Tryptophan Metabolites in the Progression of Liver Diseases

Abstract

The aim of this study was to investigate the levels of various tryptophan metabolites in patients with alcoholic liver disease (ALD) and metabolic-associated fatty liver disease (MAFLD) at different stages of the disease. The present study included 44 patients diagnosed with MAFLD, 40 patients diagnosed with ALD, and 14 healthy individuals in the control group. The levels of tryptophan and its 16 metabolites (3-OH anthranilic acid, 5-hydroxytryptophan, 5-methoxytryptamine, 6-hydroxymelatonin, indole-3-acetic acid, indole-3-butyric, indole-3-carboxaldehyde, indole-3-lactic acid, indole-3-propionic acid, kynurenic acid, kynurenine, melatonin, quinolinic acid, serotonin, tryptamine, and xanthurenic acid) in the serum were determined via high-performance liquid chromatography and tandem mass spectrometry. In patients with cirrhosis resulting from MAFLD and ALD, there are significant divergent changes in the serotonin and kynurenine pathways of tryptophan catabolism as the disease progresses. All patients with cirrhosis showed a decrease in serotonin levels (^MAFLDp = 0.038; ^ALDp < 0.001) and an increase in kynurenine levels (^MAFLDp = 0.032; ^ALDp = 0.010). A negative correlation has been established between serotonin levels and the FIB-4 index (p < 0.001). The decrease in serotonin pathway metabolites was associated with manifestations of portal hypertension (p = 0.026), the development of hepatocellular insufficiency (p = 0.008) (hypoalbuminemia; hypocoagulation), and jaundice (p < 0.001), while changes in the kynurenine pathway metabolite xanthurenic acid were associated with the development of hepatic encephalopathy (p = 0.044). Depending on the etiological factors of cirrhosis, disturbances in the metabolic profile may be involved in various pathogenetic pathways.

Keywords: ALD; MAFLD; liver cirrhosis; metabolomic profiling; tryptophan metabolite.

Figure 1

The main pathways of tryptophan catabolism in the human body. Kynurenine pathway in host immune cells and liver. Indole pyruvate pathway performed by gut microbiota. Serotonin pathway performed by enterochromaffin cells. *—metabolites whose levels were statistically highly correlated in our study with the etiology of the disease, the type of liver damage, and clinical manifestations of the disease.

Figure 2

Tryptophan metabolites’ correlation analysis depending on laboratory test for MAFLD.

Figure 3

Tryptophan metabolites’ correlation analysis depending on laboratory test for ALD.

Figure 4

Metabolite levels in the group of patients with cirrhosis of various etiologies (MAFLD and ALD) with and without ascites. (a) Level of 5-hydroxytryptophan; (b) level of serotonin.

Figure 5

Level of 5-methoxytryptamine in the group of patients with cirrhosis of various etiologies (MAFLD and ALD) with and without the clinical syndrome of jaundice.

Figure 6

Level of 5-methoxytryptamine in the group of patients with cirrhosis of various etiologies (MAFLD and ALD) with signs of portal hypertension based on EGD data (GVs and/or EVs) and without signs of portal hypertension.

Figure 7

Levels of metabolites in the group of patients with cirrhosis of various etiologies (MAFLD and ALD) with and without hepatic failure syndrome (hypocoagulation, hypoalbuminemia). (a) Level of 5-methoxytryptamine; (b) level of serotonin; (c) level of indole-3-butyric acid.

Figure 8

Receiver operating characteristic (ROC) analysis for and metabolic panel of 17 tryptophan metabolites (MAFLD vs. ALD).

Scheme 1

Changes in the tryptophan metabolite levels in patients with MAFLD compared to the control group.

Scheme 2

Changes in the tryptophan metabolites levels in patients with ALD compared to the control group.

Scheme 3

Changes in the tryptophan metabolites levels in patients with MAFLD compared to ALD.