Tryptophan for Celiac Disease

(TIARSCeD Trial)

Overseen By Gaston H Rueda, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: McMaster University

Must not be taking: Antacids, Antibiotics, MAOIs, others

Disqualifiers: Diabetes, GI diseases, Surgery, others

Compensation: Varies

Number of Visits: 4

Duration: 3 weeks

50 Participants Needed

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. ^{1 2 3 4 5}

Is 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. ^{5 6 7 8 9}

How 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. ^{2 10 11 12 13}

Eligibility 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.

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

Treatment Details

Interventions

• L-Leucine
• L-Tryptophan
• Placebo

Trial Overview 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.

Participant Groups

Group I: L-Tryptophan Active Control 1 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 Powder Placebo Group 1 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.

Who Is Running the Clinical Trial?

McMaster University

Lead Sponsor

Trials

936

Recruited

2,630,000+

Findings from Research

The study found that adults with untreated celiac disease have higher levels of pyridoxal 5'-phosphate, an active form of vitamin B6, in their cerebrospinal fluid, contradicting the expectation that vitamin B6 deficiency would inhibit serotonin metabolism.

Despite normal levels of tryptophan, the precursor for serotonin, the reduced serotonin turnover in these patients does not appear to be directly linked to vitamin B6 deficiency, suggesting that other factors may contribute to the mental health issues commonly seen in celiac disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High level of pyridoxal 5'-phosphate in the cerebrospinal fluid of adult celiac patients. Hallert, C., Allenmark, S., Larsson-Cohn, U., et al.[2018]

Celiac disease affects about 1% of the U.S. population, with higher prevalence in individuals with a family history, highlighting the importance of genetic predisposition in its diagnosis and management.

Comprehensive nutritional management and proper diagnostic strategies, including serologic testing and HLA haplotypes, are crucial for effective treatment and monitoring of celiac disease, especially given its association with various other health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Comprehensive Review of Celiac Disease/Gluten-Sensitive Enteropathies. McAllister, BP., Williams, E., Clarke, K.[2020]

In a study of 11 untreated coeliac disease patients, most showed normal brain availability of the monoamine precursors tryptophan and tyrosine, suggesting that central monoamine metabolism may not be universally impaired in these individuals.

However, 4 patients with a history of major psychiatric illness exhibited reduced brain availability of tryptophan, indicating that these individuals may require special attention in managing depression related to coeliac disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain availability of monoamine precursors in adult coeliac disease. Hallert, C., Mårtensson, J., Allgén, LG.[2019]

After one year on a gluten-free diet, adult coeliac patients showed a 33% increase in key monoamine metabolites in their cerebrospinal fluid (CSF), indicating improved brain chemistry.

The study also found a 10% increase in tryptophan levels in CSF and noted improvements in the jejunal mucosa, suggesting that the previously low levels of these metabolites were likely due to poor intestinal absorption rather than genetic factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improvement in central monoamine metabolism in adult coeliac patients starting a gluten-free diet. Hallert, C., Sedvall, G.[2019]

Untreated children with coeliac disease have significantly lower plasma concentrations of tryptophan compared to both treated children and healthy controls, which may affect their mental health.

The reduced availability of tryptophan in untreated coeliac children could lead to decreased serotonin synthesis in the brain, potentially contributing to behavioral disorders such as depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma precursor amino acids of central nervous system monoamines in children with coeliac disease. Hernanz, A., Polanco, I.[2019]

The workshop highlighted that the upper intake limit for leucine in healthy humans may be around 500 mg/(kg · d), but more research is needed to establish a safe margin for the general population.

For tryptophan, while older studies indicated that doses of 8-15 g/d were well tolerated, there is a lack of recent human data, and animal studies have not yet provided a clear consensus on safe intake levels for humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Kimura, T., Bier, DM., Taylor, CL.[2023]

In a study involving Fischer 344 rats and B6C3F1 mice, L-Tryptophan showed little toxic effect, with minimal body weight loss and high survival rates in rats, indicating it is safe at the tested doses.

No significant increase in tumor incidence was found in rats, and while some hematopoietic tumors appeared in mice, they were not statistically significant, leading to the conclusion that L-Tryptophan is not carcinogenic under the study conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioassay of L-Tryptophan for Possible Carcinogenicity (CAS No. 73-22-3). [2020]

L-tryptophan and its derivative 5-hydroxytryptophan may play a significant role in increasing serotonin synthesis, which could help in treating disorders like depression and irritable bowel syndrome.

Given that around 20% of patients with functional bowel disorders also have psychiatric issues, L-tryptophan could serve as a crucial link in understanding and managing these interconnected conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of the implications of dietary tryptophan intake in patients with irritable bowel syndrome and psychiatric disorders. Agazzi, A., De Ponti, F., De Giorgio, R., et al.[2019]

L-Tryptophan (L-Trp) is crucial for growth and can help prevent pellagra, making it an important nutrient, especially in underdeveloped countries.

Research suggests that the urinary excretory ratio of anthranilic acid to kynurenic acid could serve as a sensitive biomarker to predict the safe upper intake level of L-Trp, which is important for ensuring its safe use without adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The metabolites in the tryptophan degradation pathway might be useful to determine the tolerable upper intake level of tryptophan intake in rats. Shibata, K., Fukuwatari, T.[2023]

Celiac disease (CeD) is a complex immune-mediated condition influenced by gluten proteins, specific genetic factors (HLA-DQ2 and -DQ8), and various cofactors like intestinal microbiota, which can complicate its management beyond just a gluten-free diet.

Recent advancements in understanding CeD have led to promising new therapies currently in clinical trials, including gluten-degrading enzymes and cytokine therapies, which aim to improve patient outcomes and allow for personalized treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Co-factors, Microbes, and Immunogenetics in Celiac Disease to Guide Novel Approaches for Diagnosis and Treatment. Verdu, EF., Schuppan, D.[2022]

Celiac adults on a long-term gluten-free diet showed significant deficiencies in essential nutrients such as folates, vitamin E, iodine, calcium, and vitamin D, indicating a need for careful dietary monitoring.

Despite these deficiencies, the overall nutritional status of celiac patients was similar to that of healthy volunteers, suggesting that dietary habits in the general population may also contribute to these deficiencies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nutritional Status in Spanish Adults with Celiac Disease Following a Long-Term Gluten-Free Diet Is Similar to Non-Celiac. Ballestero-Fernández, C., Varela-Moreiras, G., Úbeda, N., et al.[2021]

Celiac disease is an autoimmune disorder triggered by gluten in genetically susceptible individuals, primarily associated with specific HLA haplotypes (DQ2 and DQ8), and can present in various forms including typical, atypical, silent, and latent.

Current diagnosis relies on histological changes in the small intestine, with serological tests like IgA anti-tissue transglutaminase showing high sensitivity (up to 98%) and specificity (around 96%), while future treatments may include gluten-degrading enzymes and immunotherapy as alternatives to the gluten-free diet.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Celiac disease: risk assessment, diagnosis, and monitoring. Setty, M., Hormaza, L., Guandalini, S.[2022]

In patients with active celiac disease, there is a significant increase in leucine and glutamine turnover, indicating heightened protein breakdown, which may contribute to their protein malnutrition status.

The study suggests that the increased renewal of intestinal epithelial cells plays a major role in whole-body protein turnover, highlighting the importance of glutamine as a fuel source for these cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Whole-body protein metabolism assessed by leucine and glutamine kinetics in adult patients with active celiac disease. Messing, B., Dutra, SL., Thuillier, F., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

High level of pyridoxal 5'-phosphate in the cerebrospinal fluid of adult celiac patients. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

A Comprehensive Review of Celiac Disease/Gluten-Sensitive Enteropathies. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Brain availability of monoamine precursors in adult coeliac disease. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Improvement in central monoamine metabolism in adult coeliac patients starting a gluten-free diet. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Plasma precursor amino acids of central nervous system monoamines in children with coeliac disease. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

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]

7. United States pubmed.ncbi.nlm.nih.gov

Bioassay of L-Tryptophan for Possible Carcinogenicity (CAS No. 73-22-3). [2020]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Review of the implications of dietary tryptophan intake in patients with irritable bowel syndrome and psychiatric disorders. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

The metabolites in the tryptophan degradation pathway might be useful to determine the tolerable upper intake level of tryptophan intake in rats. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Co-factors, Microbes, and Immunogenetics in Celiac Disease to Guide Novel Approaches for Diagnosis and Treatment. [2022]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Nutritional Status in Spanish Adults with Celiac Disease Following a Long-Term Gluten-Free Diet Is Similar to Non-Celiac. [2021]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Celiac disease: risk assessment, diagnosis, and monitoring. [2022]

13. United States pubmed.ncbi.nlm.nih.gov

Whole-body protein metabolism assessed by leucine and glutamine kinetics in adult patients with active celiac disease. [2019]