Exploring the Mechanisms of Indoxyl Sulfate Production by Oral Tryptophan Challenge Test

Cardiovascular disease (CVD) is prevalent in patients with chronic kidney disease (CKD) and is associated with extremely poor prognosis. Traditional risk factors for the general population, such as diabetes mellitus, high blood pressure, and dyslipidemia, are more common in patients with CKD but cannot fully explain the increased risk of this population. New evidence suggests that the uremic milieu itself plays a critical role in the development and progression of CVD. The gut microbiota is markedly altered in CKD, with overgrowth of bacteria that produce uremic toxins. Indoxyl sulfate (IS) is among the most representative gut-derived uremic toxins and has been most frequently implicated as a contributor to the pathogenesis of CVD in CKD. IS is converted from indole, a gut bacteria metabolite of dietary tryptophan, by two hepatic enzymes, CYP2E1 and SULT1A1. The majority of studies have assessed IS toxicity in cultured cells and animal models. However, human data have been conflicting and the benefit of using orally administered adsorbents to reduce IS levels in unselected CKD patients was not supported by results from the recent randomized controlled trials. IS levels may fluctuate widely from time to time with dietary intakes. The investigators hypothesize that a postprandial IS concentration may more reflect its toxicity than a single time point (fasting or predialysis IS) concentration measured in clinical studies. Therefore, the investigators plan to establish an oral tryptophan challenge test (OTCT) by using an oral loading of 2 gm tryptophan to simulate the postprandial increase of plasma IS. The investigators will recruit 60 healthy volunteers to undergo OTCT. A pharmacokinetic study of IS after the OTCT will be performed in 20 of them to verify and simplify the design of OTCT protocol. The results of OTCT will be integrated with whole metagenome analysis of fecal microbiota and genetic polymorphism analysis of CYP2E1 and SULT1A1 to explore the mechanisms of IS production. In addition to the known genes in microbe produces indoles, other supporting bacteria or genes will be examined by using metagenomic shotgun sequencing data.

Study Overview

• Status: Completed
• Conditions: Healthy; Chronic Kidney Diseases
• Intervention / Treatment: Dietary supplement: Doctor's Best L-Tryptophan

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Taiwan
  • New Taipei City, Taiwan, 231
    • Taipei Tzu Chi Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• (1) age older than 20 years
• (2) no exposure to antibiotics or probiotics within the 3 months before entering the study.

Exclusion Criteria:

• (1) recent gastrointestinal discomfort (such as nausea, vomiting, abdominal pain, constipation, or diarrhea) or
• (2) a history of chronic diseases including diabetes mellites, hypertension, CVD, CKD, liver disease, malignancy, and autoimmune disease.
• (3) pregnancy or breast feeding
• (4) currently use of antipsychotics, Hypnotics, Demerol, Dextromethorphan, tramadol, pentazocine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tryptophan loading; All participants are introduced to receive tryptophan loading test.	Dietary supplement: Doctor's Best L-Tryptophan; 2g tryptophan loading once

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Indoxyl sulfate	serum and urine indoxyl sulfate concentration measurement	the area under curve of serum and urine indoxyl sulfate within 72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Indole-3-acetic acid	serum and urine Indole-3-acetic acid concentration measurement	the area under curve of serum and urine Indole-3-acetic acid within 72 hours

Collaborators and Investigators

• Sponsor: Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation
• Investigators: Principal Investigator: Ting-Yun Lin, MD., Taichung Tzu Chi Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2019
• Primary Completion (Actual): November 30, 2019
• Study Completion (Actual): November 30, 2019

Study Registration Dates

• First Submitted: September 29, 2019
• First Submitted That Met QC Criteria: October 3, 2019
• First Posted (Actual): October 7, 2019

Study Record Updates

• Last Update Posted (Actual): December 10, 2019
• Last Update Submitted That Met QC Criteria: December 8, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Kidney Diseases; Renal Insufficiency, Chronic; Psychotropic Drugs; Antidepressive Agents; Antidepressive Agents, Second-Generation; Tryptophan
• Other Study ID Numbers: 08-P-055

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No