequent NFκB activation [12].

There is accumulating evidence that an epithelial barrier dysfunction is an important player in the pathogenesis of inflammatory bowel diseases (IBD) [13–16]. However, it is not clear whether a mucosal barrier defect in IBD is a primary contributor to inflammation or a secondary phenomenon. While the upper gastrointestinal tract harbours very low populations of bacteria, the number of bacteria in the colon exceeds ten times that of eukaryotic cells in the body [17]. The normal intestinal mucosal barrier efficiently separates luminal antigens from host tissues. This competence seems to be reduced in IBD [18].

The question was raised whether altered concentrations and/or an altered composition of intestinal mucus phospholipids could play a role in the pathogenesis of IBD. We could surprisingly demonstrate that total PC and lyso-PC concentrations related to protein or mucus dry weight were significantly reduced in mucus specimens acquired endoscopically in the rectum [19] as well as in the colon and terminal ileum from patients with ulcerative colitis [20]. Patients with Crohn's disease did not show a difference compared to control subjects without colonic inflammation. Interestingly, the concentration of sphingomyelin, accounting for less than 10% of total mucus phospholipids, was not different between the three groups and served as an internal control [20]. Mucus from all groups contained the same predominant PC molecular species, but notably, the spectrum was changed towards more saturated species in patients with ulcerative colitis. The percentage of disaturated PC 32:0, probably dipalmitoyl-phosphatidylcholine (DPPC), was in all much lower (< 10%) than in pulmonary surfactant, but nearly twice as high as in mucus of controls and patients suffering from Crohn's disease. In addition, the ratio of lyso-PC to PC in ulcerative colitis was shifted to lyso-PC, which is generated from PC by enzymatic cleavage of one of the fatty acid side chains by phospholipases [20].

Why the PC content of the terminal ileal and colonic mucus is decreased in patients with ulcerative colitis remains unclear. This could be due to a reduced production, reduced secretion, increased breakdown, or a combination of two or all of these mechanisms. The shift from PC to lyso-PC would be in line with an increased phospholipase A2 activity [10,21,22], which could be of bacterial origin. The reduction of the sums of the concentrations of PC and lyso-PC in the mucus from patients with ulcerative colitis suggests an additional defect of phospholipid secretion and/or synthesis in intestinal cells. Recent results from our laboratory demonstrate that PC secretion seems to be indeed reduced in biopsies from UC patients (W. Stremmel and R. Ehehalt, unpublished data).

Even patients with ulcerative colitis lacking clinical signs of inflammation at the time of sample acquisition showed an up to 70% reduced phospholipid concentration in rectal mucus. This fact points out that a decreased mucus phospholipid content could be more than a consequence of inflammation, namely a primary motor of ulcerative colitis [19,20].

Accordingly, the hydrophobicity of the colonic mucosal surface, quantified by contact angle goniometry, was significantly reduced in patients with ulcerative colitis versus those with Crohn's disease and controls. No significant correlation was found between surface hydrophobicity and clinical as well as histological disease activity within the groups. This could be demonstrated using surgical specimens from 49 patients [23].

We therefore hypothesise that one of the pathogenetic mechanisms of ulcerative colitis is a reduction of mucosal hydrophobicity caused by a lack of phospholipids which will lead to an increased invasion of the mucus layer by bacteria. These will then get into direct contact with the epithelial cells which are susceptible for an increased inflammatory response and trigger a chronic immune reaction.

Suiting these results, a beneficial role of PC or PC-containing foods, bananas or milk, on inflammatory processes has been shown for almost every part of the gastrointestinal tract [10]. In the colon, a beneficial effect of phospholipids has been demonstrated in several murine colitis models if agents were applied luminally [25,26].

Topical phospholipids are efficiently taken up by the mucus. This is evident from experiments in animal models, where hydrophobicity and mucus PC content could be enhanced by rectal or oral administration [10]. Therefore, it is reasonable to assume that the protective, surfactant-like function of mucus will be enhanced considerably if PC is substituted in a setting in which it is reduced, such as in ulcerative colitis. Correspondingly, it could be demonstrated in clinical studies conducted at our department that patients suffering from ulcerative colitis have a therapeutic benefit from orally applied PC-rich phospholipid mixtures in a retarded-release formulation [27,28].

There are many open interesting questions concerning the field of various phospholipids as a part of the intestinal barrier, including their production, secretion and function. We suggest that addressing these questions in further experiments will increase the understanding of the intestinal barrier and open up new therapeutic strategies.


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