Traumatic Brain Injury and the Gut Microbiome

Brain Injuries, Traumatic Clinical Trial

Official title:

Traumatic Brain Injury and the Gut Microbiome

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04949607
• Other study ID #: Pro00054911
• Status: Completed
• Phase: N/A
• Start date: July 28, 2021
• Est. completion date: June 8, 2022

Study information

• Verified date: July 2022
• Source: Centre for Neuro Skills
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to determine whether administration of a prebiotic, inulin, can improve the symptom complex associated with traumatic brain injury and whether inulin administration can alter the bacteria that live in the gut.

Description:

The investigators will study subjects (aged 18-70 years) with a history of moderate/severe traumatic brain injury (n=10) and healthy controls (aged 18-70 years) (n=10). All subjects will undergo a 3-month intervention of oral inulin treatment. The traumatic brain injury subjects will be administered oral inulin twice daily for 3 months. Testing including cognitive function assessment (Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and questionnaires of fatigue, mood and quality of life and sleep will occur at month 0, 3 and 6. Blood sampling for measurement of amino acid levels, hormones, short chain fatty acids and markers of neuroinflammation will be drawn before and 90 minutes (+/- 10 minutes) after a standardized meal will occur at month 0 and month 3. In addition, fecal samples for analysis of the GI microbiome will be collected at month -1, month 0, month 1, month 2, month 3, and month 6 along with an assessment of gastrointestinal health. Traumatic brain injury subjects will be selected from residents at a long term residential rehabilitation center. Healthy control subjects will be administered oral inulin twice daily with meals for 3 months. Quality of life will be assessed by questionnaires at months 0, 3 and 6. Blood sampling for measurement of amino acid levels, hormones, short chain fatty acids and markers of neuroinflammation will be drawn before and 90 minutes (+/- 10 minutes) after a standardized meal will occur at month 0 and month 3. Fecal samples will be collected at month -1, month 0, month 3 and month 6 for analysis of the GI microbiome along with an assessment of gastrointestinal health. A member of the study team will check monthly for adverse events and overall well-being and ensure compliance and ongoing consent.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 23
• Est. completion date: June 8, 2022
• Est. primary completion date: June 8, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

-Traumatic Brain Injury

Head trauma greater than two years prior manifesting in one or more of the following:

1. Loss of consciousness

2. Post-traumatic amnesia

3. Focal neurologic deficits

4. Seizures

5. Persistent symptoms of increased arousal (e.g., difficulty falling or staying asleep, anger and hypervigilance)

6. Impairment in cognitive, social, occupational, or other important areas of functioning (e.g., problems with work and relationships)

Exclusion Criteria:

• Traumatic Brain Injury

1. Unwilling to give consent. Patients with rights managed by Legal Authorized Representative must consent to participate in addition to consent from their legal agent

2. < 2 years post-injury

3. Known allergy to study agent.

4. Other medical condition or medication administration deemed exclusionary by the study investigators.

Inclusion Criteria:

• Healthy Control

1. Ages 18 to 70 years

2. Works at Centre for Neuro Skills

3. Participant is willing and able to give informed consent for participation in the study. Exclusion Criteria

• Healthy Control

1. Subjects with a history of inflammatory bowel disease, Celiac disease or active diverticular disease.

2. Known allergy to study agent.

3. Other medical condition or medication administration deemed exclusionary by the study investigators.

Related Conditions & MeSH terms

• Brain Injuries
• Brain Injuries, Traumatic
• Brain Injury, Chronic
• Wounds and Injuries

Intervention

Dietary Supplement:
• Inulin fructooligosaccharide
Subjects will be administered inulin at a starting dose of 1g twice daily (2g/day) and ramping up an additional 2g/day until the final dose of 4g twice daily (8g/day), which will continue on until the end of month 3 (week 12). After the month 3 study visit, inulin dosing will begin to ramp down over the next week.

Locations

Country	Name	City	State
United States	Centre for Neuro Skills	Bakersfield	California

Sponsors (2)

Lead Sponsor	Collaborator
Centre for Neuro Skills	University of Texas

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Characterization of fecal microbiome using molecular methods at baseline	Characterization of the fecal microbiome using a commercially available sampling kit and our lab's patented array for Polymerase Chain Reaction.	Baseline
Primary	Characterization of fecal microbiome using molecular methods at month 1	Characterization of the fecal microbiome using a commercially available sampling kit and our lab's patented array for Polymerase Chain Reaction.	month 1
Primary	Characterization of fecal microbiome using molecular methods at month 2	Characterization of the fecal microbiome using a commercially available sampling kit and our lab's patented array for Polymerase Chain Reaction.	month 2
Primary	Characterization of fecal microbiome using molecular methods at month 3	Characterization of the fecal microbiome using a commercially available sampling kit and our lab's patented array for Polymerase Chain Reaction.	month 3
Primary	Characterization of fecal microbiome using molecular methods at month 6	Characterization of the fecal microbiome using a commercially available sampling kit and our lab's patented array for Polymerase Chain Reaction.	month 6
Secondary	Sleep Quality as measured by Pittsburgh Sleep Quality Index at baseline	Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire which assesses sleep quality and disturbances over a 1 month-time interval. Minimum Score = 0 (better); Maximum Score = 21 (worse). Interpretation: Total < 5 associated with good sleep quality. Total > 5 associated with poor sleep quality.	Baseline (month 0)
Secondary	Sleep Quality as measured by Pittsburgh Sleep Quality Index at month 3	Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire which assesses sleep quality and disturbances over a 1 month-time interval. Minimum Score = 0 (better); Maximum Score = 21 (worse). Interpretation: Total < 5 associated with good sleep quality. Total > 5 associated with poor sleep quality.	month 3
Secondary	Sleep Quality as measured by Pittsburgh Sleep Quality Index at month 6	Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire which assesses sleep quality and disturbances over a 1 month-time interval. Minimum Score = 0 (better); Maximum Score = 21 (worse). Interpretation: Total < 5 associated with good sleep quality. Total > 5 associated with poor sleep quality.	month 6
Secondary	Symptoms of Growth Hormone Deficiency measured by the questionnaire Quality of Life - Assessment of Growth Hormone Deficiency in Adults at baseline	Symptoms of growth hormone deficiency will be measured using the Quality of Life - Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA). This 25-item questionnaire measures specific symptoms associated with growth hormone deficiency, with a score range of 0 to 25, with a higher score indicating worse symptoms. This assessment is completed by the Traumatic Brain Injury group only.	Baseline (month 0)
Secondary	Symptoms of Growth Hormone Deficiency measured by the questionnaire Quality of Life - Assessment of Growth Hormone Deficiency in Adults at month 3	Symptoms of growth hormone deficiency will be measured using the Quality of Life - Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA). This 25-item questionnaire measures specific symptoms associated with growth hormone deficiency, with a score range of 0 to 25, with a higher score indicating worse symptoms. This assessment is completed by the Traumatic Brain Injury group only.	month 3
Secondary	Symptoms of Growth Hormone Deficiency measured by the questionnaire Quality of Life - Assessment of Growth Hormone Deficiency in Adults at month 6	Symptoms of growth hormone deficiency will be measured using the Quality of Life - Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA). This 25-item questionnaire measures specific symptoms associated with growth hormone deficiency, with a score range of 0 to 25, with a higher score indicating worse symptoms. This assessment is completed by the Traumatic Brain Injury group only.	month 6
Secondary	Depression measured by the Beck Depression Inventory-II at baseline	The Beck Depression Inventory- II (BDI-II) assesses depressive symptom severity. The BDI-II is comprised of 21 individual items reflecting specific cognitive, affective, and physical symptoms of depression. Each item includes four statements that vary in the description of symptom of severity. Scores range from 0 to 3, with a score of "3" indicating a severe symptoms and a score of "0" indicating an absence of concern with that particular aspect of depressive symptomology. The total score is the sum of all endorsed statements. The maximum total score is 63. The BDI-II Manual designates the following raw score classifications depression severity: =13 = minimal; 14-19 = mild; 20-28 = moderate; = 29 = severe.	Baseline (month 0)
Secondary	Depression measured by the Beck Depression Inventory-II at month 3	The Beck Depression Inventory- II (BDI-II) assesses depressive symptom severity. The BDI-II is comprised of 21 individual items reflecting specific cognitive, affective, and physical symptoms of depression. Each item includes four statements that vary in the description of symptom of severity. Scores range from 0 to 3, with a score of "3" indicating a severe symptoms and a score of "0" indicating an absence of concern with that particular aspect of depressive symptomology. The total score is the sum of all endorsed statements. The maximum total score is 63. The BDI-II Manual designates the following raw score classifications depression severity: =13 = minimal; 14-19 = mild; 20-28 = moderate; = 29 = severe.	month 3
Secondary	Depression measured by the Beck Depression Inventory-II at month 6	The Beck Depression Inventory- II (BDI-II) assesses depressive symptom severity. The BDI-II is comprised of 21 individual items reflecting specific cognitive, affective, and physical symptoms of depression. Each item includes four statements that vary in the description of symptom of severity. Scores range from 0 to 3, with a score of "3" indicating a severe symptoms and a score of "0" indicating an absence of concern with that particular aspect of depressive symptomology. The total score is the sum of all endorsed statements. The maximum total score is 63. The BDI-II Manual designates the following raw score classifications depression severity: =13 = minimal; 14-19 = mild; 20-28 = moderate; = 29 = severe.	month 6
Secondary	Gastrointestinal Health measured by the Gastrointestinal Symptom Rating Scale at baseline	The Gastrointestinal Symptom Rating Scale (GSRS) is a specific 15-item questionnaire. Subjects are asked to numerically score their subjective symptoms on a scale of 1-7 (1 = no discomfort at all; 7 = very severe discomfort) . The sum of the scores for all 15 items is regarded as the GSRS total score. Total scores range from 15 (best outcome) to 105 (worst outcome).	Baseline (month 0)
Secondary	Gastrointestinal Health measured by the Gastrointestinal Symptom Rating Scale at month 1	The Gastrointestinal Symptom Rating Scale (GSRS) is a specific 15-item questionnaire. Subjects are asked to numerically score their subjective symptoms on a scale of 1-7 (1 = no discomfort at all; 7 = very severe discomfort) . The sum of the scores for all 15 items is regarded as the GSRS total score. Total scores range from 15 (best outcome) to 105 (worst outcome).	month 1
Secondary	Gastrointestinal Health measured by the Gastrointestinal Symptom Rating Scale at month 2	The Gastrointestinal Symptom Rating Scale (GSRS) is a specific 15-item questionnaire. Subjects are asked to numerically score their subjective symptoms on a scale of 1-7 (1 = no discomfort at all; 7 = very severe discomfort) . The sum of the scores for all 15 items is regarded as the GSRS total score. Total scores range from 15 (best outcome) to 105 (worst outcome).	month 2
Secondary	Gastrointestinal Health measured by the Gastrointestinal Symptom Rating Scale at month 3	The Gastrointestinal Symptom Rating Scale (GSRS) is a specific 15-item questionnaire. Subjects are asked to numerically score their subjective symptoms on a scale of 1-7 (1 = no discomfort at all; 7 = very severe discomfort) . The sum of the scores for all 15 items is regarded as the GSRS total score. Total scores range from 15 (best outcome) to 105 (worst outcome).	month 3
Secondary	Gastrointestinal Health measured by the Gastrointestinal Symptom Rating Scale at month 6	The Gastrointestinal Symptom Rating Scale (GSRS) is a specific 15-item questionnaire. Subjects are asked to numerically score their subjective symptoms on a scale of 1-7 (1 = no discomfort at all; 7 = very severe discomfort) . The sum of the scores for all 15 items is regarded as the GSRS total score. Total scores range from 15 (best outcome) to 105 (worst outcome).	month 6
Secondary	Perceptual Fatigue as measured by the Brain Injury Fatigue and Altered Cognition (BIAFAC) Questionnaire at baseline	Perceptual fatigue and perceptual cognition will be assessed using the 20-item Brain Injury Fatigue and Altered Cognition (BIAFAC) Questionnaire. Each item will be measured on an individual visual analog scale of 0 - 100, where the subject will mark how true each item is for them on the line with a pencil or pen with "0" indicating "not at all" and "100" indicating "extremely". Subtests of fatigue and cognition will be measured as well as a total score. Subscores and total scores range from 0-100, with a higher score indicating worse symptoms of BIAFAC.	Baseline (month 0)
Secondary	Perceptual Fatigue as measured by the Brain Injury Fatigue and Altered Cognition (BIAFAC) Questionnaire at month 3	Perceptual fatigue and perceptual cognition will be assessed using the 20-item Brain Injury Fatigue and Altered Cognition (BIAFAC) Questionnaire. Each item will be measured on an individual visual analog scale of 0 - 100, where the subject will mark how true each item is for them on the line with a pencil or pen with "0" indicating "not at all" and "100" indicating "extremely". Subtests of fatigue and cognition will be measured as well as a total score. Subscores and total scores range from 0-100, with a higher score indicating worse symptoms of BIAFAC.	month 3
Secondary	Perceptual Fatigue as measured by the Brain Injury Fatigue and Altered Cognition (BIAFAC) Questionnaire at month 6	Perceptual fatigue and perceptual cognition will be assessed using the 20-item Brain Injury Fatigue and Altered Cognition (BIAFAC) Questionnaire. Each item will be measured on an individual visual analog scale of 0 - 100, where the subject will mark how true each item is for them on the line with a pencil or pen with "0" indicating "not at all" and "100" indicating "extremely". Subtests of fatigue and cognition will be measured as well as a total score. Subscores and total scores range from 0-100, with a higher score indicating worse symptoms of BIAFAC.	month 6
Secondary	Perceptual Cognition as measured by the Brain Injury Fatigue and Altered Cognition (BIAFAC) Questionnaire at baseline	Perceptual fatigue and perceptual cognition will be assessed using the 20-item Brain Injury Fatigue and Altered Cognition (BIAFAC) Questionnaire. Each item will be measured on an individual visual analog scale of 0 - 100, where the subject will mark how true each item is for them on the line with a pencil or pen with "0" indicating "not at all" and "100" indicating "extremely". Subtests of fatigue and cognition will be measured as well as a total score. Subscores and total scores range from 0-100, with a higher score indicating worse symptoms of BIAFAC.	Baseline (month 0)
Secondary	Perceptual Cognition as measured by the Brain Injury Fatigue and Altered Cognition (BIAFAC) Questionnaire at month 3	Perceptual fatigue and perceptual cognition will be assessed using the 20-item Brain Injury Fatigue and Altered Cognition (BIAFAC) Questionnaire. Each item will be measured on an individual visual analog scale of 0 - 100, where the subject will mark how true each item is for them on the line with a pencil or pen with "0" indicating "not at all" and "100" indicating "extremely". Subtests of fatigue and cognition will be measured as well as a total score. Subscores and total scores range from 0-100, with a higher score indicating worse symptoms of BIAFAC.	month 3
Secondary	Perceptual Cognition as measured by the Brain Injury Fatigue and Altered Cognition (BIAFAC) Questionnaire at month 6	Perceptual fatigue and perceptual cognition will be assessed using the 20-item Brain Injury Fatigue and Altered Cognition (BIAFAC) Questionnaire. Each item will be measured on an individual visual analog scale of 0 - 100, where the subject will mark how true each item is for them on the line with a pencil or pen with "0" indicating "not at all" and "100" indicating "extremely". Subtests of fatigue and cognition will be measured as well as a total score. Subscores and total scores range from 0-100, with a higher score indicating worse symptoms of BIAFAC.	month 6
Secondary	Total BIAFAC (Brain Injury Fatigue and Altered Cognition) Score as measured by the Brain Injury Fatigue and Altered Cognition (BIAFAC) Questionnaire at baseline	Perceptual fatigue and perceptual cognition will be assessed using the 20-item Brain Injury Fatigue and Altered Cognition (BIAFAC) Questionnaire. Each item will be measured on an individual visual analog scale of 0 - 100, where the subject will mark how true each item is for them on the line with a pencil or pen with "0" indicating "not at all" and "100" indicating "extremely". Subtests of fatigue and cognition will be measured as well as a total score. Subscores and total scores range from 0-100, with a higher score indicating worse symptoms of BIAFAC.	Baseline (month 0)
Secondary	Total BIAFAC (Brain Injury Fatigue and Altered Cognition) Score as measured by the Brain Injury Fatigue and Altered Cognition (BIAFAC) Questionnaire at month 3	Perceptual fatigue and perceptual cognition will be assessed using the 20-item Brain Injury Fatigue and Altered Cognition (BIAFAC) Questionnaire. Each item will be measured on an individual visual analog scale of 0 - 100, where the subject will mark how true each item is for them on the line with a pencil or pen with "0" indicating "not at all" and "100" indicating "extremely". Subtests of fatigue and cognition will be measured as well as a total score. Subscores and total scores range from 0-100, with a higher score indicating worse symptoms of BIAFAC.	month 3
Secondary	Total BIAFAC (Brain Injury Fatigue and Altered Cognition) Score as measured by the Brain Injury Fatigue and Altered Cognition (BIAFAC) Questionnaire at month 6	Perceptual fatigue and perceptual cognition will be assessed using the 20-item Brain Injury Fatigue and Altered Cognition (BIAFAC) Questionnaire. Each item will be measured on an individual visual analog scale of 0 - 100, where the subject will mark how true each item is for them on the line with a pencil or pen with "0" indicating "not at all" and "100" indicating "extremely". Subtests of fatigue and cognition will be measured as well as a total score. Subscores and total scores range from 0-100, with a higher score indicating worse symptoms of BIAFAC.	month 6
Secondary	Cognition as assessed by the Repeatable Battery Assessment for Neuropsychological Status (RBANS) at baseline	The Repeatable Battery Assessment for Neuropsychological Status (RBANS) is a cognitive battery that has been utilized among Traumatic Brain Injury patients. It is comprised of 12 tests that assess five cognitive domains including immediate and delayed memory, language, visuospatial/constructional abilities, and attention. Immediate memory is assessed by two tests (list learning and story learning), visuospatial/constructional abilities is assessed by two tests (figure copy and line orientation), language is assessed by two tests (picture naming and semantic fluency), attention is two tests (digit span and coding), and delayed memory is assessed by four tests (list recall, list recognition, story recall and figure recall). RBANS raw subtests scores are converted to index standard scores. The RBANS has a mean score of 100 with a Standard Deviation of 15. Scores range from 40 to 160. Only the Traumatic Brain Injury group will undergo cognitive assessment.	Baseline
Secondary	Cognition as assessed by the Repeatable Battery Assessment for Neuropsychological Status (RBANS) at month 3	The Repeatable Battery Assessment for Neuropsychological Status (RBANS) is a cognitive battery that has been utilized among Traumatic Brain Injury patients. It is comprised of 12 tests that assess five cognitive domains including immediate and delayed memory, language, visuospatial/constructional abilities, and attention. Immediate memory is assessed by two tests (list learning and story learning), visuospatial/constructional abilities is assessed by two tests (figure copy and line orientation), language is assessed by two tests (picture naming and semantic fluency), attention is two tests (digit span and coding), and delayed memory is assessed by four tests (list recall, list recognition, story recall and figure recall). RBANS raw subtests scores are converted to index standard scores. The RBANS has a mean score of 100 with a Standard Deviation of 15. Scores range from 40 to 160. Only the Traumatic Brain Injury group will undergo cognitive assessment.	month 3
Secondary	Cognition as assessed by the Repeatable Battery Assessment for Neuropsychological Status (RBANS) at month 6	The Repeatable Battery Assessment for Neuropsychological Status (RBANS) is a cognitive battery that has been utilized among Traumatic Brain Injury patients. It is comprised of 12 tests that assess five cognitive domains including immediate and delayed memory, language, visuospatial/constructional abilities, and attention. Immediate memory is assessed by two tests (list learning and story learning), visuospatial/constructional abilities is assessed by two tests (figure copy and line orientation), language is assessed by two tests (picture naming and semantic fluency), attention is two tests (digit span and coding), and delayed memory is assessed by four tests (list recall, list recognition, story recall and figure recall). RBANS raw subtests scores are converted to index standard scores. The RBANS has a mean score of 100 with a Standard Deviation of 15. Scores range from 40 to 160. Only the Traumatic Brain Injury group will undergo cognitive assessment.	month 6
Secondary	1 methyl Histidine at baseline	Amino acid 1 methyl histidine (1MHis) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	1 methyl Histidine at month 3	Amino acid 1 methyl histidine (1MHis) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	3 methyl Histidine at baseline	Amino acid 3 methyl histidine (3MHis) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	3 methyl Histidine at month 3	Amino acid 3 methyl histidine (3MHis) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	L-alpha-Aminoadipic acid at baseline	Amino acid L-alpha-Aminoadipic (Aad) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	L-alpha-Aminoadipic acid at month 3	Amino acid L-alpha-Aminoadipic (Aad) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	2-Aminobutyric Acid at baseline	Amino acid 2-Aminobutyric Acid (Abu) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	2-Aminobutyric Acid at month 3	Amino acid 2-Aminobutyric Acid (Abu) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Alanine at baseline	Amino acid Alanine (Ala) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Alanine at month 3	Amino acid Asparagine (Asn) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Asparagine at baseline	Amino acid Asparagine (Asn) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Asparagine at baseline	Amino acid Asparagine (Asn) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Arginine at baseline	Amino acid Arginine (Arg) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Arginine at month 3	Amino acid Arginine (Arg) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Aspartate at baseline	Amino acid Aspartate(Asp) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Aspartate at month 3	Amino acid Aspartate(Asp) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	D, L-beta-Aminoisobutyric acid	Amino acid D, L-beta-Aminoisobutyric acid (bAid) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	D, L-beta-Aminoisobutyric acid	Amino acid D, L-beta-Aminoisobutyric acid (bAid) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	beta-Alanine at baseline	Amino acid beta-Alanine (bAla) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	beta-Alanine at month 3	Amino acid beta-Alanine (bAla) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	L-Carnosine	Amino acid L-Carnosine (Car) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	L-Carnosine	Amino acid L-Carnosine (Car) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Citrulline at baseline	Amino acid citrulline (Cit) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Citrulline at month 3	Amino acid citrulline (Cit) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Cystathionine	Amino acid Cystathionine (Cth) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Cystathionine	Amino acid Cystathionine (Cth) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Cysteine at baseline	Amino acid cysteine (Cys) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Cysteine at month 3	Amino acid cysteine (Cys) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Ethanolamine at baseline	Amino acid ethanolamine (Etn) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Ethanolamine at month 3	Amino acid ethanolamine (Etn) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Gamma aminobutyric acid at baseline	Amino acid gamma aminobutyric acid (GABA) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Gamma aminobutyric acid at month 3	Amino acid gamma aminobutyric acid (GABA) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Glutamine at baseline	Amino acid glutamine (Gln) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Glutamine at month 3	Amino acid glutamine (Gln) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Glutamate at baseline	Amino acid glutamate (Glu) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Glutamate at month 3	Amino acid glutamate (Glu) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Glycine at baseline	Amino acid glycine (Gly) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Glycine at month 3	Amino acid glycine (Gly) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Homocysteine at baseline	Amino acid homocysteine (Hcy) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Homocysteine at month 3	Amino acid homocysteine (Hcy) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Histidine at baseline	Amino acid histidine (His) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Histidine at month 3	Amino acid histidine (His) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Hydroxylysine at baseline	Amino acid hydroxylysine (Hyl) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Hydroxylysine at month 3	Amino acid hydroxylysine (Hyl) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Hydroxyproline at baseline	Amino acid hydroxyproline (Hyp) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Hydroxyproline at month 3	Amino acid hydroxyproline (Hyp) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Isoleucine at baseline	Amino acid Isoleucine (Ile) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Isoleucine at month 3	Amino acid Isoleucine (Ile) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Leucine at baseline	Amino acid Leucine (Leu) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Leucine at month 3	Amino acid Leucine (Leu) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Lysine at baseline	Amino acid Lysine (Lys) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Lysine at month 3	Amino acid Lysine (Lys) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Methionine at baseline	Amino acid Methionine (Met) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Methionine at month 3	Amino acid Methionine (Met) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Norleucine at baseline	Amino acid Norleucine (Nle) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Norleucine at month 3	Amino acid Norleucine (Nle) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Norvaline at baseline	Amino acid Norvaline (Nva) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Norvaline at month 3	Amino acid Norvaline (Nva) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Ornithine at baseline	Amino acid Ornithine (Orn) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Ornithine at month 3	Amino acid Ornithine (Orn) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	phospho-ethanolamine at baseline	Amino acid phosphoethanolamine (pEtn) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	phospho-ethanolamine at month 3	Amino acid phosphoethanolamine (pEtn) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Phenylalanine at baseline	Amino acid phenylalanine (Phe) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Phenylalanine at month 3	Amino acid phenylalanine (Phe) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Proline at baseline	Amino acid proline (Pro) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Proline at month 3	Amino acid proline (Pro) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	phospho-serine at baseline	Amino acid phospho-serine (pSer) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	phospho-serine at month 3	Amino acid phospho-serine (pSer) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Sarcosine at baseline	Amino acid sarcosine (Sar) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Sarcosine at month 3	Amino acid sarcosine (Sar) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Serine at baseline	Amino acid serine (Ser) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Serine at month 3	Amino acid serine (Ser) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Taurine at baseline	Amino acid taurine (Tau) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Taurine at month 3	Amino acid taurine (Tau) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Threonine at baseline	Amino acid threonine (Thr) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Threonine at month 3	Amino acid threonine (Thr) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Tryptophan at baseline	Amino acid tryptophan (Trp) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Tryptophan at month 3	Amino acid tryptophan (Trp) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Tyrosine at baseline	Amino acid tyrosine (Tyr) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Tyrosine at month 3	Amino acid tyrosine (Tyr) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3
Secondary	Valine at baseline	Amino acid valine (val) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	Baseline (month 0)
Secondary	Valine at month 3	Amino acid valine (val) will be measured in serum before and after a standardized meal. Results will be reported as change concentration in micrometers (uM).	month 3