Treating Microbiota and/or the Barrier
Dig Dis 2013;31:388–390
DOI: 10.1159/000354707
Lecithin as a Therapeutic Agent in
Ulcerative Colitis
Wolfgang Stremmel Annika Gauss
Department of Gastroenterology, Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany
Key Words
Mucus · Phosphatidylcholine · Lecithin · Ulcerative colitis
Abstract
Lecithin [phosphatidylcholine (PC)] was shown to account
for more than 70% of total phospholipids within the intesti-
nal mucus layer. It is arranged in lamellar membranes (sur-
factant-like particles) and establishes a hydrophobic barrier
preventing invasion of the colonic commensal microbiota.
In ulcerative colitis (UC), the mucus PC content was demon-
strated to be reduced by about 70%, irrespective of the pres-
ence of inflammation. This may be of primary pathogenetic
significance allowing bacteria to enter the mucus and in-
duce mucosal inflammation. Therefore, a new therapeutic
strategy is being developed to substitute the missing mucus
PC content in UC. Indeed, a delayed-release PC formulation
was able to compensate the lack of PC and improve the in-
flammatory activity. In randomized controlled studies, de-
layed-release PC was proven to be clinically and endoscopi-
cally effective, which now awaits a phase III authority ap-
proval trial. © 2013 S. Karger AG, Basel
© 2013 S. Karger AG, Basel
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E-Mail karger@karger.com
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The Physiologic Concept
The outer surface of our body is covered by the skin,
which is a strong corneal layer whose function is to pro-
tect the inner organs from mechanical injury and irradia-
tion. The inner surface consists of the mucosa, which pro-
tects – among others – against the invasion of microbes.
The essential component of the mucosal surface is the
mucus, which is composed of a scaffold of mucins, a fam-
ily of highly glycosylated proteins [1, 2]. They are nega-
tively charged and attract the phospholipid phosphatidyl-
choline (PC), which is another essential component of the
mucus [3–5] and synonymously called lecithin. PC is at-
tached with the positively charged choline head group to
the negatively charged carbohydrate side chains of mu-
cins. The hydrophobic carbon chains bind to a counter-
part fatty acid moiety of another PC molecule, thus form-
ing a bilayer. This typical arrangement appears as a lamel-
lar layer within the mucus [6]. In areas of oxygen exposure,
i.e. the lung, the fatty acid side chains of PC have to be
saturated (mostly palmitic acid). In contrast, in mucus of
the urogenital and gastrointestinal tract, the majority of
PC molecules contain a saturated as well as an unsatu-
rated fatty acid residue (palmitoyl, oleyl PC).
The PC bilayer creates a hydrophobic environment on
the surface of the mucus gel [7, 8]. In the lung, the PC
layer covering the inside of the alveoli and bronchioli is
157.82.153.40 - 5/20/2015 3:14:00 AM
Prof. Dr. Wolfgang Stremmel
Universitätsklinikum Heidelberg, Innere Medizin IV
University of Tokyo
Im Neuenheimer Feld 410
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DE–69120 Heidelberg (Germany)
E-Mail wolfgang.stremmel @ med.uni-heidelberg.de
defined as ‘surfactant’. It facilitates the gas exchange and
prohibits the entrance of microbes [9]. In the intestine,
the PC-containing structures are referred to as ‘surfac-
tant-like particles’ and prevent invasion of the commen-
sal flora of the colon [9]. In a healthy gut, there are 1 tril-
lion bacteria per gram of stool which live in harmony with
the organism. No inflammation or ulceration occurs un-
der normal conditions, due in part to the hydrophobic
barrier created by the mucus PC layer.
Hypothesis of the Pathogenesis of Ulcerative Colitis
It was shown that the mucus PC content in ulcerative
colitis (UC) is significantly reduced as compared to con-
trols. In fact, in rectal mucus specimens from UC pa-
tients, PC was by ca. 70% lower compared to healthy con-
trols and even patients with Crohn’s disease [10]. More-
over, in terminal ileum and transverse colon, similarly
low PC concentrations were detected [11]. As a result of
PC subspecies analysis, it became apparent that mucus
samples from UC patients contained higher proportions
of saturated fatty acid side chains than samples from con-
trols, even though absolute amounts were still low [11].
Of special interest was that the low PC content of mu-
cus in UC was also observed when the patients were in
remission, as defined by the endoscopic appearance of
‘mucosal healing’ [10, 11]. This indicates that a lack of
mucus PC in UC patients might be an intrinsic feature of
UC. It was indeed shown that the surface hydrophobicity
of the mucus gel was significantly reduced in UC com-
pared to control and Crohn’s disease samples [12]. It can
be hypothesized that in most cases of UC, the reduced
mucus PC concentrations are for a long time sufficient to
maintain an – albeit labile – barrier. However, when yet
undefined additional factors further suppress the PC con-
tents, the remaining PC concentration may fall below a
critical threshold, and the commensal microbiota can at-
tack. These factors may be hormonal changes, environ-
mental influences, or, particularly, alterations to the com-
position of the colonic flora towards colonies with higher
phospholipase activities [13].
It was indeed shown that PC is predominantly secreted
by the ileal mucosa [14]. It is suggested that the mucus
moves along the mucosal wall, from the ileum in an ab-
oral direction, via the colon to the rectum. Accordingly,
the mucus PC contents decrease continually in the aboral
direction. This phenomenon is suggested to be aggravat-
ed by the exposure of PC molecules to bacterial phospho-
lipases, which degrade PC to lysoPC (LPC) [13].
Lecithin as a Therapeutic Agent in
Ulcerative Colitis
The reduction of mucus PC towards the distal colon
could support the fact that UC always starts in the rectum
and spreads to more oral parts of the colon – the lower
the PC content of mucus, the farther the extension of co-
litis.
The reason for the low mucus PC content in UC is yet
unexplained; it might be linked, though, to the pathogen-
esis of the disease. Most likely it has something to do with
a postulated active mucosal translocation mechanism for
PC, as PC and LPC species account for >90% of surfac-
tant-like particles in mucus [3]. Experimentally radiola-
beled PC was injected into the tail veins of rats, and its
recovery was examined in bile, jejunum, ileum and colon
[14]. The immediate and most efficient appearance of in-
tact PC was registered in bile and ileum, whereas in colon
the secretion rate was negligible. One of the mechanisms
by which PC moves from blood to ileal mucus may utilize
a paracellular route of secretion through the tight junc-
tion barrier [15, 16]. The low mucus PC content as a
pathogenetic feature of UC is most likely inherited and
multifactorial, involving the various steps of the translo-
cation process across the intestinal mucosa or a disturbed
mucin scaffold of the mucus. By the radiolabeled PC in-
jection studies, it was further shown that ileal PC secre-
tion is stimulated by the luminal bile acid concentration
[14]. It is conceivable that the bile acids serve as deter-
gents which attract secreted PC, thus creating a luminal
sink. This could point to another biological function of
bile acids which are primarily used in the jejunum for
fatty acid solubilization to facilitate their most efficient
absorption. However, after fatty acid absorption is com-
pleted, bile acids travel all the way down to the terminal
ileum where re-absorption occurs. During their passage
through the ileum, they could assist in PC secretion. In-
deed, the cholestatic disease primary sclerosing cholangi-
tis, with reduced bile acid secretion, is often associated
with UC.
The Therapeutic Consequences
The lecithin story provides two main strategies for
therapeutic intervention:
(1) Due to the reduced mucus PC content, the com-
mensal microbiota can attack. Therefore, it would be
helpful to reduce the concentration of bacteria in stool,
and, in particular, to decrease bacteria expressing mem-
brane phospholipases. The reduction of the bacterial den-
sity can be achieved by topical acting antibiotics, e.g. neo-
mycin or rifaximin. It has indeed been shown that rifaxi-
157.82.153.40 - 5/20/2015 3:14:00 AM
Dig Dis 2013;31:388–390 389
DOI: 10.1159/000354707
University of Tokyo
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min is therapeutically active in Crohn’s disease [17].
Antibiotics which can selectively attack phospholipase-
carrying bacteria have not been developed.
(2) Another aim is to increase the mucus PC content
for re-establishment of an intact mucosal barrier. This
concept has recently been followed by the development
of an oral delayed-release PC preparation, which prohib-
its its absorption and enables substitution of missing PC
in colonic mucus [18].
In a monocentric randomized controlled trial, it was
shown that delayed-release PC leads to a more than 50%
improvement in 90% of active UC, and in most patients
even to clinical remission as well as endoscopic healing
[18].
Even in the most difficult-to-treat population of ste-
roid-refractory UC, 80% of the patients could be with-
drawn from steroids, and 50% achieved overall clinical
remission [19]. A dose of 3 g was shown in a phase IIB
study to be most effective, and, most importantly, signif-
icant adverse events were not recorded [20].
Most recently, the results of the monocentric studies
were confirmed in a multicenter randomized clinical
phase IIB trial [21]. Therefore, an authority approval
phase III trial has been initiated.
Disclosure Statement
The authors have no conflicts of interest to disclose.

References
1 Shirazi T, Longman RJ, Corfield AP, Probert
CSJ: Mucins and inflammatory bowel disease.
Postgrad Med J 2000;76:473–478.
2 Lamont JT: Mucus: the front line of intestinal
mucosal defense. Ann NY Acad Sci 1992;664:
190–201.
3 DeSchryver-Kecskemeti K, Eliakim R, Carroll
S, Stenson WF, Moxley MA, Alpers DH: In-
testinal surfactant-like material. A novel se-
cretory product of the rat enterocyte. J Clin
Invest 1989;84:1355–1361.
4 Butler BD, Lichtenberger LM, Hills BA: Dis-
tribution of surfactants in the canine gastro-
intestinal tract and their ability to lubricate.
Am J Physiol 1983;244:G645– G651.
5 Hicks AM, DeLong CJ, Thomas MJ, Samuel
M, Cui Z: Unique molecular signatures of
glycerophospholipid species in different rat
tissues analyzed by tandem mass spectrome-
try. Biochim Biophys Acta 2006; 1761: 1022–
1029.
6 Lichtenberger LM: The hydrophobic barrier
properties of gastrointestinal mucus. Annu
Rev Physiol 1995;57:565–583.
7 Willumeit R, Schuster A, Iliev P, Linser S, Fey-
erabend F: Phospholipids as implant coatings.
J Mater Sci Mater Med 2007;18:367–380.
8 Guo W, Andersson R, Odselius R, Ljungh A,
Wadström T, Bengmark S: Phospholipid im-
pregnation of abdominal rubber drains: resis-
tance to bacterial adherence but no effect on
drain-induced bacterial translocation. Res
Exp Med (Berl) 1993;193:285–296.
9 Hills BA: Surface-active phospholipid: a Pan-
dora’s box of clinical applications. 2. Barrier
and lubricating properties. Intern Med J 2002;
32:242–251.
10 Ehehalt R, Wagenblast J, Erben G, Lehmann
WD, Hinz U, Merle U, Stremmel W: Phos-
phatidylcholine and lysophosphatidylcholine
in intestinal mucus of ulcerative colitis pa-
tients. A quantitative approach by nanoElec-
trospray-tandem mass spectrometry. Scand J
Gastroenterol 2004;39:737–742.
11 Braun A, Treede I, Gotthardt D, Tietje A,
Zahn A, Ruhwald R, Schoenfeld U, Welsch T,
Kienle P, Erben G, Lehmann WD, Fuellekrug
J, Stremmel W, Ehehalt R: Alterations of
phospholipid concentration and species com-
position of the intestinal mucus barrier in
ulcerative colitis: a clue to pathogenesis. In-
flamm Bowel Dis 2009;15:1705–1720.
12 Braun A, Schoenfeld U, Welsch T, Kadmon
M, Funke B, Gotthardt D, Zahn A, Autsch-
bach F, Kienle P, Zharnikov M, Grunze M,
Stremmel W, Ehehalt R: Reduced hydropho-
bicity of the colonic mucosal surface in ulcer-
ative colitis as a hint at a physicochemical bar-
rier defect. Int J Colorectal Dis 2011; 26: 898–
998.
13 Hills BA: Gastric mucosal barrier: evidence
for Helicobacter pylori ingesting gastric sur-
factant and deriving protection from it. Gut
1993;34:588–593.
14 Ehehalt R, Jochims C, Lehmann WD, Erben
G, Staffer S, Reininger C, Stremmel W: Evi-
dence of luminal phosphatidylcholine secre-
tion in rat ileum. Biochim Biophys Acta 2004;
1682:63–71.
15 Alpers DH, Zhang Y, Ahnen DJ: Synthesis
and parallel secretion of rat intestinal alkaline
phosphatase and a surfactant-like particle
protein. Am J Physiol 1995; 268:E1205–
E1214.
16 Engle MJ, Grove ML, Becich MJ, Mahmood
A, Alpers DH: Appearance of surfactant-like
particles in apical medium of Caco-2 cells
may occur via tight junctions. Am J Physiol
1995;268:C1401–C1413.
17 Prantera C, Lochs H, Grimaldi M, Danese
S, Scribano ML, Gionchetti P: Retic Study
Group (Rifaximin-Eir Treatment in Crohn’s
Disease). Rifaximin-extended intestinal re-
lease induces remission in patients with mod-
erately active Crohn’s disease. Gastroenterol-
ogy 2012;142:473–481.
18 Stremmel W, Merle U, Zahn A, Autschbach
F, Hinz U, Ehehalt R: Retarded release phos-
phatidylcholine benefits patients with chron-
ic active ulcerative colitis. Gut 2005; 54: 966–
971.
19 Stremmel W, Ehehalt R, Autschbach F, Kar-
ner M: Efficacy of retarded release phospha-
tidylcholine for treatment of chronic, steroid
refractory ulcerative colitis. Ann Intern Med
2007;147:603–610.
20 Stremmel W, Braun A, Hanemann A, Ehehalt
R, Autschbach F, Karner M: Delayed release
phosphatidylcholine in chronic-active ulcer-
ative colitis: a randomized, double-blinded,
dose-finding study. J Clin Gastroenterol 2010;
44:e101–e107.
21 Karner M, Kocjan A, Stein J, v. Boyen G, Ue-
bel P, Schmidt C, Kupcinskas L, Dina I, Ha-
nemann A, Zuelch F, Keilhauer G, Stremmel
W: Modified release phosphatidylcholine
‘LT-02’ in active ulcerative colitis: a random-
ized, placebo-controlled multicentre study
(abstract). Gastroenterology 2012; 142:suppl
1.
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390 Dig Dis 2013;31:388–390 Stremmel/Gauss

DOI: 10.1159/000354707
University of Tokyo
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