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Dec 18, 2018

Gut. 2005 Jul; 54(7): 966–971.
doi: 10.1136/gut.2004.052316
PMCID: PMC1774598
PMID: 15951544
Retarded release phosphatidylcholine benefits patients with chronic active ulcerative colitis
W Stremmel,1 U Merle,1 A Zahn,1 F Autschbach,2 U Hinz,3 and R Ehehalt1
Author information Article notes Copyright and License information Disclaimer
See commentary "Reinforcing the mucus: a new therapeutic approach for ulcerative colitis?" in volume 54 on page 900.
This article has been cited by other articles in PMC.
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Background and aims: We examined the hypothesis of an anti-inflammatory effect of phosphatidylcholine in ulcerative colitis.

Methods: A phase IIA, double blind, randomised, placebo controlled study was performed in 60 patients with chronic active, non steroid dependent, ulcerative colitis, with a clinical activity index (CAI) of ⩾4. Retarded release phosphatidylcholine rich phospholipids and placebo were administered at a dose of 6 g daily over three months. The primary end point was a change in CAI towards clinical remission (CAI ⩽3) or CAI improvement by ⩾50%. Secondary end points included ⩾50% changes in endoscopic activity index (EAI), histology, and quality of life scores.

Results: Induction of clinical remission (CAI ⩽3) as the primary outcome variable was attained by 16 (53%) patients in the phosphatidylcholine treated group compared with three (10%) in the placebo group (p<0.00001). The rate of clinical remission and CAI improvement was 90% in the phosphatidylcholine group and only 10% in the placebo group. A median drop of seven points in the CAI score (70% improvement) was recorded in the phosphatidylcholine group compared with no change in the placebo group. Secondary end point analysis revealed concomitant drops in EAI and histology scores (p = 0.00016 and p = 0.0067 compared with placebo, respectively). Improvement in quality of life was reported by 16 of 29 evaluated patients in the phosphatidylcholine group compared with two of 30 in the placebo group (p = 0.00005).

Conclusion: Retarded release oral phosphatidylcholine is effective in alleviating inflammatory activity caused by ulcerative colitis.

Keywords: ulcerative colitis, lipid based therapy, phosphatidylcholine, lecithin, retarded release formula
Ulcerative colitis (UC) is a chronic inflammatory condition of the colonic mucosa that, depending on the individual, can extend from the rectum to the caecum. The aetiology of the disease is unknown. One of the proposed hypotheses is that a disturbed mucosal barrier is an initiating factor, and subsequent attacks from colonic commensal bacterial flora lead to inflammation of the mucosa.1–4 Intestinal mucosal cells are protected against the attacks of luminal bacteria by a continuous, hydrophobic, and adherent mucus layer.5,6 Phospholipids are one of the components of mucus, consisting of up to 90% phosphatidylcholine (PC) and lysophosphatidylcholine (LPC).7,8,9,10 They are found as a continuous layer at the luminal and mucosal cell side of the mucus gel and within the mucus as liposome-like aggregates.11,12 PC is largely responsible for establishing a protective hydrophobic surface and therefore plays a key role in mucosal defence. A defective PC layer may contribute to the development of inflammation and ulceration, as previously shown in humans with human immunodeficiency virus and Helicobacter pylori infection. In these conditions the pathogenesis involves impairment of phospholipid barrier function as a result of high phospholipase activity.12–15 It has been reported that PC, when topically applied to the colon, protects laboratory animals against colitis induced by acetic or trinitrobenzenesulphonic acid.16,17 In addition, PC and other selected lipids have been shown to inhibit proinflammatory signalling in a phagosome model system derived from macrophages.18

Recent analysis of rectoscopically acquired mucus aliquots revealed a significant decrease in PC and LPC content in patients with UC compared with healthy controls or patients with Crohn’s disease.10 Moreover, we have shown in rat intestinal perfusion studies that PC was indeed actively secreted by jejunum and ileum whereas secretion in the colon was only marginal.19 We therefore hypothesised that PC integrates into the distal small intestinal mucus and then moves downwards to the colon. Thus deficiency of small intestinal PC secretion in UC would be consistent with a low colonic mucus PC content and with an increase in inflammatory activity from the rectum to the caecum.

Based on the above information, the hypothesis which forms the foundation for the current study is that a local increase in PC within the colonic mucus may improve intestinal barrier function and decrease inflammatory activity in UC. We therefore supplemented the colonic mucosa of UC patients with a PC rich phospholipid mixture. In order to avoid early reabsorption in the upper small intestine, an oral retarded release PC rich preparation was developed. By encapsulation with Eudragit S 100, pH dependent release into the distal ileum is permitted which allows integration of PC into the colonic mucus. Retarded release preparations of this type have been described previously (for example, for preparation of 5-aminosalicylate and budenoside).20 To evaluate the clinical effectiveness of this novel PC rich preparation, we performed a prospective, randomised, placebo controlled, double blind study in 60 patients with long term, non-steroid dependent, chronic, active UC. Our results argue strongly that oral administration of PC has considerable therapeutic potential against UC.

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Patients and study medication
Patients were considered eligible for this phase IIA study if they were 18 years of age and presented with long term UC (duration >2 years). They were characterised by a chronic active course of ⩾4 months with a clinical activity index (CAI) of ⩾4. The clinical course was followed for a three month period. The main criterion for exclusion was treatment with steroids and/or immunosuppressive agents within the three month period before entering the study. Therefore, only patients who refused to take steroids and/or immunosuppressives, or who had a history of severe side effects with these compounds, were recruited. None of the patients had a surgical history.

Eligible patients were randomly assigned to one of two parallel groups (PC or placebo) with 30 patients each. All had been given continuous standard oral therapy with 3–4 g aminosalicylates daily for at least four months. To avoid interference of endoscopic and histological evaluation of the rectal mucosa, local application of aminosalicylates was omitted. Treatment with steroids and/or immunosuppressives was not allowed during the study. Patients were free to withdraw from the study at any time during its course. The primary efficacy end point was defined at the end of the study at three months, on patient withdrawal, or after deterioration in clinical course. The final examinations were then performed. Fifty eight patients agreed to a final colonoscopy and two did not.

Due to the difficulty in meeting the selection criteria, patients from all over Germany had to be recruited. Forty eight patients were examined at the Department of Gastroenterology, Heidelberg University Hospital, by the principal investigator or a panel of five experienced endoscopists using the standard endoscopic activity index (EAI).21 For patients from other areas of Germany (12 patients) who were unable to visit our department, the local physician/endoscopist who cared for the patient performed the required clinical and endoscopic examinations according to the study protocol (CAI and EAI criteria). Site differences in examinations by local physicians/endoscopists and the university were not observed. According to the design as a single centre study, all patients were instructed and guided through the study by the responsible principal investigator in close cooperation with the other physicians involved.

The study was approved by the institutional ethics committee of the University of Heidelberg. Written informed consent was obtained from each patient before enrolment in the study.

The study medication was provided by Allphamed Pharbil Arzneimittel GmbH (Göttingen, Germany). The PC rich phospholipid mixture (Sterpur P-30 Granulat; Stern-Lecithin and Soja GmbH, Hamburg, Germany) contained 30% PC, 21% phosphatidylethanolamine, and 8% phosphatidylinositol. Verum containing PC rich phospholipids and placebo containing microcrystalline cellulose (Avicel PH102; FMC Company, USA) were both encapsulated with Eudragit S 100 (1:1 wt/wt for each preparation). According to good manufacturing practice, both study medications were manufactured as indistinguishable granular preparations and packed into numbered boxes using random permuted blocks of six patients. Thus randomisation was done independently of the investigating team. The study medication was administered four times daily (1.5 g /dose) after meals and before retiring. Compliance was measured by obtaining a detailed study history in a personal interview at the end of the study, return of empty medication boxes, and control of daily medication recorded on a diary card. Every participant was requested to complete these diary cards daily which also included a performance report on CAI parameters. At the end of the study after all data had been collected and documented, randomisation was decoded by the manufacturer.

Earlier experiments were conducted to document that the retarded release PC preparations actually reached the colonic mucus. Seven representative UC patients on continuous standard oral therapy with 3–4 g aminosalicylates daily were chosen to potentially utilise the 5-ASA antioxidant effect in protecting PC from peroxidation. These patients, not included in the efficacy population of the main study, were treated with PC rich phospholipids according to the above regimen for one week. In these UC patients prior to and after PC administration and in seven untreated healthy individuals, the rectal mucosa was exposed by proctoscopy and specimens of rectal mucus removed by gentle swabbing of the rectal wall (10–20 cm ab ano) with a cotton wool sponge. After determination of mucus dry weight, PC species were quantified by mass spectroscopy, as previously described.10 In UC patients, baseline total PC content was 0.53 (0.14) nmol PC/mg dry wt, which was significantly lower than that obtained from seven healthy controls (1.17 (0.72) nmol PC/mg dry wt) (p = 0.0133). This finding is consistent with data from our previous study.10 After one week of PC rich phospholipid administration to these seven patients with UC, PC levels were increased by 4.5-fold to 3.23 (0.72) nmol PC/mg dry wt (p<0.00145). This concentration was even higher than that obtained from untreated controls (p = 0.0280). These data demonstrated that PC indeed reached the colonic mucus.

Efficacy and safety analysis
CAI includes number of bowel movements, presence of blood in the stool, general well being, abdominal pain, extraintestinal manifestations, and fever (all of which were recorded in a patient diary card) as well as erythrocyte sedimentation rate and haemoglobin values.21 Further assessment criteria included EAI according to Rachmilewitz21 and life quality index (LQI), as measured using the inflammatory bowel disease questionnaire-Deutschland (IBDQ-D).22 Histology scores for biopsies at entry and at the end of the study were evaluated by an independent pathologist, blinded to the clinical information, using index parameters described by Truelove and Richards.23 Histological appearance in a given biopsy was scored from 0–4 as follows: 0 = no; 1 = mild inactive; 2 = mild active; 3 = moderate active, and 4 = severe active inflammation. The score taken into account for evaluation was the value of the scored rectal/sigmoidal mucosal biopsies. Patients were further evaluated with regard to extension of disease.

Patients were observed and questioned regarding adverse events and were instructed to report any symptoms. All adverse events were recorded during the three month study period. As additional safety parameters, white blood cell count, creatinine, urea, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase, lipase, amylase, and cholesterol were determined after 2, 6, and 12 weeks or when clinical conditions required control.

Statistical analysis
Quantitative results of PC determination during the preceding experiments were analysed using the t test for comparison between UC patients and healthy subjects, and the t test for paired groups of UC patients before and after PC rich phospholipid administration.

For the main study, the change in CAI was considered as the primary end point. Cut off values for the primary end point evaluation were: (a) number of patients with a reduction in CAI of ⩾50% from baseline24 and (b) achievement of clinical remission (CAI ⩽3).24,25 Baseline CAI was defined as the mean activity in the week before the start of the study and was compared with the CAI at the end of the study. Secondary end points included the number of patients with ⩾50% improvement in the following variables over the evaluation period: EAI, histology score of rectal/sigmoidal mucosal biopsies, and IBDQ-D. Life quality was determined by the mean value of the 32 items of the IBDQ-D and by subgroup analysis. Furthermore, disease extension during the study period was evaluated. The study analysis was by intention to treat.

Statistical analysis was performed using SAS software (release 8.02; SAS Institute, Inc., Cary, North Carolina, USA). Non-parametric statistical methods were used to analyse study end points in both treatment groups, judged by the Shapiro-Wilk test. Comparison of changes in primary and secondary study end points between the two treatment groups was performed using Fisher’s exact test. The distribution of changes in scores obtained from the PC and placebo groups were analysed using the Mann-Whitney U test. Differences between scores obtained at entry and at the end of the study for each individual patient were compared within both treatment groups using Wilcoxon’s signed rank test. Study entry parameters were compared between the PC rich phospholipid group and the placebo group using the Mann-Whitney U test for continuous variables and Fisher’s exact test for categorical data. Continuous variables were expressed as median with interquartile range (IQR). The distribution of changes in CAI, EAI, and LQI at entry and at the end of the study was presented by box and whisker plots. Two sided p values were reported in all cases and an effect was considered statistically significant at a p value of ⩽0.05.

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Patient characteristics
Between April 2000 and October 2002, 60 patients were recruited into the study and randomly assigned to one of the two groups of 30 patients each. Patients were comparable in age, sex, extension of disease, EAI, histology, and life quality scores (table 1). For CAI, the PC group had a significantly higher score compared with the placebo group (p = 0.0071). This was due to a higher blood in stool content in the PC group (median score 2 (IQR 2–3) v 2 (IQR 1–2) in the placebo group; p = 0.0003). For all other CAI parameters there were no significant differences between the two groups.

Table 1
 Patient characteristics at entry into the study for the phosphatidylcholine (PC) and placebo groups

Treatment group PC group (n = 30) Placebo group (n = 30) p Value

    Male 19 17
    Female 11 13
Age (median (IQR)) 35.5 (24–58) 36.5 (28–46) 0.773†

    Pancolitis 13 16 0.606*‡
    To right flexure 2 1
    To transversum 4 1
    To left flexure 8 2
    To sigma 2 9
    To rectum 1 1
CAI (median (IQR)) 10 (7–12) 7 (5–9) 0.0071†
EAI (median (IQR)) 7 (6–8) 6.5 (6–8) 0.725†
Histology score

    No/mild inactive 2 5
    Mild/moderate active 15 11
    Severe active 8 7
    Not determined 5 7
LQI (median (IQR)) 3.0 (2.3–3.5) 3.3 (2.8–3.8) 0.170†
    Not determined 1 0
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IQR, interquartile range; CAI, clinical activity index; EAI, endoscopic activity index; LQI, life quality index.

*Fisher’s exact test; †Mann-Whitney U test; ‡p value is given for differences between rates of patients with pancolitis versus patients with partial colitis.

Treatment efficacy
Primary end point analysis
Clinical activity index
Two cut off values for primary end point analysis were chosen: (1) the absolute threshold value of CAI ⩽3, defining clinical remission24,25 and (2) the relative improvement in CAI ⩾50% (table 2). Clinical remission was observed in 16 PC treated patients (53%) but only in three (10%) patients in the placebo group (p = 0.00063). Improvement in CAI ⩾50% was recorded in 27 of 30 PC patients but only in three of 30 placebo patients (all three also achieved clinical remission) (p<0.0001). With regard to the magnitude of change over the study period, median CAI in the PC group decreased from 10 (IQR 7–12) to 3 (1–5) (p<0.0001). In the placebo group, CAI increased from 7 (IQR 5–9) to 9 (5–11) (p = 0.139) (see also fig 1A).

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Figure 1
  Comparison of changes in disease activity. Distribution of data presented as a box and whisker plot: minimum, 25th percentile, median, 75th percentile, maximum, outliers (symbols), and extreme values (*). (A) Primary end point analysis. Clinical activity index score showed a median decrease of 7 (interquartile range (IQR) −8 to −5) in the PC group compared with a median decrease of 0 (IQR 0–2) in the placebo group (p<0.00001). (B) Secondary end point analysis. Endoscopic activity index score showed a median reduction of 3 (IQR −4 to −2) in the PC group compared with a median reduction of 0 (IQR 0–1) in the placebo group (p<0.00001). Life quality index score showed a median increase of 2.06 (IQR 1.11–3.0) in the PC group compared with a median of 0 (IQR −0.11 to 0.14) in the placebo group (p<0.00001).

Table 2
 Rates of response over the study period in the phosphatidylcholine (PC) and placebo groups

Treatment group PC group (n = 30) Placebo group (n = 30) p Value*
Primary end point analysis

    Clinical remission/improvement (⩾50%)

        Yes 27 3
        No 3 27
    Clinical remission (CAI ⩽3)

        Yes 16 3
        No 14 27
    ΔCAI (⩾50%)

        Decreased 27 3
        Unchanged 3 23
        Increased 0 4
Secondary end point analysis

    ΔEAI (⩾50%)

        Decreased 11 0
        Unchanged 18 27
        Increased 0 2
        Not determined 1 1
    ΔHistology score (⩾50%)

        Decreased 13 3
        Unchanged 11 19
        Increased 1 1
        Not determined 5 7
    ΔLife quality index (⩾50%)

        Increased 16 2
        Unchanged 13 28
        Decreased 0 0
        Not determined 1 0
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CAI, clinical activity index; EAI, endoscopic activity index.

*Fisher’s exact test.

Secondary end point analysis
Endoscopic activity index and histology score
In parallel with the clinical results there was an improvement in EAI in 11 of 29 evaluated PC patients compared with none of 29 placebo patients (table 2). This corresponded to a median reduction in score from 7 (IQR 6–8) to 4 (3–5) (p<0.0001) compared with no difference in the placebo group (6.5 (IQR 6–8) v 7 (6–9); p = 0.144) (see also fig 1B). An improvement in histology score was also noted in 13 of 25 evaluated patients in the PC group versus three of 23 of the placebo group (p = 0.0067) (table 2). An initial median score of 3 (IQR 2–4) decreased to 2 (1–2) (<0.0001) in the PC group (median drop of 1 point; p = 0.0056) while with placebo unchanged median values of 2 (IQR 2–4) and 2 (1–4) (p = 0.406) were obtained.

Disease extension
With regard to extension of disease, 19 of 30 patients (63.3%) in the PC group showed a median reduction in the length of the affected area of 40 cm. In the placebo group, this parameter remained unchanged in the majority of patients. Five of 29 placebo patients (17.2%) demonstrated a marginal increase in this parameter (that is, from 5 to 10 cm).

Quality of life
Treatment efficacy was reflected in all subjective quality of life parameters, including bowel symptoms, systemic symptoms, and emotional and social functions, each of which improved (p<0.00001) with PC treatment compared with placebo. A >50% increase in total LQI was recorded by 16 of 29 evaluated patients receiving PC. Placebo treated patients continued to experience poor to moderate quality of life, with only two of 28 patients responding in a positive manner (table 2). In the PC group, median LQI score increased from 3.0 (IQR 2.3–3.5) to 5.1 (4.4–5.8) (p<0.0001) compared with no change in the placebo group (see also fig 1C).

Study withdrawal
Only one patient in the PC group withdrew from the study prematurely due to psychological decompensation while in the placebo group nine patients withdrew due to deterioration in clinical condition (p = 0.0122). The reasons for discontinuation varied among individual patients. In five placebo patients, although the overall CAI did not deteriorate, the incentive to complete the study was lacking as subjective expectations of improvement were not met. Additionally, four patients withdrew due to CAI deterioration. In these patients, CAI increased by 5–11 points compared with baseline values, suggesting acute exacerbation of the disease, which was not alleviated by standard therapy with aminosalicylates alone.

Adverse events
During the study approximately 50% of patients experienced tolerable bloating, corresponding to grade 1 of the SAE grading (NCI common terminology criteria for adverse events). However, no significant differences were found between the incidence in the PC and placebo groups. No other major adverse or side effects were observed. Additional biochemical and haematological safety tests also did not reveal significant changes.

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The aim of the present study was to evaluate the efficacy of retarded release PC in inflammatory activity in UC. A retarded release preparation given orally is more suitable for integration into the colonic mucus compared with rectal instillation, in which superficial and short exposure of PC is expected.

The retarded release PC rich phospholipid preparation administered at a dose of 6 g/day reached the rectal mucus, resulting in higher PC concentrations (see methods). These levels of PC even surpassed concentrations seen in healthy individuals. Although this justifies the dose of PC administered in this phase IIA study, a formal dose finding study (phase IIB) is pending to determine the optimal dose for efficacy. Interestingly, PC concentrations measured in non-treated UC patients were lower than in healthy controls. This supports our earlier findings: in a larger cohort of inactive UC patients, a significantly lower PC concentration was detected in the rectal mucus compared with healthy controls and patients with Crohn’s disease.10 This may be of potentially pathophysiological significance. The underlying molecular mechanisms need to be explored.

For efficacy evaluation, it was essential to minimise spontaneous remission and maximise study drug related remission. Therefore, only patients with longstanding UC (>2 years) and chronic active disease were included in the study. Patients receiving steroids and/or immunosuppressive agents were not included for similar reasons. However, standard therapy with aminosalicylates was provided to both groups to ensure some protective. To enable detection of significant clinical changes, only patients with a CAI ⩾4 were included. Median baseline CAI scores in the PC and placebo groups were 10 and 7, respectively. This and the other patient characteristics indicate that moderate to severe disease activity was indeed present at entry to the study (table 1).

Primary end point analysis revealed induction of clinical remission in 16 (53%) PC treated patients compared with only three (10%) in the placebo group. Moreover, the rate of clinical remission/improvement (⩾50%) was 90% in the PC group compared with 10% in placebo patients. While it is more difficult for the higher CAI group to reach the clinical remission margin (CAI ⩽3), it is easier to achieve improvement of ⩾50%, and vice versa for patients with a low CAI. The use of both of these cut off values counterbalanced differences in baseline CAIs in the PC and placebo group (see table 1). Apart from the significant number of responders in the PC group, the magnitude of CAI improvement (70%) was impressive (fig 1). PC treated patients also demonstrated improvement in all other secondary end points assessed. This included EAI and histology score, reduction of disease extension, as well as LQI, with all of its subcategories. The only side effect noted was bloating which was observed in the PC and placebo groups. This may be due to Eudragit S 100 encapsulation.

In contrast with the rapid anti-inflammatory effects usually observed with steroids, improvement with retarded release PC rich phospholipids was gradual and was first seen after 2–4 weeks, as documented in the patient diary cards. The design of the study did not allow a more accurate time-response analysis. An ongoing dose finding study with a homogeneous study population with regard to disease extent and activity will provide data on the time course of improvement.

The anti-inflammatory effect of PC in UC could be attributed to the fact that it is lacking in colonic mucus.10 Thus supplementation with PC may help to reconstitute the structure and density of the mucus to serve as a protective mechanical shield. In addition, PC as a hydrophobic lipid may exert a general defensive action by preventing attacks from commensal colonic flora. Alternatively, PC could also be incorporated into mucosal cell membranes where it influences signalling processes involved in inflammation. Recent studies using an in vitro phagosomal test model system support the notion that PC is involved in signalling networks that inhibit proinflammatory signalling “states” in membranes.18 Accordingly, it would be most interesting to test purified phospholipids for their potential to inhibit mucosal inflammation which could be the basis for an effective and harmless lipid based therapy in IBD.

Although larger studies are needed for definitive confirmation, our results from the present proof of concept study (phase IIA) indicate that oral retarded release PC is safe and clinically useful in UC patients, as reflected by the decrease in overall inflammatory activity with an associated significant increase in quality of life. Long term PC application may be able to maintain clinical remission without the considerable adverse effects seen following steroid and immunosuppressive therapy.

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We thank Dr Wolf-Dieter Lehmann (DKFZ, Heidelberg, Germany) for providing technical support in mass spectrometry analyses and Jens Wagenblast for performing PC quantifications.

This work was supported by a grant from the Dietmar Hopp Foundation.

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  • CAI, clinical activity index

  • EAI, endoscopic activity index

  • IBD, inflammatory bowel disease

  • IBDQ-D, inflammatory bowel disease questionnaire-Deutschland

  • IQR, interquartile range

  • LPC, lysophosphatidylcholine

  • LQI, life quality index

  • PC, phosphatidylcholine

  • UC, ulcerative colitis
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Conflict of interest: None declared.

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Tristan Loscha

Thread starter
Dec 18, 2018

Gut. 2005 Jul; 54(7): 900–903.
doi: 10.1136/gut.2004.058453
PMCID: PMC1774597
PMID: 15951531
Reinforcing the mucus: a new therapeutic approach for ulcerative colitis?
P R Gibson and J G Muir
Author information Article notes Copyright and License information Disclaimer
See the article "Retarded release phosphatidylcholine benefits patients with chronic active ulcerative colitis" on page 966.
This article has been cited by other articles in PMC.
The treatment of active mucosal inflammation in ulcerative colitis remains challenging. Current therapies have limited efficacy and may be associated with clinically significant adverse effects. There is room for new therapeutic approaches. While nearly all of our current pharmacological approaches involve attacking various immune and inflammatory pathways in order to facilitate healing, few in the clinician’s current arsenal are directed towards enhancing or protecting the colonic epithelial barrier. Is this situation about to change?

The understanding of the pathogenesis of ulcerative colitis has not considerably progressed over the last decade. The proponents of concepts that the primary abnormalities lie within immune and inflammatory mechanisms have stumbled in attempts to explain the striking features of ulcerative colitis, such as the diffuse nature of the inflammation, its confinement to the mucosal compartment, and its distribution in the large bowel. The alternative concept that primary abnormalities lie within an abnormal epithelial barrier sits more comfortably with these characteristic features of the disease.1 The barrier has regional differences in structure, composition, and function, which offer simple explanations for, for example, disease distribution. The nature of the inflammatory response in ulcerative colitis—intense polymorph infiltration and predominant antibody mediated (TH2) responses with less prominent T cell activation—is most consistent with exposure of the immune system to large numbers of different “foreign” molecules.2 Such events might be anticipated in a situation where multiple molecules are able to pass through a deficient epithelial barrier. This is in marked contrast with the situation in Crohn’s disease where the patchy inflammation involving deeper layers of the intestinal wall and draining lymph nodes, together with dominant T cell activation and TH1-type cytokine profile that characterises the response to a limited number of antigens specifically taken up and presented to T cells via follicle associated epithelial cells.2,3

Studies that date back more than 20 years have demonstrated that the colonic epithelium is abnormal in structure and function in patients with ulcerative colitis. The epithelium comprises cells that are metabolically abnormal (such as deficient β-oxidation4 or sulphation of phenols5), respond abnormally to stress (as shown by the response in vitro after its separation from the basement membrane6,7), and have an abnormal cell membrane (such as abnormal permeability8). The mucus layer is abnormal, both in its thickness9 and composition (such as abnormal glycosylation of mucins10–12 and abnormalities of the phospholipid component13). Many of these abnormalities are independent of the presence of mucosal inflammation, although whether they are primary abnormalities or secondary to other processes has never been definitively demonstrated. Why such abnormalities are present—whether autoimmune injury to the epithelium is occurring, whether there might be a genetic basis for epithelial structure or function, whether there are luminal factors that might induce abnormal behaviour of the epithelium, or a combination of any or all of these—has been the basis of much study and speculation without definitive answers.

Targeting the epithelial barrier in order to reduce the stimulus to inflammatory events, to enhance healing of actively inflamed mucosa, and to prevent relapse have also been the subject of much speculation and study. Approaches have ranged from improving the regenerative ability of the epithelium (such as the use of growth factors14,15), to trying to enhance energy substrate supply (using butyrate enemas16), and to enhancing the mucous barrier (with trefoil peptides15,17 or inhibition of bacterial sulphatases with bismuth18). None of these approaches has yet to be promoted from potential therapy to use in regular practice because, for example, the theoretical basis was misguided, efficacy was limited, or further development was hindered by funding difficulties and commercial realities. Will further attention to colonic mucus change this situation?

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The normal colon is lined by a layer of mucus that is more than 100 μm thick.9 The mucus serves essential functions. It is a lubricant ensuring low friction between moving structures (luminal contents) and the epithelium. This conceptually simple but essential protective function is predominantly the responsibility of surface acting phospholipids.19 They form an oligolamellar lining that converts the hydrophilic epithelial surface into a hydrophobic one that interfaces with luminal contents. The tight packing together of fatty acid chains provides a good basis for a hydrophobic barrier. Indeed, the regions of the gastrointestinal tract with the most developed hydrophobicity are the stomach and colon, where the potential for injurious insults from luminal factors are the greatest.20 Most attention in recent years has been paid to other mucous components that subserve complementary protective functions. Mucins are glycoproteins that function to exclude large molecules (polymers with a molecular weight >20 000) that are not glycoproteins, and to trap other molecules either non-specifically via general “stickiness” or more specifically via carbohydrate structures (lectin binding sites) that may be similar to those on the cell surface.21 Such trapped matter can be discarded by the constant removal of mucus. It is no surprise then that mucus secretion is increased in the face of threats and this may be mediated, at least in part, by immune events.22 The mucus environment also supports the presence of other protective proteins and peptides such as secretory IgA,23 lactoferrin,24 and trefoil peptides.25

Of all of these components, it has not been clear what is or are the most important from functional, pathogenic, or treatment points of view. Much of the glamour and excitement have surrounded the mucin glycoproteins and other secreted proteins within the mucus. However, recent evidence suggests that the phospholipid component might be a critical factor that can be readily modulated when the mucous barrier is failing.

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Phospholipids, the major lipid components of mucus, are amphiphilic molecules and contain a polar head group and non-polar hydrocarbon (fatty acid) tails. The major classes of phospholipids include phosphatidylcholine (PC), phosphatidylethanolamine, phosphatidylinostiol, and phosphatidylserine. In colonic mucus, PC and lysophosphatidylcholine (LPC) are the major species.13 LPC is an intermediate in the metabolism of PC but is also produced after the hydrolysis of PC by phospholipase A2.26 Orientation of the lipophilic region of the phospholipid and the nature of the fatty acids characterise the hydrophobicity of the mucus gel layer.20 The fatty acid tails extend into the lumen to form a “non-wettable” resistant layer.20,27 They also extend from the mucosal cell side of the mucus gel.27 In mucus, the PC species typically contain one saturated (palmitic acid 16:0 or stearic acid 18:0) and one unsaturated (oleic acid 18:1or linoleic acid 18:2) fatty acid with PC (that is, PC 16:0/18:1 and PC 18:0/18:2).13 This contrasts with the PC of pulmonary surfactant, dipalmitoylphosphatidylcholine, which contains two saturated fatty acids, palmitic acid (PC 16:0/16:0).19

The origin of PC in mucus has not been established and more research is required to understand how, when, and where these surface active phospholipids are synthesised, stored, and secreted. In animal studies, there is some evidence that PC is primarily secreted by the jejunum and ileum, suggesting that PC is delivered to the mucus via the lumen.13 In these studies, the contribution of PC produced via the colonic epithelium appeared to be minimal. It seems somewhat surprising and highly unlikely that a local source of PC secretion into the mucosal gel layer is not operational. Goblet cells are an obvious site for further investigation. Approaches that have been used to understand the role of surface active phospholipids in the gastric mucosa and as pulmonary surfactant could be readily employed to gain a greater understanding about the production of mucous PC in the colon. A great deal has been learnt by the use of special probes and stains specific for lipophilic areas and choline based phospholipids (see Lichtenberger20), and their application to colonic mucus seems warranted.

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As outlined above, mucus is abnormal in patients with ulcerative colitis. There is, however, limited knowledge regarding the phospholipid component of colonic mucus in ulcerative colitis. Recently, quantitatively less PC and LPC were reported in samples taken from the rectal mucosa of patients with ulcerative colitis than from healthy controls and patients with Crohn’s disease.13 This could be due to reduced production, increased breakdown, or both.

If indeed goblet cells do contribute to the PC content of colonic mucus, they might play more than a passive role in PC depletion of mucus. Goblet cell depletion is a more prominent pathological feature of ulcerative colitis than for Crohn’s colitis. While it might just reflect excessive stimulation of the goblet cells to discharge their mucus, the cells might also be defective in their ability to incorporate PC into the mucus, offering another candidate for the primary abnormality in ulcerative colitis.

Control of PC biosynthesis is a key in the apoptotic programme so that agents that induce apoptosis turn off the biosynthesis of PC.28 Most epithelial cell death in ulcerative colitis appears to follow an apoptotic pathway.29,30 Thus the increased apoptosis that is occurring in the epithelium may deplete the pool of PC by inhibiting its biosynthesis.

PC can be destroyed within the epithelium, thereby depleting the pool of PC available for secretion into mucus, or can be destroyed within the mucus itself. Mucosal phospholipase A2 activity is increased in patients with ulcerative colitis or Crohn’s disease31,32 and this activity resides in the epithelium.33 Protein kinase C, which is involved in several signal transduction pathways linked with inflammatory responses (see Brown and colleagues34), activates a PC specific phospholipase C in the plasma membrane with subsequent breakdown of PC.35 Indeed, colonic mucosa from patients with ulcerative colitis has significantly elevated activity of protein kinase C in the particulate fraction compared with that in normal mucosal samples.36 Insertion of fluorescent analogues of PC into the plasma membrane of cells followed by activation of protein kinase C with phorbol esters has been used to follow the movement of PC and its metabolites via fluorescent microscopy.37 A similar approach could be used to gain a greater understanding about the fate of PC in the colonic mucus in ulcerative colitis and in healthy individuals.

Once phospholipids enter the mucus they remain vulnerable to the action of phospholipases, which may be of epithelial origin or derive from mucosa associated bacteria. In the stomach, Helicobacter pylori colonises the mucous layer in part by producing phospholipases A1, A2, and C, and can extract the host phospholipids for its own protective coating.20H pylori can also generate high concentrations of ammonium ion that competes with phospholipids for negatively charged glycoprotein binding sites.20 It is intriguing to speculate about the possible role of a H pylori-like bacterium that might be responsible (in part at least) for the breakdown of the colonic mucous barrier in ulcerative colitis. Large numbers of bacteria are found within the depleted mucous layer of these patients,38,39 but whether such bacteria are efficient producers of phospholipases is not known.

The net result of reduced biosynthesis and increased breakdown of phospholipids within the mucosa might be a PC starved system in ulcerative colitis with subsequent depletion of PC available for mucus. Indeed, the observation that plasma phospholipid levels are low in patients with severe ulcerative colitis supports such a concept.40 If this situation were combined with excessive destruction of PC within the mucus layer itself, the ability of PC to offer adequate barrier and lubricant function might be severely compromised. Could correction of phospholipid deficiency of the mucosa and/or mucus be of therapeutic value in ulcerative colitis?

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Phospholipids are readily taken up by mucus, so that the mucous content can be substantially increased by their topical administration. In experimental animals, where there is no abnormality of mucus, topical PC protects the mucosa from luminal insults in the form of acetic acid and trinitrobenzenesulphonic acid, which usually induce colitis.41,42 It might be anticipated that the protective and lubricant function of mucus would be considerably enhanced by topical application of PC in a situation such as ulcerative colitis where PC content is reduced.13 Such a simple concept has recently been evaluated43 and the results of a randomised controlled trial are reported in this issue of Gut (see page 966). Delivery to the large bowel lumen was achieved by coating of PC enriched phospholipids with Eudragit-S 100. Release of phospholipids from this pH dependent coating would be expected to predominantly occur in the terminal ileum and proximal colon, a situation mimicking the putative main source of phospholipids in the colonic mucus. Details of the origin (for example, from soy or egg), and the type of phospholipids and fatty acid species used in this study were not described. Nevertheless, PC was successfully incorporated into rectal mucus confirming that the delivery system works.

In a population of 60 patients with chronically active disease, the efficacy of the PC was astoundingly good over a three month treatment period. Compared with a response of 10% in the placebo arm, 90% of the phospholipid treated group responded and 53% were in remission after three months of therapy. No clinically significant side effects were noted. Is this too good to be true?

There were problems with the study design. Despite being described as a single centre study, end points were scored in multiple centres for practical reasons. However, as blinding and randomisation seemed appropriate, heterogeneity of assessment is unlikely to be a significant factor in skewing the results. There were also no data on the time course of efficacy, although a comment in the discussion indicated a slow onset of effect over weeks. The dearth of adverse events in a three month study is somewhat surprising to those used to dealing with randomised controlled drug trials. This suggests laxity in documenting every minor event but again does not detract from the efficacy demonstrated. The placebo treated patients faired badly. A 10% response (and remission) rate is at the lower end of what might be anticipated in most trials, except that patients with chronically active disease, as selected, might have a lower placebo response. The choice of placebo, Eudragit-S 100 coated cellulose, may not have been appropriate. Cellulose would be delivered to the colonic lumen in an identical fashion to that of the phospholipids and, since it is not fermented by colonic bacteria, it might be considered benign and inert. However, cellulose might potentially be abrasive to the mucosa, this being a postulated mechanism by which non-fermentable fibre stimulates epithelial proliferation in fibre starved atrophic colon in otherwise healthy rats.44 The placebo therefore might have worsened the outcome. On the other hand, there is no evidence that non-fermented fibre is detrimental to the course of ulcerative colitis. Whatever the case, it is still reasonable to say that three months of therapy with PC rich phospholipids delivered to the colonic lumen were convincingly efficacious in inducing remission in patients with chronically active ulcerative colitis.

What about the mechanism of action? It would be precarious to assign this efficacy to the improved hydrophobicity and barrier function of the mucus without confirmatory data. The hydrophobicity of the mucosal layer can be quantified from the “contact angle” after a drop of saline is placed on the mucosal surface.27 Whether this simple test can be carried out on biopsy specimens or even at colonoscopy is uncertain, but such an assessment in patients with ulcerative colitis seems worthwhile. Alternatively, effects on mucus might only be a minor player in the efficacy. Replenishment of the epithelial pool of PC, with its potential positive effects on improving epithelial health, limiting epithelial destruction, and suppressing its involvement with inflammatory mechanisms, as discussed above, might also be an important mechanism of action.

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The findings that treatment with PC rich phospholipids permits healing of otherwise difficult to treat ulcerative colitis opens a new approach to the treatment of ulcerative colitis. There is the important need to confirm the results using a more appropriate placebo (perhaps free unsaturated fatty acid such as linoleic acid in place of the cellulose), to determine the appropriate dose, and to define the time course of effect. Additional questions are raised by the complex nature of the phospholipid mixture used. For example, is the effect observed indeed due to the PC component or is the active moiety a minor part of the phospholipid mixture, such as the unsaturated fatty acid component? The question of how this phospholipid mixture is achieving its efficacy, particularly whether it is acting via reinforcement of the mucus, as seems logical, or by other mechanisms, needs to be addressed.

While there has been much previous focus on the mucin glycoproteins, this work shows that more attention needs to be drawn to the less glamorous lipid component, which is not simply playing an inert structural role in the mucus gel layer but rather is a dynamic component of a complex barrier system. The putative efficacy of PC might be enhanced by better distribution using spreading agents. Perhaps liposomes of PC could be used to introduce other therapies such as anti-inflammatory drugs or even antisense RNA that will assist with epithelial healing—two for the price of one! There is also the potential to introduce phospholipids and fatty acid species, such as arachidonic and butyric acids that may have cytoprotective properties. Welcome phospholipids to the cutting edge of ulcerative colitis!

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Conflict of interest: None declared.

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