Professional Documents
Culture Documents
Introduction
Patients with coeliac disease report that their condi- Before the discovery of gluten as the causative agent
tion is “tricky to find, hard to treat and impossible to in coeliac disease, a number of cumbersome attempts
cure”. 1 However, a new understanding has emerged were made to treat the condition.4 For instance, systemic
of the mechanisms that produce the characteristic corticosteroids have been tried, but they are no longer
dietary gluten-induced damage to the small bowel used routinely owing to their association with systemic
mucosa, which has enabled improvements in the adverse events.5 The concept of a gluten-free diet as a valid
diagnosis and treatment of coeliac disease. The disor- treatment for coeliac disease dates back to the 1950s; since
der occurs in response to the digestion of wheat, rye then, this method has been the only available and effective
and barley that contains gluten in individuals carry- approach.4 Strict adherence to the diet results in recovery
ing either HLA‑DQ2 or HLA‑DQ8. 2 Therefore, the of the small bowel mucosa and alleviation of symptoms
development of villous atrophy in the small bowel and might also prevent the development of complications
mucosa and crypt hyperplasia with substantial T-cell- related to coeliac disease such as osteoporotic fractures
mediated and humoral responses in coeliac disease are and small bowel lymphoma.6 However, adherence to the
promoted by both genetic and environmental factors. diet can remain inadequate as the gluten-free diet is costly
Such immune-mediated enteropathy is characterized and particularly restrictive in nature, and the replacement
by a variety of symptoms, including a wide range of products are often less palatable than gluten-containing
abdominal complaints and extraintestinal manifest food and have poor availability.7 Patients who are unable
ations such as short stature, infertility, osteoporosis to adhere to the gluten-free diet are at risk of continu-
and neurological problems. The advent of highly accu- ous gluten-induced health problems. 7 Furthermore, a
rate serological tests (such as endomysial and trans small subgroup of patients with coeliac disease do not
glutaminase 2 [TG2] autoantibody assays) has enabled respond to the gluten-free diet and thus need additional
the identification of the increasing incidence of coeliac immunotherapy.7 In view of these obvious problems with Department of
disease. Historically, the prevalence of coeliac disease the gluten-free diet, patients with coeliac disease feel that Gastroenterology and
Alimentary Tract
was 0.01%, but according to current data it is 1–2% an unmet need exists for alternative therapies to treat Surgery, Tampere
in Western countries. 3 This percentage means that their condition.1 This article reviews the current knowl- University Hospital and
~7–14 million people in Europe have coeliac disease and edge regarding the disease pathogenesis and the latest School of Medicine,
(K. Kaukinen), Tampere
that ~3 million people in the USA have the condition. advances towards developing novel t reatment options Center for Child Health
Coeliac disease would then be one of the most common for coeliac disease. Research, University of
Tampere and Tampere
food-related lifelong disorders worldwide. University Hospital,
Luminal processing of gluten (K. Lindfors, M. Mäki),
University of Tampere,
Cereals, including wheat, rye and barley, are staple
FI‑33014 Tampere,
Competing interests foods and important sources of nutrients, dietary fibre Finland.
M. Mäki declares associations with the following companies:
Alvine Pharmaceuticals, BioLineRx, Flamentera AG, ImmusanT.
and other health-promoting compounds. Gluten is
Correspondence to:
See article online for full details of the relationships. The other the major structural component of these cereals and K. Kaukinen
authors declare no competing interests. has unique viscoelastic properties that are essential for katri.kaukinen@uta.fi
are also able to exert their proteolytic function in the pH obtained from patients with coeliac disease, pretreated
range present in the human gastrointestinal tract, and they gliadin had less harmful effects than untreated gliadin.34
are all at least moderately resistant to the prevailing harsh All these data suggest that this approach might be
environment.18,22 The treatment of gluten peptides in vitro successful and should be further developed and optimized.
with PEP from either A. niger or F. meningosepticum leads
to a reduced response of intestinal T cells from patients Probiotics
with coeliac disease.23,24 Furthermore, in a randomized, The knowledge that various microbes are able to degrade
double-blind, cross-over clinical study, pretreatment with or alter gluten, together with data demonstrating dys-
PEP prevented gluten-induced malabsorption in over half biosis in the lumen of patients with coeliac disease, have
of patients with coeliac disease.25 prompted consideration of the use of probiotics as a non-
dietary therapy.36,37 Interestingly, data show that levels of
Enzyme therapy Bifidobacterium are lower in both the faeces and small
In addition to the aforementioned microbes, cereal seeds intestinal mucosa of patients with coeliac disease than
also contain a mixture of endogenous proteases capable in patients without coeliac disease.36,37 In cell culture and
of degrading gluten during germination to provide animal experiments, bifidobacteria reduce the severity
nutrients for the growing seedling. One such enzyme of the toxic effects of gluten seen in patients with coeliac
present in barley is cysteine proteinase EP‑B2. The suit- disease.38–40 Together, the above-mentioned insights have
ability of cysteine proteinase EP‑B2 as a candidate drug opened up prospects of developing an alternative therapy
for coeliac disease lies in its stability and activity in the for coeliac disease based on bifidobacteria. An explora-
conditions of the gastrointestinal tract.26 An early proof- tory, randomized, double-blind, placebo-controlled
of-concept study demonstrated that cysteine proteinase clinical study has concluded that the administration of
EP‑B2 can effectively digest gluten in the rat stomach the Bifidobacterium infantis natren life start strain to
in a dose and time-dependent manner.27 Similar results untreated patients with coeliac disease might alleviate
have also been obtained in experiments carried out using symptoms, but has no effect on increased intestinal per-
gluten‑sensitive rhesus macaques.28 meability or active coeliac-type immune response.41 The
As PEP and cysteine proteinase EP‑B2 have comple- applicability of bifidobacteria as an alternative treatment
mentary sequence specificities, researchers have surmised for patients with coeliac disease thus clearly warrants
that a combination of these enzymes would actually be a further investigations. For instance, such studies could
dramatically superior therapeutic approach for the treat- be performed with VSL#3® (Sigma-Tau Pharmaceuticals,
ment of coeliac disease than either enzyme being used on Gaithersburg, MD, USA), a commercially available pro-
its own.29 To this end, a combination enzyme product, biotic product that contains four different bifidobacteria
ALV003 (Alvine Pharmaceuticals, San Carlos, CA, USA), and Lactobacillus species that hydrolyse gliadin.42
consisting of a 1:1 mixture of barley cysteine proteinase
EP‑B2 and S. capsulate PEP, has been formulated.30 A Polymeric binders
clinical study found that ALV003 was safe and well toler- Quite distinct from the approaches mentioned earlier
ated; no serious adverse events or allergic reactions were seeking novel treatments for coeliac disease are the poly-
observed during the 4‑week follow-up after a single dose.31 meric binders, which sequester gluten in the small intesti-
Moreover, the drug has been reported to prevent the nal lumen and in so doing prevent its harmful downstream
gliadin-induced T‑cell response in patients with coeliac effects (Figure 1). One such gluten-binding molecule is
disease ex vivo.32 On the basis of these encouraging results, poly(hydroxyethyl methacrylate-co-styrene sulfonate)
this drug candidate has entered phase IIa clinical trials. (P[HEMA-co-SS]), which reduces digestion of gluten
Although the results await publication in a peer-reviewed in vitro, thereby decreasing the formation of toxic pep-
journal, preliminary data suggests that the compound can tides associated with coeliac disease.43 The polymer is able
attenuate gluten-induced small bowel mucosal injury in to reverse gliadin-induced alterations in epithelial cells43
patients with coeliac disease.33 and to reduce the secretion of proinflammatory cytokines
Following up on the concept of combination enzyme ex vivo in mucosal biopsy specimens from patients with
therapy, an entire array of enzymes found in germinating coeliac disease.44 Moreover, in different mouse models
cereals has been tested for the ability to degrade gliadin.34,35 used in coeliac disease research, the sequestrant can atten-
The major advantage of such an approach is that the pro- uate gliadin-induced changes in the intestinal barrier and
tease preparation contains all the enzymes evolutionarily T‑cell activation.43,44 However, a potential concern about
selected for total cleavage of storage proteins in germinat- this approach is the question of whether P(HEMA-co-SS)
ing kernels. Studies have shown that a solution prepared also binds nutrients other than gluten and could thus pre-
from wheat, rye or barley that contains all germinating dispose patients to nutritional deficiencies. Nevertheless,
cereal enzymes is able to degrade gliadin in vitro to short this binding might not be a major issue, as the therapeu-
peptides that are probably <10 amino acids in length.34,35 tic approach using P(HEMA-co-SS) is suggested as an
Moreover, gliadin pretreated with such an enzyme cocktail adjunctive therapy for coeliac disease to detoxify traces
has a reduced capacity to induce harmful effects on intest of gluten contamination in the diet. Before proceeding
inal epithelial cells and to activate the T cells of patients to clinical trials in patients with coeliac disease, the drug
with coeliac disease.34 Similarly, ex vivo experiments in BL‑7010 that is based on this polymer needs to undergo
an organ culture of small bowel mucosal biopsy samples safety assessments in healthy volunteers.
whereas their number in the small intestine is reduced.93 could be further developed and tested in future clinical
In addition, the expression of MADCAM1 is aug- trials.106 This organ culture response probably occurs via
mented in the duodenum of patients with coeliac disease.94 switching off the CD4+ type 1 T helper response. However,
Altogether, these data suggest that lymphocyte homing to it remains unclear how increasing the type 2 T helper
the small intestine could be a suitable drug target in coeliac response will prevent the activation of intraepithelial
disease, similarly to IBD (Figure 3).95 A phase II clinical lymphocytes, which probably has a major role in epithelial
trial with a CCR9 antagonist96 has been completed, but the damage2 or inducing tolerance.
results have not yet been published.
No studies targeting either integrin α4β7 or Conclusions
MADCAM1 in coeliac disease have been published. Intense research efforts to develop alternative treatments
However, some studies do suggest a cause for concern with for coeliac disease to replace or at least supplement the
this approach. Firstly, it has been reported that the expres- gluten-free diet are ongoing (Figure 4). Suggested thera-
sion of integrin α4β7 and CCR9 is required for the induc- peutic approaches range from enzyme supplementation
tion of oral immune tolerance in mice.97 Secondly, in the therapy to blockers of intestinal permeability, TG2 and
absence of functional CCR9, intestinal inflammation HLA‑DQ molecules to lymphocyte blocking. Moreover,
(other than coeliac disease) has been exacerbated in mice efforts have also been made to manage coeliac disease by
and interestingly, this phenomenon parallels a deficiency vaccination or suppression of the inflammatory immune
of regulatory T cells in the intestinal lamina propria, response with hookworm infections. Some of the novel
which leads to a weakened immune defence.98,99 A further treatment and/or management options have already
aspect of this strategy to be taken into consideration is that entered clinical trials, but before marketing (presumably
blocking lymphocyte homing to the small intestine is not initially as supplemental therapy), more testing in large
antigen-specific and might thus predispose patients to phase III clinical trials is called for. Whilst choosing new
gastrointestinal infections in general. treatment strategies, one must consider the possible risks
versus benefits of the various treatments for a disease
Vaccination and other strategies that is generally benign and reversed by a gluten-free
As discussed earlier, the majority of approaches aimed diet that causes no major recognized adverse events. For
at the development of novel treatment options for instance, it would be ethically (and economically) accept-
coeliac disease are based on the inhibition of a specific able to treat refractory coeliac disease with antibodies and
deleterious event or a cascade occurring during the patho immune modulators, which will at best temporarily inhibit
genesis. Nonetheless, other means have also been sought, the migration or the local activation of immune cells. Such
including the induction of tolerance by vaccinations or an aggressive and costly approach in an uncomplicated
suppression of the inflammatory immune response by benign disease would be unrealistic, whereas the use of
hookworm infection.100,101 The identification of major enzymes (as safely used for many years to treat pancreatic
T-cell gluten epitopes100,102 has made the vaccination insufficiency) seems to be a much more reasonable option,
approach possible. A vaccine is already in phase I clinical at least to alleviate the restrictions of the gluten-free diet.
trials, where the safety and tolerability of the first peptide Prevention strategies by vaccination might be even
vaccine based on HLA‑DQ2 recognition of gluten pep- more attractive than novel treatment modalities of a
tides, Nexvax2® (ImmusanT, Cambridge, MA, USA), will manifest disease if proven safe and effective. In addition,
be tested.103 This trial notwithstanding, unsolved issues patients with coeliac disease and most clinicians treating
related to this strategy include the lack of information the patients will want to be convinced that the new drug
on the capacity of peptide injections to spread to involve for coeliac disease is able to prevent the development of
other subdominant epitopes that also probably exist in the gluten-induced damage to the small bowel mucosa.
gluten. Moreover, it is assumed that the peptide vaccines Such treatment trials will require large numbers of
induce tolerance through regulatory T cells,104 but it is patients. In this respect, the development of reliable non-
currently not known whether the potential vaccine for invasive surrogate markers for gluten-induced damage
coeliac disease could overcome the unresponsiveness to to the small bowel and effective patient-related outcome
suppression by regulatory T cells of the effector T cells of measures would be of help. The development of a novel
patients with coeliac disease.86 medication that is as effective and safe as the gluten-free
The rationale behind the hookworm approach is that diet is still in its early days and the conventional dietary
parasitic helminth infections, which have decreased world- treatment will thus hold its place for the time being.
wide over time, are thought to have an important role in
modulating the host’s immune system. Interestingly, a
phase II clinical trial with Necator americanus has been Review criteria
completed in coeliac disease. However, inoculating A search of the MEDLINE database was performed
patients who have coeliac disease with N. americanus did using the search terms “celiac disease”, “gluten”,
not reduce the severity of symptoms and did not prevent “gluten-free diet”, “novel treatment”, “drug”, “therapy”,
deterioration of the small bowel mucosa.101 Regardless “pathogenesis” and “histopathology”. Only English
of this finding, the infection did suppress inflammatory language full-text articles and abstracts were considered.
responses in organ cultures of small bowel samples,105 Articles included reviews and original publications, no
implying that a strategy using N. americanus infection publication data restrictions were applied.
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transglutaminase‑2 affect permeability of transglutaminase 2 epitope contributed by three University Hospital (grant numbers 9P020 and 9P033),
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