ArticlePDF Available

Are Non-Celiac Autoimmune Diseases Responsive to Gluten-Free Diet?

  • . Chaim Sheba Medical Center, the Zabludowicz Center for Autoimmune Diseases, Tel-Hashomer, Israel and Ariel University, Ariel, Israel


Genetic risk factors for autoimmune diseases are constantly discovered, however, environmental factors are laggingbehind and the precipitating events leading to development of autoimmune diseases remain enigmatic. Gluten is a well-established inducing nutrient in celiac disease and gluten withdrawal is the only current effective therapy. More and more studies have shown that non-celiac autoimmune diseases can partially respond to gluten free diet. The present editorial reviews those conditions and suggest multiple potential mechanisms that might operate in clinical amelioration of non-celiac autoimmune diseases.
International Journal of Celiac Disease, 2017, Vol. 5, No. 4, 164-167
Available online at
©Science and Education Publishing
Are Non-Celiac Autoimmune Diseases Responsive to
Gluten-Free Diet?
Aaron Lerner1,2, Ajay Ramesh1, Torsten Matthias2,*
1B. Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
2AESKU.KIPP Institute, Wendelsheim, Germany
*Corresponding author:
Abstract Genetic risk factors for autoimmune diseases are constantly discovered, however, environmental factors
are laggingbehind and the precipitating events leading to development of autoimmune diseases remain enigmatic.
Gluten is a well-established inducing nutrient in celiac disease and gluten withdrawal is the only current effective
therapy. More and more studies have shown that non-celiac autoimmune diseases can partially respond to gluten free
diet. The present editorial reviews those conditions and suggest multiple potential mechanisms that might operate in
clinical amelioration of non-celiac autoimmune diseases.
Keywords: gluten free diet, autoimmune disease, gluten, nutrition, mechanisms, autoimmunity
Cite This Article: Aaron Lerner, Ajay Ramesh, and Torsten Matthias, “Are Non-Celiac Autoimmune
Diseases Responsive to Gluten-Free Diet?International Journal of Celiac Disease, vol. 5, no. 4 (2017): 164-167.
doi: 10.12691/ijcd-5-4-6.
1. Introduction
It is well known that autoimmune diseases (ADs) have
two major causative background: genetic and environmental
[1,2,3]. Due to the fact that ADs incidence is markedly
increased in the Western countries in the last decades [4,5],
it is logical to assume that the surge is due to changing
environment, much more than genetic modifications or
adaptations. Taking into account that the worldwide wheat
consumption and gluten intake are likewise increasing, in
the last decades [6], it is tempting to speculate that a
positive association exist between the two and the surge of
ADs. There is no doubt that, at least for celiac disease
(CD), the increase in prevalence is tightly relayed to the
increased wheat consumption around the world [4,7].
Since CD is associated with multiple ADs, a question
arises does gluten consumption contribute to the surge in
the non-CD autoimmune conditions and if so, does gluten
withdrawal might as well benefit the autoimmune affected
In this regard, the case reported by the Iranian group on
the positive effect of gluten-free diet (GFD) in refractory
inflammatory bowel disease is very interesting [8] and
brings up the topic of GFD in non-CD autoimmune condition.
Rostami-Nejad et al. described a young male with
refractory left-sided ulcerative colitis with normal bulbar
and duodenal biopsies and CD associated serology. Upon
GFD, his symptoms disappeared and the colonic pathology
improved. It should be noted that other recent reports on
Crohn’s disease patients reported that GFD might be
beneficial in reducing gastrointestinal symptoms, disease
activity index and drug responsiveness [9,10,11]. The present
editorial will review the non-CD ADs that under certain
circumstances responded to GFD, and the potential mechanism
relaying gluten withdrawal to the improvement of
autoimmune diseases and their responsiveness.
2. GFD in none Classical Gluten
Dependent Autoimmune Conditions
The subject of GFD in other peripheral, non-enteric
ADs was reviewed in the past [12,13] and most recently
extensively described [14]. Interestingly, in a most recent
editorial on the subject of indications for GFD, those non-
CD, systemic ADs were not mentioned [15].
3. Potential Mechanisms of Gluten Free
Nutritional Therapy in Non-Enteric
Autoimmune Diseases
The list of all diseases in Table 1 is associated with CD
and GFD [39] and multiple autoantibodies that are
circulating in the patient’s blood circulation [40].
Suspicions about the benefit of GFD as a complementary
treatment, either as a causal factor in the pathogenesis, or
improvement of symptoms, was raised and reviewed lately
[41,42].The fact that GFD have protective effects on the
cumulative prevalence of additional autoimmune diseases
in CD patients [43,44], opens a window of opportunities
to explore the topic of gluten as a driver of autoimmunity
and the place of GFD in ADs dietary therapy.
Not less interesting are the potential pathways by which
gluten withdrawal might impact the initiation and the
progression of autoimmunity. Following are some of those
potential mechanisms.
International Journal of Celiac Disease 165
a. Shared genes. CD shares HLA and various non-HLA
genes with associated ADs [45,46,47,48].
b. Increases intestinal permeability and leaky gut
induction. Various processed food ingredients and additives
were proved or suspected to breach tight junction
functional integrity [6,39].Gluten is one of them [6,49,50].
WillGFD attenuate the leaky gut process?
c. Microbiome/dysbiome imbalance. The dysbiotic
repertoire related to animal models of specific ADs was
recently summarized [3], and multiple publications exist
on the dysbiosis in CD and other human ADs [39,51].
Gluten affects microbiome composition and diversity as
shown in animal models and on humans [14,39]. Can
gluten drive systemic autoimmunity through its effects on
the human microbiome?
d. Pro-inflammatory and potentially auto immunogenic
effects. Gluten is immunogenic, cytotoxic, pro-inflammatory
and activates several immune pathways (including IL-17). It
increases apoptosis, suppresses cell viability and differentiation,
induces oxidative stress and affects epigenetic behavior [14].
e. Increased amount, toxicity and immunogenicity.
Contemporary gluten has evolved tremendously since its
discovery in the Fertile Crescent around 15000 years ago
[2]. The wheat gluten content increased about 8 folds, its
worldwide consumption expanded, its toxicity and
immunogenicity rose and created a geoepidemiology. This
dynamics paralleled the increased incidence of CD and
other ADs [2,4,5,52,53]
f. Intestinal post translational modification of protein
(PTMP) represents a key regulator in autoimmunity, by
transforming naïve/self or non-self-peptides to auto
immunogenic ones. [3,39,54]. Gluten is an ideal substrate
for enzymatic PTMP, tissue and microbial transglutaminases
being typical examples [3,54,55,56].
g. Tissue and microbial transglutaminases are
extensively distributed in the human body and intestinal
lumen, respectively [39,54,57]. Human transglutaminase
plays a role in end organ affected ADs. Autoimmune
thyroiditis, rheumatoid arthritis, IgA nephropathy,
dermatitis herpetiformis and gluten ataxia are some of the
examples [58-63]. On the other hand, gluten/gliadin
peptides are internalized systemically and are secreted in
the human urine [64,65], or appear in the mice pancreas
following oral administration [66]. One wonders if in the
absence of gluten, no immunogenic or neo-epitopes’
complexes will be available to drive autoimmunity.
h. HLA-DQ2/8-restricted gluten specific T cells have
been observed to migrate from the intestinal lamina
propria into peripheral blood upon gluten challenge,
representing an additional mechanism for extraintestinal
manifestations in CD, or potentially reaching peripheral
organs in other ADs and thus, ameliorated on GFD [67].
Table 1. Summarizes the peripheral/systemic AD sthat were described to partially respond to GFD
Disease type
Improved Parameter
Rheumatoid arthritis
Clinical and joint ultrasound improvement
Atheroprotective and anti-inflammatory
Type 1 diabetes mellitus
Preserve beta cell function
Improve insulin secretion
Lower HbA1c
Improved quality of life
Autoimmune thyroiditis
Normalization of subclinical hypothyroidism
Decrease in anti-thyroid autoantibodies
Autoimmune hepatitis
Treatment-free sustained remission
Multiple sclerosis Clinical improvement [28,29,30]
Clinical and severity indeximprovement,
Decrease the expression of CD associated antibodies
Clinical, pathological and disease activity improvement
Non-celiac autoimmune diseases that partially respond to GFD. Adapted from ref [12,13,14].
4. Conclusions
We are far away from unraveling the mechanisms by
which GFD can alleviate non-celiac ADs initiation or
progression and there are more questions than answers on
this very challenging topic.
[1] Lerner A, Blank M, Shoenfeld Y. Celiac disease and
autoimmunity.Isr J Med Sci 1996; 32: 33-36.
[2] Lerner A. The last two millennias eco-catastrophes are the driving
forces for the potential genetic advantage mechanisms in celiac
disease. Med Hypotheses. 2011; 77: 773-6.
[3] Lerner A, Aminov R, Matthias T. Dysbiosis may trigger
autoimmune diseases via inappropriate posttranslational
modification of host proteins. Front in Microbiol.2016; 7: 84.
[4] Lerner A, Jermias P, Matthias T. The world incidence of celiac
disease is increasing: a review. Internat. J. Of Recent Scient. Res.
2015; 7: 5491-5496.
[5] Lerner A, Jeremias P, Matthias T. The world incidence and
prevalence of autoimmune diseases is increasing: A review.
Internat J Celiac Disease. 2015; 3: 151-155.
[6] Lerner A, Matthias T. Changes in intestinal tight junction permeability
associated with industrial food additives explain the rising incidence
of autoimmune disease. Autoimmun Rev. 2015; 14: 479-89.
[7] Catassi C, Gatti S, Lionetti E. World perspective and celiac
disease epidemiology. Dig Dis. 2015; 33: 141-6.
[8] Rostami-Nejad M, Sadeghi A, Asadzadeh-Aghdaei H, Rismantab
S, Reza Zali M. Gluten-free Diet for Refractory Inflammatory
Bowel Disease; A Case Report. Internatiol J of Celiac Dis. 2017, 5:
[9] Catassi C, Elli L, Bonaz B, Bouma G, Carroccio A, Castillejo G,
et al. Diagnosis of Non-CeliacGluten Sensitivity (NCGS): The
Salerno Experts' Criteria. Nutrients. 2015; 7: 4966-77.
[10] Aziz I, Pearson K, Priest J, Sanders D. A Study Evaluating the
Bidirectional Relationship Between Inflammatory Bowel Disease
and Self-reported Non-celiac Gluten Sensitivity. Inflamm Bowel
Dis 2015; 21: 847-53.
[11] Hans H ,Christopher F, Robert S, Michael D, Millie D. Prevalence
of a Gluten-free Diet and Improvement of Clinical Symptoms in
Patients with Inflammatory Bowel Diseases. Inflamm Bowel Dis
2014; 20: 1194-7.
166 International Journal of Celiac Disease
[12] San Mauro Martín I, Garicano Vilar E, Collado Yurrutia L,
Ciudad Cabañas MJ. [Is gluten the great etiopathogenic agent of
disease in the XXI century?]. Nutricion Hospitalaria. 2014; 30:
[13] El-Chammas K, Danner E. Gluten-free diet in nonceliac disease.
Nutr in Clin Pract 2011; 26: 294-9.
[14] Lerner A, Shoenfeld Y, Matthias T. Gluten; essential for wheat
survival but detrimental to human health. Nutr Rev. In press. 2017.
[15] Rostami K, Bold J, Parr A, Johnson MW. Gluten-Free Diet
Indications, Safety, Quality, Labels, and Challenges. Nutrients.
2017 Aug 8; 9(8). pii: E846.
[16] Hafström I, Ringertz B, Spångberg A, von Zweigbergk L,
Brannemark S, Nylander I, Rönnelid J, Laasonen L, Klareskog L.
A vegan diet free of gluten improves the signs and symptoms of
rheumatoid arthritis: the effects on arthritis correlate with a
reduction in antibodies to food antigens. Rheumatol (Oxford) 2001;
40: 1175-9.
[17] Iagnocco A, Ceccarelli F, Mennini M, Rutigliano IM, Perricone C,
Nenna R, et al. Subclinical synovitis detected by ultrasound in
children affected by coeliac disease: a frequent manifestation
improved by a gluten-free diet. Clin Exp Rheumatol. 2014; 32:
[18] Elkan AC, Sjöberg B, Kolsrud B, Ringertz B, Hafström I,
Frostegård J. Gluten-free vegan diet induces decreased LDL and
oxidized LDL levels and raised atheroprotective natural antibodies
against phosphorylcholine in patients with rheumatoid arthritis: a
randomized study. Arthr Res and Ther 2008; 10: R34-41.
[19] Antvorskov JC, Josefsen K, Engkilde K, Funda DP, Buschard K.
Dietary gluten and the development of type 1 diabetes.
Diabetologia. 2014; 57: 1770-80.
[20] Pastore MR, Bazzigaluppi E, Belloni C, Arcovio C, Bonifacio E,
Bosi E. Six months of gluten-free diet do not influence
autoantibody titers, but improve insulin secretion in subjects at
high risk for type 1 diabetes. J of Clin Endocrinol and Metabol
2003; 88: 162-5.
[21] Svensson J, Sildorf SM, Pipper CB, Kyvsgaard JN, Bøjstrup J,
Pociot FM, et al.Potential beneficial effects of a gluten-free diet in
newly diagnosed children with type 1 diabetes: a pilot
study.Springerplus. 2016; 5: 994.
[22] Pham-Short A, Donaghue KC, Ambler G, Garnett S, Craig ME.
Quality of Life in Type 1 Diabetes and Celiac Disease: Role of the
Gluten-Free Diet. J Pediatr. 2016; 179: 131-138. e1.
[23] Sategna-Guidetti C, Volta U, Ciacci C, Usai P, Carlino A, De
Franceschi L, Camera A, Pelli A, Brossa C. Prevalence of thyroid
disorders in untreated adult celiac disease patients and effect of
gluten withdrawal: an Italian multicenter study. Amer J of
Gastroenterol 2001; 96: 751-7.
[24] Toscano V, Conti FG, Anastasi E, Mariani P, Tiberti C, Poggi M,
Montuori M, Monti S, Laureti S, Cipolletta E, et al. Importance of
gluten in the induction of endocrine autoantibodies and organ
dysfunction in adolescent celiac patients. Amer J of Gastroenterol
2000; 95: 1742-8.
[25] Nastasio S, Sciveres M, Riva S, Filippeschi IP, Vajro P, Maggiore
G. Celiac disease-associated autoimmune hepatitis in childhood:
long-term response to treatment. J of Pediatr Gastroenterol and
Nutr 2013; 56: 671-4.
[26] Colecchia A, Di Biase AR, Scaioli E, Festi D. Coeliac disease and
autoimmune hepatitis: Gluten-free diet can influence liver disease
outcome. Digest Liv Dis 2011; 43: 247-9.
[27] Iqbal U, Chaudhary A, Karim MA, Siddiqui MA, Anwar H,
Merrell N. Association of Autoimmune Hepatitis and Celiac
Disease: Role of Gluten-Free Diet in Reversing Liver Dysfunction.
J Investig Med High Impact Case Rep. 2017; 5:
[28] Rodrigo L, Hernández-Lahoz C, Fuentes D, Alvarez N, López-
Vázquez A, González S. Prevalence of celiac disease in multiple
sclerosis. BMC Neurol2011; 11: 31-7.
[29] Finsterer J, Leutmezer F. Celiac disease with cerebral and
peripheral nerve involvement mimicking multiple sclerosis. J of
Med Life. 2014; 7: 440-4.
[30] von Geldern G, Mowry EM. The influence of nutritional factors
on the prognosis of multiple sclerosis. Nat Rev Neurol 2012; 8:
[31] Michaëlsson G, Gerdén B, Hagforsen E, Nilsson B, Pihl-Lundin I,
Kraaz W, Hjelmquist G, Lööf L. Psoriasis patients with antibodies
to gliadin can be improved by a gluten-free diet. Brit J of
Dermatol 2000; 142: 44-51.
[32] Addolorato G, Parente A, de Lorenzi G, D’angelo Di Paola ME,
Abenavoli L, Leggio L, Capristo E, De Simone C, Rotoli M,
Rapaccini GL, et al. Rapid regression of psoriasis in a coeliac
patient after gluten-free diet. A case report and review of the
literature. Digest 2003; 68: 9-12.
[33] Frikha F, Snoussi M, Bahloul Z. Osteomalacia associated with
cutaneous psoriasis as the presenting feature of coeliac disease: a
case report. Pan Afr Med J 2012; 11: 58.
[34] De Boer WA, Tytgat GN. A patient with osteomalacia as single
presenting symptom of gluten-sensitive enteropathy. J of Intern
Med 1992; 232: 81-5.
[35] Afifi L, Danesh MJ, Lee KM, Beroukhim K, Farahnik B, Ahn RS,
et al. Dietary Behaviors in Psoriasis: Patient-Reported Outcomes from
a U.S. National Survey. Dermatol Ther (Heidelb). 2017; 7: 227-242.
[36] Michaëlsson G, Ahs S, Hammarström I, Lundin IP, Hagforsen E.
Gluten-free diet in psoriasis patients with antibodies to gliadin
results in decreased expression of tissue transglutaminase and
fewer Ki67+ cells in the dermis. Acta Dermato- Venereologica.
2003; 83: 425-9.
[37] D'Erme AM, Kovacikova Curkova A, Agnoletti AF, Milanesi N,
Simonacci F et al. Gluten-free diet as a therapeutic approach in
psoriatic patients: if yes, when. G Ital Dermatol Venereol. 2015;
150: 317-20.
[38] Khandalavala BN, Nirmalraj MC. Rapid partial repigmentation of
vitiligo in a young female adult with a gluten-free diet. Case Rep
Dermatol. 2014; 6: 283-7.
[39] Lerner A, Matthias T. Extraintestinal manifestations of CD:
Common pathways in the gut-remote organs’ axes. Internat J
Celiac Dis. 2017; 5: 24-27.
[40] Shaoul R. Lerner A. Associated autoantibodies in celiac disease.
Autoimmun. Rev. 2007; 6: 559-565.
[41] San Mauro Martín I, Garicano Vilar E, Collado Yurrutia L,
Ciudad Cabañas MJ. [Is gluten the great etiopathogenic agent of
disease in the XXI century?]. Nutricion Hospitalaria. 2014; 30:
[42] El-Chammas K, Danner E. Gluten-free diet in nonceliac disease.
Nutr in Clin Pract 2011; 26: 294-9.
[43] Cosnes J, Cellier C, Viola S, Colombel JF, Michaud L, Sarles J,
Hugot JP, Ginies JL, Dabadie A, Mouterde O, et al. Incidence of
autoimmune diseases in celiac disease: protective effect of the
gluten-free diet. Clin Gastroenterol and Hepatol 2008; 6: 753-8.
[44] Ferretti G, Bacchetti T, Masciangelo S, Saturni L. Celiac disease,
inflammation and oxidative damage: a nutrigenetic approach.
Nutrients 2012; 4: 243-57.
[45] Richard-Miceli C, Criswell LA. Emerging patterns of genetic
overlap across autoimmune disorders. Genome Med 2014; 4: 6-14.
[46] Gutierrez-Achury J, Coutinho de Almeida R, Wijmenga C. Shared
genetics in coeliac disease and other immune-mediated diseases. J
of Internl Med 2011; 269: 591-603.
[47] Fortune MD, Guo H, Burren O, Schofield E, Walker NM, Ban M,
Sawcer SJ, Bowes J, Worthington J, Barton A, et al. Statistical
colocalization of genetic risk variants for related autoimmune
diseases in the context of common controls. Nat Genet 2015; 47:
[48] Lundin KE, Wijmenga C. Coeliac disease and autoimmune
disease-genetic overlap and screening.Nat Rev Gastroenterol
Hepatol. 2015; 12: 507-15.
[49] Fasano A. Leaky gut and autoimmune diseases. Clin Rev Allergy
Immunol. 2012; 42: 71-78.
[50] Hollon J, Puppa EL, Greenwald B, Goldberg E, Guerrerio A,
Fasano A. Effect of gliadin on permeability of intestinal biopsy
explants from celiac disease patients and patients with non-celiac
gluten sensitivity. Nutrients. 2015; 7: 1565-1576.
[51] Wu,HJ, Wu,E. The role of gut microbiota in immune homeostasis
and autoimmunity. Gut Microbes. 2012; 3, 4-14.
[52] Manzel A, Muller DN, Hafler DA, Erdman SE, Linker RA, et al.
Role of "Western diet" in inflammatory autoimmune diseases.
Curr Allergy Asthma Rep 2014; 14: 404.
[53] Selmi C, Tsuneyama K. Nutrition, geoepidemiology, and
autoimmunity. Autoimmun Rev. 2010; 9: A267-270.
[54] Lerner A, Aminov R, Matthias T. Intestinal dysbiotic
transglutaminases are potential environmental drivers of systemic
autoimmunogenesis. Frontiers in Microbiology, 2017; 8; article 66.
[55] Lerner A, Matthias T. Possible association between celiac disease
and bacterial transglutaminase in food processing: a hypothesis.
Nutr Rev. 2015; 73: 544-552.
International Journal of Celiac Disease 167
[56] Matthias T, Jeremias P, Neidhöfer S, Lerner A. The industrial
food additive microbial transglutaminase, mimics the tissue
transglutaminase and is immunogenic in celiac disease patients.
Autoimmun Rev, 2016; 15: 1111-1119.
[57] Lerner A, Neidhöfer S, Matthias T. Transglutaminase 2 and anti
transglutaminase 2 autoantibodies in celiac disease and beyond:
Part A: TG2 double-edged sword: gut and extraintestinal
involvement. Immunome Research, 2015; 11: 101-105.
[58] Lerner A, Jeremias P, Matthias T. The gut-thyroid axis and celiac
disease. Endocrinol Cennections, 2017: 6: R52-R58.
[59] Lerner A, Matthias T. Rheumatoid arthritis-celiac disease
relationship: joints get that gut feeling. Autoimm Rev. 2015: 14:
[60] Lerner A, Neidhöfer S, Matthias T. Beyond the joint: what’s
happening in the gut. Internat J Celiac Dis. 2016; 4: 127-129.
[61] Lerner A, Berthelot L, Jeremias P, Abbad L, Matthias T, Monteiro
RC.. Gut-kidney axis: gluten, transglutaminase, celiac disease and
IgA nephropathy JCCI, 2017; 8: 499-503.
[62] Reunala T, Salmi TT, Hervonen K. Dermatitis herpetiformis:
pathognomonic transglutaminase IgA deposits in the skin and
excellent prognosis on a gluten-free diet. Acta Derm Venereol.
2015; 95: 917-22.
[63] Hadjivassiliou M, Mäki M, Sanders DS, Williamson CA,
Grünewald RA, Woodroofe NM, Korponay-Szabó IR.
Autoantibody targeting of brain and intestinal transglutaminase in
gluten ataxia. Neurology. 2006; 66: 373-7.
[64] Moreno ML, Cebolla Á, Muñoz-Suano A, Carrillo-Carrion C,
Comino I, Pizarro Á, et al. Detection of gluten immunogenic
peptides in the urine of patients with coeliac disease reveals
transgressions in the gluten-free diet and incomplete mucosal
healing. Gut. 2017; 66: 250-257.
[65] Moreno ML, Rodríguez-Herrera A, Sousa C, Comino
I.Biomarkers to Monitor Gluten-Free Diet Compliance in Celiac
Patients.Nutrients. 2017 Jan 6; 9(1). pii: E46.
[66] Bruun SW, Josefsen K, Tanassi JT, Marek A, Pedersen MH,
Sidenius U, et al. Large Gliadin Peptides Detected in the Pancreas
of NOD and Healthy Mice following Oral Administration. J
Diabetes Res. 2016; 2016: 2424306.
[67] Ráki M, Fallang LE, Brottveit M, Bergseng E, Quarsten H, Lundin
KE, Sollid LM. Tetramer visualization of gut-homing gluten-
specific T cells in the peripheral blood of celiac disease patients.
Proc Natl Acad Sci U S A. 2007; 104: 2831-6.
... 19 Above all, gluten increases intestinal permeability, compromising tight junction functional integrity, and thus increases leakage from the gut. [11][12][13]18,20 The detrimental effects of gluten might exacerbate non-gluten-dependent autoimmune diseases Several observations relating gluten intake to human diseases have prompted the current study: a surge in CD prevalence has been in parallel with worldwide augmentation of gluten intake 2,21 ; partial improvement in the extraintestinal manifestations of CD has been documented in patients on a GFD 22 ; there are hints that non-celiac conditions might be ameliorated on a GFD 18,23 ; and potential side effects from gluten consumption have been identified. 18 The objectives of the present study were: (1) to systematically review the use and performance of a GFD in multiple classical non-gluten-dependent ADs, (2) to discuss the impacts of a GFD on luminal events, and (3) to summarize potential mechanisms and pathways in the gut -remote organs axis. ...
... Its consumption augments oxidative stress; affects epigenetic phenomena; is immunogenic, pro-inflammatory, and cytotoxic; activates the IL-17 pathways; induces apoptosis; and (finally) suppresses cell viability and differentiation. 18,23 It is a prime substrate for human and microbial transglutaminases, thus increasing its immunogenicity. 8,9,[11][12][13]18,22,23 Notably, gluten is not only an offending molecule in gluten-dependent diseases; recently, it was suggested that it impacts other ADs and neurodegenerative conditions as well. ...
... 18,23 It is a prime substrate for human and microbial transglutaminases, thus increasing its immunogenicity. 8,9,[11][12][13]18,22,23 Notably, gluten is not only an offending molecule in gluten-dependent diseases; recently, it was suggested that it impacts other ADs and neurodegenerative conditions as well. [114][115][116][117][118] Based on the above, what might be the beneficial effects of gluten withdrawal on human enteric ecoevents? ...
Full-text available
Context: A gluten-free diet (GFD) is the recommended treatment for gluten-dependent disease. In addition, gluten withdrawal is popular and occasionally is suggested as a treatment for other autoimmune diseases (ADs). Objective: The current systematic review summarizes those entities and discusses the logic behind using a GFD in classical non-gluten-dependentADs. Data sources: A search for medical articles in PubMed/MEDLINE, Web of Sciences, LILACS, and Scielo published between 1960 and 2020 was conducted, using the key words for various ADs and GFDs. Data exxtraction: Eight-three articles were included in the systematic review (using PRISMA guidelines). Data analysis: Reduction in symptoms of ADs after observance of a GFD was observed in 911 out of 1408 patients (64.7%) and in 66 out of the 83 selected studies (79.5%). The age of the patients ranged from 9 months to 69 years. The duration of the GFD varied from 1 month to 9 years. A GFD can suppress several harmful intraluminal intestinal events. Potential mechanisms and pathways for the action of GFD in the gut - remote organs' axis have been suggested. Conclusion: A GFD might represent a novel nutritional therapeutic strategy for classical non-gluten-dependent autoimmune conditions.
... It affects adaptive and innate immune systems and T reg cells functions [45]. However, a word of caution is advised since most of those side effects were describe in vitro and on animal models and there are not enough studies performed in human [45].There are no defined recommendations to start gluten-free diet (GFD) in nonceliac gluten dependent disease, nor in other autoimmune diseases or neurodegenerative condition, unless gluten related diseases are associated and properly diagnosed [45,52,53]. On the other hand, before implementing gluten withdrawal, one has to consider the difficulties in compliance and the various gluten free-diet side effects [54,55]. ...
... Gluten is the offending nutrient in various gluten-dependent diseases like CD, dermatitis herpetiformis, gluten ataxia, gluten allergy and potentially in non-celiac sensitive conditions [13,14,45]. Despite being the major protein in wheat-the most frequently consumed staple food, it has some harmful effects on human health [13,45,52,53]. It plays a role in the extraintestinal manifestation of CD [16], including in brain pathologies [16][17][18]20,21,[24][25][26], hence its involvement in neurodegenerative conditions has just started to be explored. ...
... Various functional food supplements, recently summarized by Chander et al., 2018, might decrease gluten exposure. Nutraceuticals are beneficial for PD and AD [93,94,124] and can potentially prevent or treat intestinal barrier dysfunctions and decrease intestinal permeability, thus counteracting the gluten effects on the tight junction functional integrity [12,13,16,45,52,53]. Since tTG and microbial TG can turn naïve gluten peptide to immunogenic molecules [38,39], their specific inhibitors might decrease the cross-linked gluten peptide load on the brain [62,125]. ...
Full-text available
Wheat is a most favored staple food worldwide and its major protein is gluten. It is involved in several gluten dependent diseases and lately was suggested to play a role in non-celiac autoimmune diseases. Its involvement in neurodegenerative conditions was recently suggested but no cause-and-effect relationship were established. The present narrative review expands on various aspects of the gluten-gut-brain axes events, mechanisms and pathways that connect wheat and gluten consumption to neurodegenerative disease. Gluten induced dysbiosis, increased intestinal permeabillity, enteric and systemic side effects, cross-reactive antibodies, and the sequence of homologies between brain antigens and gluten are highlighted. This combination may suggest molecular mimicry, alluding to some autoimmune aspects between gluten and neurodegenerative disease. The proverb of Hippocrates coined in 400 BC, “let food be thy medicine,” is critically discussed in the frame of gluten and potential neurodegeneration evolvement.
... 1. Gluten withdrawal might be beneficial in non-classical gluten-dependent conditions Presently, the well described gluten-affected ADs like celiac, dermatitis herpetiformis, and gluten ataxia will not be discussed. Most recently, literature was summarized showing that, under certain circumstances, autoimmune thyroiditis, autoimmune Hepatitis, multiple sclerosis, psoriasis, rheumatoid arthritis, type 1 diabetes, inflammatory bowel diseases, and vitiligo can partially respond to GFD [3,7]. Intriguingly, a screen of Medline for GFD and 150 autoimmune conditions, as listed by the American autoimmune-related diseases association, Inc. ...
... The following celiac-associated autoimmune conditions were described to improve their accompanied condition's clinical picture or disease activity under GFD: Noteworthy are the isolated autoimmune conditions where GFD was described to benefit the patients: IgA nephropathy, painful endometriosis, and the eight ADs described above [3,7]. ...
... Several potential mechanisms can be envisioned for the beneficial place of the nutritional therapy, applying GFD in those non-celiac, celiac-associated Ads, or extra-intestinal manifestation of celiac disease [3][4][5]7,10]. Starting from the vast genetic background shared by many of those ADs, going through the evolutionary changes of the wheat with its increased gluten content and gluten itself become more immunogenic and toxic. The multiple systemic and cellular side effects of gluten described above and its intestinal permeability effect resulting in break of the functional integrity of the tight junction might represent additional autoimmune inducing mechanisms. ...
... Although tTG is considered a biomarker and an accurate serology indicator of total villous atrophy CD, its role is not limited to CD. In fact, it has a role in numerous human diseases (Table 4) and manifests with a broad spectrum of symptoms (Table 5) [17,25,29,30,31,153,155,156]. Studies suggest a role for infectious agents in the production of tTG2 antibodies. ...
... tTG2 is expressed in multiple cell types, in both intracellular and extracellular compartments [155,156,17,158]. It is involved in a variety of cellular processes, including adhesion, migration, growth, survival, apoptosis, differentiation, exocytosis, wound healing, angiogenesis, autophagy, cyto-protection and extracellular matrix organization [158,159]. ...
Full-text available
A 16-year-old boy with nonresponsive celiac disease (NRCD), dermatitis herpetiformis, short stature, and failure to thrive, presented to this Functional Medicine practitioner because he had exceedingly high tissue transglutaminase (tTG) antibodies and poor growth, despite 10 months on a meticulous gluten-free diet (GFD). Immunological testing showed elevated antibody production against multiple peptides of wheat, food antigens, intestinal barrier dysfunction, lipopolysaccharide (LPS) antibodies, and polyreactive autoimmune reactions. An elimination diet, nutraceutical protocols to modulate the microbiome, address intestinal permeability, lower inflammation, and remove underlying bacterial infection were initiated. Global anti-inflammatory lifestyle modifications were recommended. Within 3 months of treatment, the patient’s tTG antibodies decreased by 14% for the first time since strict gluten elimination. Within 15 months, tTG IgG antibodies were nearly normal at 1.61 (0.03-1.60, ELISA Index). Test results improved dramatically in tandem with clinical progress. On a GFD and after initiating and maintaining these dietary and lifestyle changes, he gained 12 inches and 40 pounds. To our knowledge, this is the first published case of complete reversal of NRCD and failure to thrive by addressing endotoxin and lifestyle outside of a GFD.
... The question, whether primary biliary cirrhosis in RA is a cause, consequence, or coincidence, is still open [23]. A very interesting subject is the response of RA patients to gluten elimination [19,24,25]. It appears that a subset of RA patients, mainly those positive to anti gliadin antibodies or other CD associated antibodies, might benefit from a gluten free diet. ...
... Being a universal food additive for multiple food processed industries, not only for the bakeries [68], gluten might affect non-celiac ADs. In fact, some of RA patients, mainly those with anti-gliadin/gluten antibodies, can benefit from gluten withdrawal [19,24,25,69,70]. The response of the CD rheumatological manifestations to gluten elimination reinforce the additional mechanism of articular pathology in CD that might benefit gluten-free diet. ...
... Moreover, another important question that is yet to be answered is about the role of gluten-free diet in non-CD, SS patients. Several papers have reported benefits of the gluten free diet in various non-celiac autoimmune diseases, but results remain controversial [58,59] . Considering all the drawbacks of a gluten-free diet in the absence of gluten-intolerance, the role of gluten-free diet in SS remains to be studied and cannot be recommended yet on the basis of current evidence. ...
Full-text available
Background: Celiac disease (CD) is a systemic, chronic immune-mediated disease triggered by gluten ingestion in genetically-susceptible individuals, with a prevalence of 1% worldwide. Sjogren's syndrome (SS) is also a systemic autoimmune disease, mainly characterized by ocular and oral sicca symptoms and signs. Sharing a common genetic background, CD and SS are known associated autoimmune diseases, but currently available guidelines are not reporting it. Case summary: We report the case of a 39-year-old woman, who was in the care of her rheumatologist for 2 years with SS. On routine follow-up she was found to have iron deficiency, without anemia. She had no gastrointestinal complaints and denied any obvious source of blood loss. IgA tissue transglutaminase antibodies were positive and endoscopy with duodenal biopsies revealed crypt hyperplasia and villous atrophy. A diagnosis of CD was set and gluten-free diet was recommended. Conclusion: We present a review of existing data in the literature regarding the association of the two diseases, summarizing prevalence studies of CD in SS patients and the other way around. Screening recommendations and future research perspectives are also discussed, highlighting clinically relevant unanswered questions with respect to the association of CD with SS.
... An attentive reader may find information in the literature that certain genetic factors associated with celiac disease are also common in other diseases. Thus, a gluten-free diet may be helpful in these cases (42). Often, the literature mentions the positive impact of this diet on health. ...
Full-text available
A gluten-free diet is a special type of diet intended for people with gluten intolerance. The introduction of targeted screening into the practice has improved celiac diagnosis, with an increase of newly diagnosed patients who have remained life-long dependents on a gluten-free diet. On the other hand, the gluten-free diet has also been voluntarily adopted by people with other diagnoses, or even healthy individuals. It is expected that in the future, the gluten-free diet’s consumption is set to increase, due to its increased popularity with these populations. In this situation, gluten-free diets have been misinterpreted as a "miracle drug" that is effective on a variety of problems. Here we report on the past and present production and supply of gluten-free products and ultimately about their future position. The medical community will also be confronted with the future problems of people who are dependent on a gluten-free diet and, on the contrary, with the complications arising with the consumers of a gluten-free diet without medical reasons. Compliance to the principles of a gluten-free diet should be maintained, and should not be recommended to healthy persons or persons without relevant reasons.
Full-text available
Microbial transglutaminase (mTG) is a bacterial survival factor, frequently used as a food additive to glue processed nutrients. As a result, new immunogenic epitopes are generated that might drive autoimmunity. Presently, its contribution to autoimmunity through epitope similarity and cross-reactivity was investigated. Emboss Matcher was used to perform sequence alignment between mTG and various antigens implicated in many autoimmune diseases. Monoclonal and polyclonal antibodies made specifically against mTG were applied to 77 different human tissue antigens using ELISA. Six antigens were detected to share significant homology with mTG immunogenic sequences, representing major targets of common autoimmune conditions. Polyclonal antibody to mTG reacted significantly with 17 out of 77 tissue antigens. This reaction was most pronounced with mitochondrial M2, ANA, and extractable nuclear antigens. The results indicate that sequence similarity and cross-reactivity between mTG and various tissue antigens are possible, supporting the relationship between mTG and the development of autoimmune disorders. 150W
Full-text available
Introduction: Parkinson's disease is characterized by non-motor/motor dysfunction midbrain neuronal death and α-synuclein deposits. The accepted hypothesis is that unknown environmental factors induce α-synuclein accumulation in the brain via the enteric nervous system. Material and methods: Monoclonal antibodies made against recombinant α-synuclein protein or α-synuclein epitope 118-123 were applied to the antigens of 180 frequently consumed food products. The specificity of those antibody-antigen reactions was confirmed by serial dilution and inhibition studies. The Basic Local Alignment Search Tool sequence matching program was used for sequence homologies. Results: While the antibody made against recombinant α-synuclein reacted significantly with 86/180 specific food antigens, the antibody made against α-synuclein epitope 118-123 reacted with only 32/180 tested food antigens. The food proteins with the greatest number of peptides that matched with α-synuclein were yeast, soybean, latex hevein, wheat germ agglutinin, potato, peanut, bean agglutinin, pea lectin, shrimp, bromelain, and lentil lectin. Conclusions: The cross-reactivity and sequence homology between α-synuclein and frequently consumed foods, reinforces the autoimmune aspect of Parkinson's disease. It is hypothesized that luminal food peptides that share cross-reactive epitopes with human α-synuclein and have molecular similarity with brain antigens are involved in the synucleinopathy. The findings deserve further confirmation by extensive research.
Parkinson’s disease is characterized by nonmotor/motor dysfunction, midbrain dopaminergic neuronal death, and α-synuclein (aSN) deposits. The current hypothesis is that aSN accumulates in the enteric nervous system to reach the brain. However, invertebrate, vertebrate, and nutritional sources of aSN reach the luminal compartment. Submitted to local amyloidogenic forces, the oligomerized proteins’ cargo can be sensed and sampled by a specialized mucosal cell to be transmitted to the adjacent enteric nervous system, starting their upward journey to the brain. The present narrative review extends the current mucosal origin of Parkinson’s disease, presenting the possibility that the disease starts in the intestinal lumen. If substantiated, eliminating the nutritional sources of aSN (eg, applying a vegetarian diet) might revolutionize the currently used dopaminergic pharmacologic therapy.
Full-text available
Some factors include environmental triggers have role in development of intestinal inflammation in inflammatory bowel disease (IBD). A number of patients with IBD, experience improvement in their gastrointestinal symptoms and disease course when avoiding gluten. To highlight this issue we present a 28years old male patient, known case of ulcerative colitis, was admitted to the hospital for a flare-up of his disease. He presented with bloody diarrhea despite the fact that he was on long term variable dose of oral and topical Asacol since 4 years ago and azathioprine 2.5mg/kg/day prescribed for his persistent symptoms since last year. In spite of drug adherence, he experienced 3 flare-ups during past year and refused receiving prednisolone. Colonoscopy demonstrated severe erythema, multiple erosions and friability through the left colon from rectum up to splenic flexure. Histopathological evaluation revealed crypt architecture distortion with moderate increase in lymphoplasmacytic infiltration as well as neutrophilic activity in the form of cryptitis and crypt abscess formation. Upper GI endoscopy followed by duodenal biopsies and serological evaluation were negative for celiac disease. Before considering anti-TNF agents, patient underwent a gluten-free diet (GFD) and with a positive response, it continued for 6 weeks. After 6 weeks GFD his bloody diarrhea was nearly resolved and 12 weeks later most of his symptoms disappeared and entered to the full clinical remission. He stopped the diet and 12 weeks later his symptoms returned and experienced another relapse that again improved on GFD. As an environmental factor, gluten represents a strong antigen that might be implicated in the pathogenesis of at least a number of patients with IBD. Dietary restriction of gluten might be useful in some IBD patients during the exacerbation of their disease.
Full-text available
A gluten-free diet (GFD) is the safest treatment modality in patient with coeliac disease (CD) and other gluten-related disorders. Contamination and diet compliance are important factors behind persistent symptoms in patients with gluten related-disorders, in particular CD. How much gluten can be tolerated, how safe are the current gluten-free (GF) products, what are the benefits and side effects of GFD? Recent studies published in Nutrients on gluten-free products’ quality, availability, safety, as well as challenges related to a GFD are discussed.
Full-text available
Introduction: Psoriasis patients demonstrate high interest in the role of diet on their skin condition. However, data are lacking to describe dietary interventions among psoriasis patients and associated outcomes. This study aims to identify common dietary habits, interventions and perceptions among patients with psoriasis, and to examine patient-reported skin outcomes in response to these interventions. Methods: We administered a 61-question survey to the National Psoriasis Foundation membership asking psoriasis patients about dietary habits, modifications, skin responses, and perceptions. Results: A total of 1206 psoriasis patients responded to the survey. Compared to age- and sex-matched controls, psoriasis patients consumed significantly less sugar, whole grain fiber, dairy, and calcium (p < 0.001), while consuming more fruits, vegetables, and legumes (p < 0.01). Eighty-six percent of respondents reported use of a dietary modification. The percentage of patients reporting skin improvement was greatest after reducing alcohol (53.8%), gluten (53.4%), nightshades (52.1%), and after adding fish oil/omega-3 (44.6%), vegetables (42.5%), and oral vitamin D (41%). Specific diets with the most patients reporting a favorable skin response were Pagano (72.2%), vegan (70%), and Paleolithic (68.9%). Additionally, 41.8% of psoriasis respondents reported that a motivation for attempting dietary changes was to improve overall health. Conclusion: This national survey is among the first to report the dietary behaviors of patients with psoriasis. The data provided from this large cohort may benefit patients and clinicians as they discuss the role of diet in managing both psoriasis and associated cardiometabolic comorbidities.
Full-text available
Both, celiac disease and IgA nephropathy are autoimmune diseases that are IgA mediated and share multiple clinical, pathophysiological, genetic, nutritional and immunological aspects. In view of recent observations and wider understanding of the central role played by the intestinal ecosystem in celiac disease and IgA nephropathy development, the present review highlights those shared aspects, concentrating on potential nutritional therapeutic strategies in IgA nephropathy.
Full-text available
Autoimmune hepatitis (AIH) is a chronic inflammation of liver with unclear etiology. It is frequently associated other autoimmune diseases, and its association with celiac disease (CD) is well established. In this article, we describe the case of a 50-year-old male with long-standing AIH taking azathioprine for 10 years, evaluated for flares in transaminases. Despite adding high-dose corticosteroids, his transaminases and bilirubin remained high. Serology for CD was ordered, which revealed elevated tissue transglutaminase antibody IgG and endomysial IgA, which was further confirmed by endoscopic biopsy. Strict gluten-free diet was advised and now for over 2 years he is in remission with azathioprine and budesonide. This emphasizes the role of gluten-free diet in reversing liver dysfunction in patients with AIH, and clinicians should consider screening for CD in patients with AIH with persistent elevation of liver enzymes despite immunosuppressant treatment.
Full-text available
Autoimmune thyroiditis has an increased prevalence in patients with celiac disease and vice versa. The objective of the current review is to highlight the epidemiological, clinical, serological, pathological, pathophysiological, hormonal, genetic and immunological factors shared between the two entities. They might represent the two ends of the gut-thyroid axis where the cross-talks' pathways are still unrivalled. New observations are reviewed, highlighting some gut- thyroid interrelated pathways that potentially might lead to new therapeutic strategies.
Full-text available
Rheumatoid arthritis and celiac disease belong to the autoimmune disease family. Despite being separate entities they share multiple serological and genetic aspects. Celiac disease associated serum bio-markers are observed in rheumatoid arthritis. Contrary to their specific HLA pre-disposition, the diseases share multiple non-HLA loci. Those genes are crucial for activation and regulation of adaptive and innate immunity. Recently, light was shed on the interaction between host genetics and microbiota composition in relation to celiac disease and rheumatoid arthritis susceptibility, connecting bugs and us and autoimmunity. The present editorial updates and clarifies those aspects.
Full-text available
Protein-glutamine γ-glutamyltransferases (transglutaminases, Tgs) belong to the class of transferases. They catalyze the formation of an isopeptide bond between the acyl group at the end of the side chain of protein- or peptide-bound glutamine residues and the first order 𝜀-amine groups of protein- or peptide-bound lysine. The Tgs are considered to be universal protein cross-linkers, and they play an essential role in a number of human diseases. In this review, we discuss mainly the bacterial Tgs in terms of the functionality of the enzymes and a potential role they may play in bacterial survival. Since microbial transglutaminases (mTgs) are functionally similar to the human homologs, they may be involved in the human disease provocation. We suggest here a potential involvement of Tgs in the pathologies such as autoimmune diseases. In this hypothesis, the endogenous mTgs that are secreted by the gut microbiota, especially in a dysbiotic configuration, are potential drivers of systemic autoimmunity, via the enzymatic posttranslational modification of peptides in the gut lumen. These mTg activities directed toward cross-linking of naïve proteins can potentially generate neo-epitopes that are not only immunogenic but may also activate some immune response cascades leading to the pathological autoimmune processes.
Full-text available
Gluten-free diet (GFD) is the only treatment for celiac disease (CD). There is a general consensus that strict GFD adherence in CD patients leads to full clinical and histological remission accompanied by improvement in quality of life and reduced long-term complications. Despite the importance of monitoring the GFD, there are no clear guidelines for assessing the outcome or for exploring its adherence. Available methods are insufficiently accurate to identify occasional gluten exposure that may cause intestinal mucosal damage. Serological tests are highly sensitive and specific for diagnosis, but do not predict recovery and are not useful for follow-up. The use of serial endoscopies, it is invasive and impractical for frequent monitoring, and dietary interview can be subjective. Therefore, the detection of gluten immunogenic peptides (GIP) in feces and urine have been proposed as new non-invasive biomarkers to detect gluten intake and verify GFD compliance in CD patients. These simple immunoassays in human samples could overcome some key unresolved scientific and clinical problems in CD management. It is a significant advance that opens up new possibilities for the clinicians to evaluate the CD treatment, GFD compliance, and improvement in the quality of life of CD patients.
Genetic and environmental risk factors for celiac disease are well established, however, the precipitating events leading to development of celiac disease and associated conditions remain enigmatic. Being a multi-faced, multi-organ disease and the multiple extra intestinal phenotypes of celiac disease, further more add to its complexity. The present editorial summarizes the potential mechanisms connecting gut eco system events to remote organ manifestations and dysfunctions in celiac disease. It is suggested that nutrients, the microbiome/dysbiome interplay, the local post translational modification of naive proteins, the leaky gut and the leaked immunogenic or toxic molecules or complexes and the circulating pro-inflammatory immune cells and cytokines are at the basis of the gut-remote organ pathologies, in CD.