Case Control Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 7, 2020; 26(45): 7173-7190
Published online Dec 7, 2020. doi: 10.3748/wjg.v26.i45.7173
Alteration of fecal tryptophan metabolism correlates with shifted microbiota and may be involved in pathogenesis of colorectal cancer
Xi-Zhen Sun, Dong-Yan Zhao, Yuan-Chen Zhou, Qian-Qian Wang, Geng Qin, Shu-Kun Yao
Xi-Zhen Sun, Dong-Yan Zhao, Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
Xi-Zhen Sun, Dong-Yan Zhao, Yuan-Chen Zhou, Geng Qin, Shu-Kun Yao, Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
Yuan-Chen Zhou, Qian-Qian Wang, Peking University China-Japan Friendship School of Clinical Medicine, Peking University, Beijing 100029, China
Author contributions: Sun XZ designed and performed the study, analyzed the data, and drafted the manuscript; Sun XZ, Zhou YC, and Qin G collected the clinical data and fecal samples from the subjects; Zhao DY gave guidance on experiment operation and data interpretation, and contributed to manuscript revision; Yao SK designed the study, supervised the study performance, revised the manuscript, and obtained the funding.
Supported by National Key Research and Development Plan for Precision Medicine Research, No. 2017YFC0910002.
Institutional review board statement: This study was approved by the Ethics Committee of China-Japan Friendship Hospital (No. 2018-116-K85).
Informed consent statement: All patients signed an informed consent form before study enrollment.
Conflict-of-interest statement: All authors report no conflicts of interest.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Shu-Kun Yao, MD, PhD, Professor, Department of Gastroenterology, China-Japan Friendship Hospital, 2nd Yinghua East Road, Chaoyang District, Beijing 100029, China.
Received: September 20, 2020
Peer-review started: September 20, 2020
First decision: September 29, 2020
Revised: October 12, 2020
Accepted: November 2, 2020
Article in press: November 2, 2020
Published online: December 7, 2020
Research background

Population aging has resulted in a substantial increase in the number of new colorectal cancer (CRC) cases globally. Gut microbiota and metabolite interactions are involved in the pathogenesis of CRC via various genetic and epigenetic alterations. Gut tryptophan (Trp) metabolites are produced by microbiota and/or host metabolism. Some of them were thought to play a role in CRC in animal and in vitro studies.

Research motivation

Few studies on fecal Trp metabolism have been found, especially its interaction with gut microbiota. Therefore, it is meaningful to study the characteristics of gut Trp metabolism in patients with CRC.

Research objectives

To investigate the features of Trp metabolism in CRC patients and the correlation between fecal Trp metabolites and gut microbiota.

Research methods

Subjects meeting the inclusion and exclusion criteria were included in the study. Their demographic and clinical features were collected. Fecal Trp, kynurenine (KYN), and indoles (metabolites of Trp metabolized by gut microbiota) were examined by ultraperformance liquid chromatography coupled to tandem mass spectrometry. Gut barrier marker and indoleamine 2,3-dioxygenase 1 (IDO1) mRNA were analyzed by quantitative real-time polymerase chain reaction. Zonula occludens-1 (ZO-1) protein expression was analyzed by immunohistochemistry. The gut microbiota was detected by 16S ribosomal RNA gene sequencing. Correlations between fecal metabolites and other parameters were examined in all patients.

Research results

The absolute concentration of KYN and the ratio of KYN to Trp were increased in the feces of patients with CRC compared to HCs, while the indoles to Trp ratio was decreased. Colon IDO1 mRNA levels were positively associated with fecal KYN/Trp ratio and ZO-1 mRNA levels were positively correlated with the indoles/Trp ratio. The genera Asaccharobacter (Actinobacteria) and Parabacteroides (Bacteroidetes), and several members of the phylum Firmicutes (Clostridium XlVb, Fusicatenibacter, Anaerofilum, and Anaerostipes) decreased in CRC and exhibited a positive correlation with indoles in all subjects.

Research conclusions

CRC gut Trp metabolism was characterized by a decreased Trp indole pathway in feces, which is positively correlated with bowel gut barrier function, and an increased kynurenine pathway activity in colon tissue. In addition, correlations between differentially abundant bacterial genera and imbalanced fecal Trp metabolism were also found in this study.

Research perspectives

This preliminary study investigated the alteration of gut Trp metabolism and the possible mechanism of Trp metabolites in CRC pathophysiology. In the future, we will focus on the following aspects. First, we will detect Trp and Trp metabolites in both feces and colon tissues to further study the “tumor microenvironment”. Second, it is necessary to study the dietary habits of CRC patients and explore the relationship between the diet and gut Trp metabolism. Supplementation with indoles in diet may also have an inhibitory effect on the HC-adenoma-carcinoma sequence in humans.