Diet ModificationAryl-IMMUNENCT03059862
The Role of Dietary Tryptophan on Aryl Hydrocarbon Receptor Activation
A study testing L-tryptophan in people with Diet Modification, run by McMaster University at 1 site in Canada.
Trial summary
This study evaluates the role of dietary L-tryptophan, an essential amino acid, in the activation of a specific cellular component: the aryl hydrocarbon receptor. Read more about this study
- Who is it for?
- Ages 18 to 75 yearsHealthy volunteers can take part
- Conditions the study is for
- Diet Modification
- What is being tested?
- L-tryptophan
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 20 participants
- Where
- 1 siteCanada
- Study dates
- 1 Nov 2017to 30 Jun 2018
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Healthy volunteer between 18 and 75 years of age.
Who cannot join
- Rome IV criteria for any functional gastrointestinal disorder.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: The Role of Tryptophan on Aryl Hydrocarbon Receptor Activation: a Randomized, Double Blind, Placebo-controlled, Crossover Design Pilot Trial
This study evaluates the role of dietary L-tryptophan, an essential amino acid, in the activation of a specific cellular component: the aryl hydrocarbon receptor.
Read the detailed description
The Aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor implicated in a range of key cellular events. In the gut, AHR is crucial for maintaining intestinal barrier immune homeostasis. The physiology of the AHR, however, is not completely understood; its precise gut luminal activators and functional consequences are unknown.
Some AHR ligands originate from the diet. Commensals play crucial roles in metabolizing tryptophan and other amino acids such as tyrosine, with the subsequent production of tryptophan metabolites. Previous studies show that inflammatory bowel disease (IBD) patients have impaired production of AHR agonists by the microbiota. Furthermore, dietary supplementation with tryptophan ameliorates clinical parameters of colitis in rodent models. Whether these findings translate into human pathophysiology has not been explored.
In the present study, the investigators will evaluate the effect of high- versus low-tryptophan diet on AHR activation in healthy participants. Briefly, participants will be instructed to follow a standardized low-tryptophan diet and will be randomized to a 3-week L-tryptophan supplement or placebo. Later, after a 2-week washout period, participants will crossover to the other arm. In addition, the effect of tryptophan and microbiota-derived metabolites on AHR activation will be analyzed.
- Conditions
- Diet Modification
- Being tested
- L-tryptophan, Placebo
- Keywords
- immunity, Aryl-hydrocarbon receptor, immune homeostasis, microbiota, tryptophan
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-tryptophanDietary supplement
3 g/day of L-tryptophan added to the standardized low-tryptophan diet. Duration: 3 weeks.
PlaceboDietary supplement
A placebo will be added to the standardized low-tryptophan diet. Duration: 3 weeks.
| Study group | Role | What they receive |
|---|---|---|
| Low-tryptophan diet and L-tryptophan. | Experimental | Standardized low-tryptophan diet (500-1000 mg of L-tryptophan and 1800 kcal) + L-tryptophan supplements (3 g/day). Receives: Dietary Supplement: L-tryptophan |
| Low-tryptophan diet and placebo | Placebo comparator | Standardized low-tryptophan diet (500-1000 mg of L-tryptophan and 1800 kcal) + placebo. Receives: Dietary Supplement: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
AHR activation levels in stool and duodenal content.
Changes in AHR activation levels will be assessed in stool and duodenal samples before and after the intervention (high- and low-tryptophan diets) using an AHR cell-reporter line.
Measured: three weeks
Secondary outcomes (6)
Bacterial and fungal microbiota composition in stool, duodenum and rectum/sigmoid biopsies.
Changes in bacterial and fungal microbiota composition will be assessed before and after the intervention in stool samples, duodenum and rectum biopsies.
Measured: Three weeks
Tryptophan metabolites levels, including host and bacterial catabolites, in blood, urine and stool.
Changes in tryptophan metabolites leves will be compared before and after the intervention, in blood, urine and stool samples.
Measured: Three weeks
mRNA levels in duodenal and rectum/sigmoid biopsies.
Changes in mRNA levels in duodenal and rectum/sigmoid biopsies will be assessed before and after the intervention.
Measured: three weeks
Cytokines in serum.
Changes in cytokines in the serum (IL-22, IL-6, IL-2, IL-10, IL-12p70, IL-23p19, IFNγ, TNFα and CRP will be measured by ELISA in cell culture supernatants after stimulation with LPS, curdlan and ConA ) will be measured before and after the intervention and patients will be grouped into two categories for each measurement: high vs. low, according to the cutoff reference test value for each of the cytokines.
Measured: three weeks.
Gastrointestinal symptoms
Changes in gastrointestinal symptoms before and after the intervention will be assessed using a validated questionnaire (The Gastrointestinal Symptoms Rating Scale)
Measured: three weeks.
Mood
Changes in mood before and after the intervention will be assessed using a validated questionnaire (Hospital anxiety and depression scale)
Measured: three weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Feb 2017
- Study start1 Nov 2017
- Primary completion30 Apr 2018
- Study completion30 Jun 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (11)Papers the sponsor has linked to this study.
- Other trials for Diet ModificationStudies of the same condition, open and under way.
- More trials run by McMaster UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- All subjects will be following a standardized low-tryptophan diet and randomized to L-tryptophan supplements or placebo, for three weeks. After a 2 weeks washout period, subjects will crossover to the other arm.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- McMaster University
- Sponsor type
- University, hospital or other
- Collaborators
- National Research Agency, France, Canadian Institutes of Health Research (CIHR)
- Responsible party
- Sponsor
- Investigators
- Premysl Bercik, MD, PhD, Principal investigator, McMaster University, Department of Medicine, Division of Gastroenterology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03059862
- Sponsor's protocol ID
- Aryl-IMMUNE
- Acronym
- Aryl-IMMUNE
- Status last verified
- Apr 2023
- First submitted
- 18 Jan 2017
- Last updated
- 13 Apr 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Barouki R, Coumoul X, Fernandez-Salguero PM. The aryl hydrocarbon receptor, more than a xenobiotic-interacting protein. FEBS Lett. 2007 Jul 31;581(19):3608-15. doi: 10.1016/j.febslet.2007.03.046. Epub 2007 Mar 30.
PubMed 17412325Behnsen J, Raffatellu M. Keeping the peace: aryl hydrocarbon receptor signaling modulates the mucosal microbiota. Immunity. 2013 Aug 22;39(2):206-7. doi: 10.1016/j.immuni.2013.08.012.
PubMed 23973218Bender DA. Biochemistry of tryptophan in health and disease. Mol Aspects Med. 1983;6(2):101-97. doi: 10.1016/0098-2997(83)90005-5. No abstract available.
PubMed 6371429Cynober L, Bier DM, Kadowaki M, Morris SM Jr, Elango R, Smriga M. Proposals for Upper Limits of Safe Intake for Arginine and Tryptophan in Young Adults and an Upper Limit of Safe Intake for Leucine in the Elderly. J Nutr. 2016 Dec;146(12):2652S-2654S. doi: 10.3945/jn.115.228478. Epub 2016 Nov 9.
PubMed 27934658Hubbard TD, Murray IA, Bisson WH, Lahoti TS, Gowda K, Amin SG, Patterson AD, Perdew GH. Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles. Sci Rep. 2015 Aug 3;5:12689. doi: 10.1038/srep12689.
PubMed 26235394Kiss EA, Vonarbourg C, Kopfmann S, Hobeika E, Finke D, Esser C, Diefenbach A. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science. 2011 Dec 16;334(6062):1561-5. doi: 10.1126/science.1214914. Epub 2011 Oct 27.
PubMed 22033518Kiss EA, Vonarbourg C. Aryl hydrocarbon receptor: a molecular link between postnatal lymphoid follicle formation and diet. Gut Microbes. 2012 Nov-Dec;3(6):577-82. doi: 10.4161/gmic.21865. Epub 2012 Aug 22.
PubMed 22909905Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR, Grigorieva EF, Wilhelm C, Veldhoen M. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell. 2011 Oct 28;147(3):629-40. doi: 10.1016/j.cell.2011.09.025. Epub 2011 Oct 13.
PubMed 21999944Zelante T, Iannitti RG, Cunha C, De Luca A, Giovannini G, Pieraccini G, Zecchi R, D'Angelo C, Massi-Benedetti C, Fallarino F, Carvalho A, Puccetti P, Romani L. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. 2013 Aug 22;39(2):372-85. doi: 10.1016/j.immuni.2013.08.003.
PubMed 23973224Qiu J, Heller JJ, Guo X, Chen ZM, Fish K, Fu YX, Zhou L. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity. 2012 Jan 27;36(1):92-104. doi: 10.1016/j.immuni.2011.11.011. Epub 2011 Dec 15.
PubMed 22177117Lamas B, Richard ML, Leducq V, Pham HP, Michel ML, Da Costa G, Bridonneau C, Jegou S, Hoffmann TW, Natividad JM, Brot L, Taleb S, Couturier-Maillard A, Nion-Larmurier I, Merabtene F, Seksik P, Bourrier A, Cosnes J, Ryffel B, Beaugerie L, Launay JM, Langella P, Xavier RJ, Sokol H. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med. 2016 Jun;22(6):598-605. doi: 10.1038/nm.4102. Epub 2016 May 9.
PubMed 27158904
Study at a glance
From the registry record, last updated by the sponsor on 13 Apr 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Role of Tryptophan on Aryl Hydrocarbon Receptor Activation: a Randomized, Double Blind, Placebo-controlled, Crossover Design Pilot Trial
- ClinicalTrials.gov ID
- NCT03059862
- Acronym / sponsor ID
- Aryl-IMMUNE / Aryl-IMMUNE
- Conditions
- Diet Modification
- Keywords
- immunity, Aryl-hydrocarbon receptor, immune homeostasis, microbiota, tryptophan
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- McMaster UniversityUniversity, hospital or other
- Collaborators
- National Research Agency, France, Canadian Institutes of Health Research (CIHR)
- Study start
- 1 Nov 2017 (actual)
- Primary completion
- 30 Apr 2018 (actual)
- Study completion
- 30 Jun 2018 (actual)
- First posted
- 23 Feb 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study evaluates the role of dietary L-tryptophan, an essential amino acid, in the activation of a specific cellular component: the aryl hydrocarbon receptor.
Detailed description
The Aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor implicated in a range of key cellular events. In the gut, AHR is crucial for maintaining intestinal barrier immune homeostasis. The physiology of the AHR, however, is not completely understood; its precise gut luminal activators and functional consequences are unknown.
Some AHR ligands originate from the diet. Commensals play crucial roles in metabolizing tryptophan and other amino acids such as tyrosine, with the subsequent production of tryptophan metabolites. Previous studies show that inflammatory bowel disease (IBD) patients have impaired production of AHR agonists by the microbiota. Furthermore, dietary supplementation with tryptophan ameliorates clinical parameters of colitis in rodent models. Whether these findings translate into human pathophysiology has not been explored.
In the present study, the investigators will evaluate the effect of high- versus low-tryptophan diet on AHR activation in healthy participants. Briefly, participants will be instructed to follow a standardized low-tryptophan diet and will be randomized to a 3-week L-tryptophan supplement or placebo. Later, after a 2-week washout period, participants will crossover to the other arm. In addition, the effect of tryptophan and microbiota-derived metabolites on AHR activation will be analyzed.
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- All subjects will be following a standardized low-tryptophan diet and randomized to L-tryptophan supplements or placebo, for three weeks. After a 2 weeks washout period, subjects will crossover to the other arm.
| Arm | Type | Receives |
|---|---|---|
| Low-tryptophan diet and L-tryptophan. | Experimental | Dietary Supplement: L-tryptophanStandardized low-tryptophan diet (500-1000 mg of L-tryptophan and 1800 kcal) + L-tryptophan supplements (3 g/day). |
| Low-tryptophan diet and placebo | Placebo comparator | Dietary Supplement: PlaceboStandardized low-tryptophan diet (500-1000 mg of L-tryptophan and 1800 kcal) + placebo. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Healthy volunteer between 18 and 75 years of age.
Key exclusion criteria (1 listed)
- Rome IV criteria for any functional gastrointestinal disorder.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| L-tryptophan3 g/day of L-tryptophan added to the standardized low-tryptophan diet. Duration: 3 weeks. | Dietary supplement | Low-tryptophan diet and L-tryptophan. |
| PlaceboA placebo will be added to the standardized low-tryptophan diet. Duration: 3 weeks. | Dietary supplement | Low-tryptophan diet and placebo |
Primary outcome
AHR activation levels in stool and duodenal content.
Time frame: three weeks
Changes in AHR activation levels will be assessed in stool and duodenal samples before and after the intervention (high- and low-tryptophan diets) using an AHR cell-reporter line.
6 secondary outcomes
Bacterial and fungal microbiota composition in stool, duodenum and rectum/sigmoid biopsies.
Time frame: Three weeks
Tryptophan metabolites levels, including host and bacterial catabolites, in blood, urine and stool.
Time frame: Three weeks
mRNA levels in duodenal and rectum/sigmoid biopsies.
Time frame: three weeks
Cytokines in serum.
Time frame: three weeks.
Gastrointestinal symptoms
Time frame: three weeks.
Mood
Time frame: three weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Apr 2023.
- Background: PubMed 17412325Barouki R, Coumoul X, Fernandez-Salguero PM. The aryl hydrocarbon receptor, more than a xenobiotic-interacting protein. FEBS Lett. 2007 Jul 31;581(19):3608-15. doi: 10.1016/j.febslet.2007.03.046. Epub 2007 Mar 30.
- Background: PubMed 23973218Behnsen J, Raffatellu M. Keeping the peace: aryl hydrocarbon receptor signaling modulates the mucosal microbiota. Immunity. 2013 Aug 22;39(2):206-7. doi: 10.1016/j.immuni.2013.08.012.
- Background: PubMed 6371429Bender DA. Biochemistry of tryptophan in health and disease. Mol Aspects Med. 1983;6(2):101-97. doi: 10.1016/0098-2997(83)90005-5. No abstract available.
- Background: PubMed 27934658Cynober L, Bier DM, Kadowaki M, Morris SM Jr, Elango R, Smriga M. Proposals for Upper Limits of Safe Intake for Arginine and Tryptophan in Young Adults and an Upper Limit of Safe Intake for Leucine in the Elderly. J Nutr. 2016 Dec;146(12):2652S-2654S. doi: 10.3945/jn.115.228478. Epub 2016 Nov 9.
- Background: PubMed 26235394Hubbard TD, Murray IA, Bisson WH, Lahoti TS, Gowda K, Amin SG, Patterson AD, Perdew GH. Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles. Sci Rep. 2015 Aug 3;5:12689. doi: 10.1038/srep12689.
- Background: PubMed 22033518Kiss EA, Vonarbourg C, Kopfmann S, Hobeika E, Finke D, Esser C, Diefenbach A. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science. 2011 Dec 16;334(6062):1561-5. doi: 10.1126/science.1214914. Epub 2011 Oct 27.
- Background: PubMed 22909905Kiss EA, Vonarbourg C. Aryl hydrocarbon receptor: a molecular link between postnatal lymphoid follicle formation and diet. Gut Microbes. 2012 Nov-Dec;3(6):577-82. doi: 10.4161/gmic.21865. Epub 2012 Aug 22.
- Background: PubMed 21999944Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR, Grigorieva EF, Wilhelm C, Veldhoen M. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell. 2011 Oct 28;147(3):629-40. doi: 10.1016/j.cell.2011.09.025. Epub 2011 Oct 13.
- Background: PubMed 23973224Zelante T, Iannitti RG, Cunha C, De Luca A, Giovannini G, Pieraccini G, Zecchi R, D'Angelo C, Massi-Benedetti C, Fallarino F, Carvalho A, Puccetti P, Romani L. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. 2013 Aug 22;39(2):372-85. doi: 10.1016/j.immuni.2013.08.003.
- Background: PubMed 22177117Qiu J, Heller JJ, Guo X, Chen ZM, Fish K, Fu YX, Zhou L. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity. 2012 Jan 27;36(1):92-104. doi: 10.1016/j.immuni.2011.11.011. Epub 2011 Dec 15.
- Results publication: PubMed 27158904Lamas B, Richard ML, Leducq V, Pham HP, Michel ML, Da Costa G, Bridonneau C, Jegou S, Hoffmann TW, Natividad JM, Brot L, Taleb S, Couturier-Maillard A, Nion-Larmurier I, Merabtene F, Seksik P, Bourrier A, Cosnes J, Ryffel B, Beaugerie L, Launay JM, Langella P, Xavier RJ, Sokol H. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med. 2016 Jun;22(6):598-605. doi: 10.1038/nm.4102. Epub 2016 May 9.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Premysl Bercik, MD, PhD principal investigator
McMaster University, Department of Medicine, Division of Gastroenterology
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing L-tryptophan in people with Diet Modification, run by McMaster University at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
AHR activation levels in stool and duodenal content. (time frame: three weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03059862, which also lists 11 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Apr 2023.