Tryptophan for Celiac Disease
(TIARSCeD Trial)
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: McMaster University
Must not be taking: Antacids, Antibiotics, MAOIs, others
Disqualifiers: Diabetes, GI diseases, Surgery, others
Trial Summary
What is the purpose of this trial?This is a prospective, randomized, double-blind, placebo-controlled exploratory trial to evaluate the effect of L-tryptophan supplementation on celiac-related symptoms in individuals who have biopsy-confirmed celiac disease (CeD) and symptoms non-responsive to a gluten-free diet (GFD). Fifty participants, aged 18 to 75 years, who self-report persistent CeD-related symptoms despite taking a GFD for more than 1 year and who score \> 40 on the Celiac Symptom Index (CSI) will be randomized to receive L-tryptophan or placebo for 3 weeks.
Will I have to stop taking my current medications?
The trial requires that you stop taking certain medications, such as acid anti-secretory and antacid medications, antibiotics, antibacterial agents, probiotics, lithium, and monoamine oxidase inhibitors (MAOIs). If you are on any of these, you would need to stop them to participate.
What evidence supports the effectiveness of the treatment L-Leucine, L-Tryptophan, Placebo, Control, Dummy Treatment for celiac disease?
Research shows that tryptophan levels in the brain can be affected in people with celiac disease, and increasing tryptophan might help with related mood issues like depression. This suggests that tryptophan could potentially be beneficial for some symptoms of celiac disease.
12345Is L-Tryptophan safe for humans?
L-Tryptophan is generally considered safe for humans, with older studies suggesting it is well tolerated at doses of 8-15 grams per day. Animal studies have shown no significant toxic effects or cancer risk, but human research was limited after the late 1980s.
56789How does the treatment L-Leucine, L-Tryptophan differ from other treatments for celiac disease?
The treatment using L-Leucine and L-Tryptophan is unique because it involves amino acids that may influence protein metabolism and immune responses, unlike the standard gluten-free diet which focuses on eliminating gluten. This approach could offer a novel way to manage celiac disease by potentially addressing underlying metabolic or immune factors.
210111213Eligibility Criteria
This trial is for adults aged 18-75 with celiac disease who still have symptoms despite following a gluten-free diet for over a year. Participants must have confirmed celiac disease with specific tests and score above 40 on the Celiac Symptom Index. People taking certain medications, those with other autoimmune or systemic diseases, gastrointestinal issues besides benign conditions, recent participants in dietary studies, substance abusers, and individuals with lactose/fructose intolerance cannot join.Inclusion Criteria
I have been diagnosed with celiac disease confirmed by a biopsy and blood test.
I am between 18 and 75 years old.
I still have celiac symptoms after a year on a gluten-free diet.
Exclusion Criteria
I do not have conditions like inflammatory bowel disease or type 1 diabetes.
You have problems with alcohol or drugs.
I do not have serious stomach or intestine diseases except for minor conditions.
+10 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Treatment
Participants receive L-tryptophan or placebo for 3 weeks, with dietary counseling and monitoring
3 weeks
3 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The study is testing if L-Tryptophan supplements can help reduce symptoms of celiac disease that persist even after following a gluten-free diet. Half of the participants will receive L-Tryptophan while the other half will get a placebo without knowing which one they're taking (double-blind). The treatment period lasts for three weeks.
2Treatment groups
Active Control
Placebo Group
Group I: L-TryptophanActive Control1 Intervention
L-tryptophan\* supplements (Tryptan, Valeant Canada LP): each treatment capsule contains 500 mg of L-Tryptophan; talc and magnesium stearate.
Study participants will be instructed to take 2 x 500 mg capsules (1000 mg) every 8 hrs, three times a day. (total daily dose: 3000 mg) for a total of 3 weeks.
Instructions will be printed on the label of the pill container.
Group II: Freedom SimpleCap PowderPlacebo Group1 Intervention
500 mg of SimpleCap Powder. Study participants will be instructed to take 2 x 500 mg capsules (1000 mg) every 8 hrs, three times a day. (total daily dose: 3000 mg) for a total of 3 weeks.
Instructions will be printed on the label of the pill container.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
McMaster UniversityHamilton, Canada
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Who Is Running the Clinical Trial?
McMaster UniversityLead Sponsor
References
High level of pyridoxal 5'-phosphate in the cerebrospinal fluid of adult celiac patients. [2018]Adults with intestinal malabsorption due to celiac disease show reduced central serotonin metabolism, probably induced by a lack of essential dietary factors. Investigating a role proposed for vitamin B6 deficiency, a regular finding in untreated celiacs, the present study yields no support for the hypothesis that direct inhibition at the decarboxylation step by vitamin B6 deficiency accounts for low central serotonin turnover in adult celiacs: 11 untreated patients showing reduced 5-HIAA in the cerebrospinal fluid (71+/- 26.8 pmol/ml) had a significantly higher concentration of the metabolically active B6 vitamer pyridoxal 5'-phosphate in lumbar cerebrospinal fluid (0.06 +/- 0.34 ng/ml) than controls (0.24 +/- 0.07 ng/ml) (p less than 0.01). Cerebrospinal fluid tryptophan, precursor of serotonin, was normal (2035 %/- 649 pmol/ml). Raised pyridoxal 5'-phosphate in the cerebrospinal fluid in untreated celiac disease is an unexpected finding. Possibly it is secondary to the diminished central monamine metabolism in these patients, but further studies are needed bearing in mind that mental depression is a major cause for disability in adult celiac disease.
A Comprehensive Review of Celiac Disease/Gluten-Sensitive Enteropathies. [2020]Celiac disease is a complex immune-mediated gluten-sensitive enteropathy with protean clinical manifestations. It is manifest in genetically predisposed individuals who ingest gluten in varying amounts. In broad terms, it is thought to affect 1% of the population in the USA. More specifically, the prevalence increases drastically from 1:133 in patients not-at-risk, to 1:56 in symptomatic patients, to 1:39 in patients with a second-degree relative with the diagnosis, and to 1:22 in patients with a first-degree relative with the diagnosis. It may be associated with several immune-mediated phenomena, autoimmune diseases, and complicated by vitamin and other trace element deficiencies, bone disease, and malignancy. Our understanding of celiac disease has evolved rapidly over the past two decades. This has led to several lines of enquiry on the condition and potential treatment options. More recently, several entities including gluten intolerance, non-celiac gluten sensitivity, and seronegative celiac disease have been described. These conditions are distinct from allergies or intolerance to wheat or wheat products. There are challenges in defining some of these entities since a large number of patients self-report these conditions. The absence of confirmatory diagnostic tests poses an added dilemma in distinguishing these entities. The differences in spectrum of symptoms and highlights of the variability between the pediatric and adult populations have been studied in some detail. The role of screening for celiac disease is examined in both the general population and "at risk" populations. Diagnostic strategies including the best available serologic testing, utility of HLA haplotypes DQ2 and DQ8 which are seen in over 90% of patients with celiac disease as compared with approximately 40% of the general population, and endoscopic evaluation are also reviewed. Comprehensive nutritional management after diagnosis is key to sustained health in patients with celiac disease. Simple algorithms for care based on a comprehensive multidisciplinary approach are proposed. Refractory and non-responsive celiac diseases in the setting of a gluten-free diet are examined as are novel non-dietary therapies. Finally, the association of other disease states including psychiatric illness, infertility, lymphoproliferative malignancy, and mortality is explored with special attention paid to autoimmune and atopic disease.
Brain availability of monoamine precursors in adult coeliac disease. [2019]Adults with untreated coeliac disease show signs of reduced central monoamine metabolism. The reason is obscure, and in the present study we investigated the brain availability of the monoamine precursors tryptophan and tyrosine in 11 untreated coeliac patients. The brain availability appeared to be unaffected in most of the patients, and the rise in serum tryptophan levels after oral casein administration was similar in coeliac and control subjects. Four of the 11 coeliac patients showed impaired brain availability with respect to tryptophan. Since they comprised all with a history of major psychiatric illness, this observation may have therapeutical implications for the management of depression in adult coeliac patients.
Improvement in central monoamine metabolism in adult coeliac patients starting a gluten-free diet. [2019]Adult coeliac patients taking a gluten-free diet for one year showed an increase of 33% in the concentrations in CSF of major monoamine metabolites (5-HIAA, HVA and MOPEG). Tryptophan in CSF rose by 10%. There was concomitant morphological improvement in the jejunal mucosa, and the results would seem to indicate that the reduced central monoamine metabolism in untreated adult coeliacs is not primarily genetically determined but is probably related to the poor intestinal absorption.
Plasma precursor amino acids of central nervous system monoamines in children with coeliac disease. [2019]Some children with coeliac disease show behavioural disorders such as depression and other signs which have been correlated with reduced central monoamine metabolism. We have therefore investigated the brain availability of the monoamine precursors tryptophan and tyrosine in 15 untreated children with coeliac disease and 12 treated children with coeliac disease as well as in 12 control children. Significantly decreased plasma concentrations of tryptophan were found in untreated children (mean (SD) 13 (4) mumols/l, p less than 0.001) compared with treated children (31 (13) mumols/l), and in both groups of coeliac children when compared with control children (81 (22) mumols/l). A significantly lower ratio of plasma tryptophan to large neutral amino acids (tyrosine, valine, isoleucine, leucine, and phenylalanine) was also observed, which could indicate impaired brain availability of tryptophan in coeliac children and was more pronounced in untreated children. The impaired availability of tryptophan could produce decreased central serotonin synthesis and in turn behaviour disorders in children with coeliac disease.
Summary of workshop discussions on establishing upper limits for amino acids with specific attention to available data for the essential amino acids leucine and tryptophan. [2023]The morning of the first day of the 8th Amino Acid Assessment Workshop was organized and co-sponsored by the International Council on Amino Acid Science (ICAAS) and the International Life Sciences Institute Research Foundation and was focused on the International Life Sciences Institute Research Foundation's approach to establishing upper limits of nutrients. The remainder of d 1 and all of d 2 were focused on the safety of leucine and tryptophan, with special emphasis on determining the upper level of the safe range of intake. It was recognized that some toxicological frameworks, mainly the key-events dose response framework, might be applicable to amino acids and provide appropriate assistance to regulators in establishing upper limits for amino acids as a group of nutrients used in dietary supplements. ICAAS-funded projects for determining the upper intake limits for the essential amino acid leucine provided the main pool of leucine data discussed at the workshop. The acute clinical study suggests 500 mg/(kg · d) as a possible upper limit for leucine in healthy humans, but the safety margin needed to widen this limit to the general population has not been determined. For tryptophan, the workshop participants found less ground for consensus. Older efficacy studies suggested that tryptophan at 8-15 g/d was well tolerated, but human research was abruptly terminated in the late 1980s and no new data are available. Animal results obtained in pigs and rodents were discussed and 2 possible strategies for applying those outcomes to humans were described.
Bioassay of L-Tryptophan for Possible Carcinogenicity (CAS No. 73-22-3). [2020]L-Tryptophan is an essential amino acid for humans, and a precursor of the neurohormones serotonin (5-hydroxytryptamine) and melatonin (N-acetyl-5-methoxytryptamine), and the B vitamin nicotinic acid. It is found in small concentrations in casein, and in many foods. A bioassay of the amino acid L-tryptophan for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats and 35 mice of each sex were administered L-tryptophan at one of two doses, either 25,000 or 50,000 ppm, 5 days per week for 78 weeks, and then observed for 26 or 27 weeks. Matched controls consisted of groups of 15 rats or 15 mice of each sex. All surviving rats and mice were killed at 104 or 105 weeks. L-Tryptophan had little toxic effect on the rats; mean body weight loss was minimal and survival of dosed groups of both sexes was high. In the mice, mean body weights of dosed animals were lower than those of controls throughout most of the bioassay, particularly in the females. Sufficient numbers of rats were at risk to termination of the study for development of late-appearing tumors, and sufficient numbers of mice were at risk beyond 52 weeks of the study for development of tumors. No neoplasms occurred in a statistically significant incidence among dosed rats when compared with controls. In both male and female mice, neoplasms of the hematopoietic system occurred at higher incidences in the low-dose groups than in the matched-control groups (males: controls 0/12, low-dose 9/34, high-dose 2/33; females: controls 2/13, low-dose 6/33, high-dose 1/35). These incidences, however, are not statistically significant, using the Bonferroni correction, and therefore, no tumors are considered to be related to the administration of the test chemical. It is concluded that under the conditions of this bioassay, L-tryptophan was not carcinogenic for Fischer 344 rats or B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative Synonym: L-a
Review of the implications of dietary tryptophan intake in patients with irritable bowel syndrome and psychiatric disorders. [2019]In this review, we address the possible role of the essential amino acid L-tryptophan or its metabolic derivative 5-hydroxytryptophan in the modulation of serotonin (5-hydroxytryptamine) synthesis and thereby in affecting the pathophysiology of central and peripheral nervous system disorders, including depression and irritable bowel syndrome. L-Tryptophan may represent a link between apparently disparate functional disorders and is of interest for general gastroenterologists, neurogastroenterologists, and neurologists. On the basis of estimates showing that approximately 20% of patients with functional bowel disorders seeking care in referral centres have psychiatric comorbidity, we attempt to provide a conceptual framework for defining the possible role of L-tryptophan in this population.
The metabolites in the tryptophan degradation pathway might be useful to determine the tolerable upper intake level of tryptophan intake in rats. [2023]L-Tryptophan (L-Trp) is a rate-limiting amino acid for growth in people from underdeveloped countries. Because L-Trp is also a precursor to nicotinamide, administration of the free form of L-Trp is a very good method of preventing pellagra. Furthermore, L-Trp has shown some effectiveness for the treatment of a variety of other conditions typically associated with low serotonin levels in the brain. Therefore, information about the no-observed-adverse-effect level and lowest-observed-adverse-effect level of L-Trp is needed. However, it is not possible to experimentally obtain such data in humans due to ethical considerations. The aim of the present workshop was to identify biomarkers that could be used before the appearance of adverse effects of L-Trp. We reviewed the published research using rats to develop an index of the metabolic upper intake level for L-Trp to be used instead of the tolerable upper intake level (UL). These results show that the urinary excretory ratio of anthranilic acid:kynurenic acid is potentially the most sensitive and appropriate surrogate breakpoint index to predict the UL of L-Trp.
Co-factors, Microbes, and Immunogenetics in Celiac Disease to Guide Novel Approaches for Diagnosis and Treatment. [2022]Celiac disease (CeD) is a frequent immune-mediated disease that affects not only the small intestine but also many extraintestinal sites. The role of gluten proteins as dietary triggers, HLA-DQ2 or -DQ8 as major necessary genetic predisposition, and tissue transglutaminase (TG2) as mechanistically involved autoantigen, are unique features of CeD. Recent research implicates many cofactors working in synergism with these key triggers, including the intestinal microbiota and their metabolites, nongluten dietary triggers, intestinal barrier defects, novel immune cell phenotypes, and mediators and cytokines. In addition, apart from HLA-DQ2 and -DQ8, multiple and complex predisposing genetic factors and interactions have been defined, most of which overlap with predispositions in other, usually autoimmune, diseases that are linked to CeD. The resultant better understanding of CeD pathogenesis, and its manifold manifestations has already paved the way for novel therapeutic approaches beyond the lifelong strict gluten-free diet, which poses a burden to patients and often does not lead to complete mucosal healing. Thus, supported by improved mouse models for CeD and in vitro organoid cultures, several targeted therapies are in phase 2-3 clinical studies, such as highly effective gluten-degrading oral enzymes, inhibition of TG2, cytokine therapies, induction of tolerance to gluten ingestion, along with adjunctive and preventive approaches using beneficial probiotics and micronutrients. These developments are supported by novel noninvasive markers of CeD severity and activity that may be used as companion diagnostics, allow easy-to perform and reliable monitoring of patients, and finally support personalized therapy for CeD.
Nutritional Status in Spanish Adults with Celiac Disease Following a Long-Term Gluten-Free Diet Is Similar to Non-Celiac. [2021]The only available treatment for celiac disease is life-long gluten exclusion. We conducted a cross-sectional age- and gender-matched study in 64 celiac adults on a long-term (>1 year) gluten-free diet and 74 non-celiac volunteers from Spain, using dietary, anthropometric, and biochemical parameters, as well as assessing bone mineral density and physical activity. Celiac adults had deficient intake (below 2/3 of the recommended intake) for folates, vitamin E, and iodine and low intake of calcium (below 80% of the recommended intake). Iron intake was also below 2/3 of the recommended intake in celiac women. Vitamin D intake was extremely low, and 34% of celiac patients had moderately deficient plasma levels. According to bone mineral density, celiac women may be more prone to osteopenia and osteoporosis. However, we found a perfectly analogous nutritional status scenario in celiac as compared to healthy volunteers, with the dietary deviations found being similar to those of the Spanish population, i.e., both groups followed a high-lipid, high-protein, and low-carbohydrate diet. Values for biochemical parameters were found within the reference ranges. Celiac disease had no influence on body weight, but body fat in celiac patients tended to be higher. According to our results, vitamin D, calcium, folates, vitamin E, iodine, and iron nutritional status should be specifically assessed and monitored in the celiac population.
Celiac disease: risk assessment, diagnosis, and monitoring. [2022]Celiac disease is an autoimmune disorder occurring in genetically susceptible individuals, triggered by gluten and related prolamins. Well identified haplotypes in the human leukocyte antigen (HLA) class II region (either DQ2 [DQA*0501-DQB*0201] or DQ8 [DQA*0301-DQB1*0302]) confer a large part of the genetic susceptibility to celiac disease.Celiac disease originates as a result of a combined action involving both adaptive and innate immunity. The adaptive immune response to gluten has been well described, with the identification of specific peptide sequences demonstrating HLA-DQ2 or -DQ8 restrictive binding motifs across various gluten proteins. As for innate immunity, through specific natural killer receptors expressed on their surface, intra-epithelial lymphocytes recognize nonclassical major histocompatibility complex (MHC)-I molecules such as MICA, which are induced on the surface of enterocytes by stress and inflammation, and this interaction leads to their activation to become lymphokine-activated killing cells. Four possible presentations of celiac disease are recognized: (i) typical, characterized mostly by gastrointestinal signs and symptoms; (ii) atypical or extraintestinal, where gastrointestinal signs/symptoms are minimal or absent and a number of other manifestations are present; (iii) silent, where the small intestinal mucosa is damaged and celiac disease autoimmunity can be detected by serology, but there are no symptoms; and, finally, (iv) latent, where individuals possess genetic compatibility with celiac disease and may also show positive autoimmune serology, that have a normal mucosa morphology and may or may not be symptomatic.The diagnosis of celiac disease still rests on the demonstration of changes in the histology of the small intestinal mucosa. The classic celiac lesion occurs in the proximal small intestine with histologic changes of villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytosis. Currently, serological screening tests are utilized primarily to identify those individuals in need of a diagnostic endoscopic biopsy. The serum levels of immunoglobulin (Ig)A anti-tissue transglutaminase (or TG2) are the first choice in screening for celiac disease, displaying the highest levels of sensitivity (up to 98%) and specificity (around 96%). Anti-endomysium antibodies-IgA (EMA), on the other hand, have close to 100% specificity and a sensitivity of greater than 90%. The interplay between gliadin peptides and TG2 is responsible for the generation of novel antigenic epitopes, the TG2-generated deamidated gliadin peptides. Such peptides represent much more celiac disease-specific epitopes than native peptides, and deamidated gliadin antibodies (DGP) have shown promising results as serological markers for celiac disease. Serology has also been employed in monitoring the response to a gluten-free diet.Despite the gluten-free diet being so effective, there is a growing demand for alternative treatment options. In the future, new forms of treatment may include the use of gluten-degrading enzymes to be ingested with meals, the development of alternative, gluten-free grains by genetic modification, the use of substrates regulating intestinal permeability to prevent gluten entry across the epithelium, and, finally, the availability of different forms of immunotherapy.
Whole-body protein metabolism assessed by leucine and glutamine kinetics in adult patients with active celiac disease. [2019]To assess the effect of increased renewal of intestinal epithelial cells on leucine and glutamine (Gln) turnover, 4-hour intravenous infusions of L-[1-(13)C]leucine and L-[2-(15)N]Gln were administered to five adult patients with active celiac disease in the postabsorptive state. There was a 35% increase in leucine flux (micromoles per kilogram per hour) in patients (117 +/- 17) compared with healthy controls (96 +/- 11, P