IBS May Have a Causal Effect on Increased Tryptophan Metabolites Levels: Insights from a Bidirectional Two-Sample Mendelian Randomization Study

Abstract

Background: Irritable Bowel Syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by abdominal pain and altered bowel habits. Tryptophan, an essential amino acid derived from dietary proteins, can be metabolized into various compounds by the gut microbiome. Emerging evidence suggests that tryptophan metabolites play a role in functional gastrointestinal disorders. However, the causal relationship between tryptophan metabolites and IBS remains to be fully elucidated.

Objective: This study aims to evaluate the potential causal relationship between tryptophan metabolites and IBS using Mendelian randomization (MR).

Methods: Instrumental variables (IVs) were selected from summary data of genome-wide association studies (GWAS) for tryptophan and IBS. SNPs potentially influencing MR results were excluded through outlier detection using MR-PRESSO. Bidirectional two-sample MR analyses were conducted using the inverse-variance weighted (IVW), MR-Egger regression, weighted median, weighted mode, and simple mode methods. The MR-Egger intercept test was employed to assess pleiotropy and heterogeneity among IVs, with visualization of the MR results through scatter plots, funnel plots, and forest plots.

Results: Genetically predicted tryptophan metabolites were not associated with the risk of IBS. In the reverse direction, genetically predicted IBS was associated with increased levels of tryptophan, serotonin, and kynurenine in the IVW analysis. Sensitivity and replication analyses confirmed these findings.

Conclusion: The findings of this Mendelian randomization study suggest that IBS may lead to elevated levels of tryptophan, serotonin, and kynurenine. These results have important implications for understanding the interplay between tryptophan metabolism and IBS in clinical settings. Further research is warranted to explore the underlying mechanisms.

Keywords: Irritable bowel syndrome; Mendelian randomization; causal relationship; kynurenine; tryptophan metabolites.

Figure 1.

The outline of the methodology. (A) The assumptions for MR analysis. (B) The flow of two-sample MR analysis. IVs, instrumental variables; IVW, inverse-variance weighted; MR, Mendelian randomization; WM, weighted median; MR-PRESSO, MR pleiotropy residual sum and outlier; IBS, irritable bowel syndrome.

Figure 2.

Overall design of the MR analysis framework in this study. A flow chart depicts how the MR analysis was conducted step by step in this study. Abbreviation: LD, linkage disequilibrium.

Figure 3.

Estimation of the causal relationship between tryptophan metabolites and IBS using different MR methods. Beta: A positive value indicates that an increase in the exposure factors leads to an increase in the outcome variable. OR > 1 indicates an increased risk, and OR < 1 indicates a decreased risk. No causal relationship between tryptophan and its metabolic byproducts as a risk factor for IBS development (P > .05). Abbreviations: CI, confidence interval; MR, Mendelian randomization; OR, odds ratio; SE, standard error; SNP, single nucleotide polymorphism.

Figure 4.

Scatter plots of genetic correlations of tryptophan metabolites and IBS using different MR methods. Lines trending upward indicate a positive correlation, on the contrary, lines trending downward inficate a negative correlation. Bidirectional MR analyses first exposed tryptophan and its metabolic byproducts to IBS outcomes, yielding no causal link (P > .05): (A) the scatter plot of MR analysis between tryptophan and IBS, (B) the scatter plot of MR analysis between pyruvate and IBS, and (C) the scatter plot of MR analysis between kynurenine and IBS. Abbreviation: MR, Mendelian randomization.

Figure 5.

Estimation of the causal relationship between IBS and tryptophan with its metabolites using different MR methods. Beta: A positive value indicates that an increase in the exposure factors leads to an increase in the outcome variable. OR > 1 indicates an increased risk, and OR < 1 indicates a decreased risk. Changes in the concentration of these metabolites within IBS patients were observed. Abbreviations: CI, confidence interval; IBS, irritable bowel syndrome; MR, Mendelian randomization; OR, odds ratio; SE, standard error; SNP, single nucleotide polymorphism.

Figure 6.

Scatter plots of genetic correlations of IBS and tryptophan metabolites using different MR methods. Lines trending upward indicate a positive correlation, on the contrary, lines trending downward inficate a negative correlation. IBS exposure revealed positive correlations with tryptophan, serotonin, and kynurenic acid (P < .05): (A) the scatter plot of MR analysis between IBS and tryptophan, (B) the scatter plot of MR analysis between IBS and pyruvate, (C) the scatter plot of MR analysis between IBS and kynurenine, (D) the scatter plot of MR analysis between IBS and serotonin. Kynurenine, (E) the scatter plot of MR analysis between IBS and indoleacetate, and (F) the scatter plot of MR analysis between IBS and indolepropionate. Abbreviation: MR, Mendelian randomization.