Changes in Tryptophan Metabolism on Serotonin and Kynurenine Pathways in Patients with Irritable Bowel Syndrome.

(1) Background: L-tryptophan is a substrate for the synthesis of many biological compounds through the serotonin and kynurenine pathways. These compounds have a significant influence on gastrointestinal functions and mental processes. The aim of the study was to evaluate the urinary excretion of selected tryptophan metabolites in patients with constipation-predominant and diarrhoea-predominant irritable bowel syndrome (IBS-C and IBS-D, respectively), related to somatic and mental symptoms. (2) Methods: 120 people were included in the study and three groups were distinguished, with 40 individuals each, including healthy subjects (controls), patients with IBS-C and patients with IBS-D. The Gastrointestinal Symptoms Rating Scale (GSRS-IBS) was used to assess the severity of abdominal symptoms. The Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Depression Rating Scale (HAM-D) were used to evaluate the mental state of patients. Using liquid chromatography tandem mass spectrometry (LC-MS/MS), L-tryptophan and the following metabolites in urine, related to the creatinine level, were measured: 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QA). (3) Results: In both groups of patients with IBS, changes in tryptophan metabolism were found as compared to the control group. We observed an increase in the activity of the serotonin pathway and a positive correlation between the 5-HIAA level and the GSRS score (p < 0.01) and HAM-A score (p < 0.001) in IBS-D patients. The IBS-C group was characterized by a higher concentration of kynurenines (KYN, QA) in urine. Moreover, the QA (p < 0.001) and KYNA (p < 0.05) levels were correlated with the HAM-D score among IBS-C patients. (4) Conclusions: Various changes in the tryptophan metabolism pathway can determine the differences in the clinical picture of irritable bowel syndrome. These results should be included in the nutritional and pharmacological treatment of this syndrome.

Beneficial Effect of Increased Tryptophan Intake on Its Metabolism and Mental State of the Elderly.

The elderly often suffer from sleep disorders and depression, which contribute to mood disorders. In our previous work, we showed that elderly individuals with mood disorders had a lower intake of TRP and recommended a TRP-based dietary intervention to improve the mental state of such individuals. In this work, we assessed the impact of a TRP-rich diet on the mental state of, and TRP metabolism in, elderly individuals with mood disorders. Forty elderly individuals with depression and sleep disorders and an equal number of elderly subjects without mood disorders were enrolled in this study. TRP intake was evaluated with the nutrition calculator. Patients with mood disorders had a lower TRP intake than their normal counterparts and received a TRP-rich diet with TRP content of 25 mg per kilogram of the body per day for 12 weeks. The mental state was assessed before and after this dietary intervention with the Hamilton Depression Rating Scale (HAM-D) and the Insomnia Severity Index (ISI). At those times, urinary levels of TRP and its metabolites 5-hydroxyindoleacetic acid (5-HIAA), L-kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QA) were determined by liquid chromatography with tandem mass spectrometry and related to creatinine level. After TRP-based dietary intervention, the score of ISI and HAM-D decreased by more than half. A correlation analysis reveals that TRP, 5-HIAA, and KYNA might have anti-depressive action, while KYN and QA-pro-depressive. The levels of TRP, 5-HIAA, and KYNA in urine of mood disorder patients increased, while the levels of KYN and QA decreased. In conclusion, dietary consumption of adequate amount of tryptophan has a beneficial effect on mental health of the elderly with mood disorders and improves metabolism of this amino acid. Therefore, a TRP-enriched diet may be considered as a component of the treatment of elderly individuals with mood disorders.

Tryptophan Metabolism in Postmenopausal Women with Functional Constipation.

Constipation belongs to conditions commonly reported by postmenopausal women, but the mechanism behind this association is not fully known. The aim of the present study was to determine the relationship between some metabolites of tryptophan (TRP) and the occurrence and severity of abdominal symptoms (Rome IV) in postmenopausal women with functional constipation (FC, n = 40) as compared with age-adjusted postmenopausal women without FC. All women controlled their TRP intake in their daily diet. Urinary levels of TRP and its metabolites, 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), and 3-indoxyl sulfate (indican, 3-IS), were determined by liquid chromatography/tandem mass spectrometry. Dysbiosis was assessed by a hydrogen-methane breath test. Women with FC consumed less TRP and had a lower urinary level of 5-HIAA, but higher levels of KYN and 3-IS compared with controls. The severity of symptoms showed a negative correlation with the 5-HIAA level, and a positive correlation with the 3-IS level. In conclusion, changes in TRP metabolism may contribute to FC in postmenopausal women, and dysbiosis may underlie this contribution.

The role of serotonin in pathogenesis of unclassified irritable bowel syndrome.

The pathogenesis of irritable bowel syndrome (IBS) has not been clearly understood. Numerous factors, including neurotransmitters, can interfere with the functions of the digestive tract. AIM: The aim of present study was to determine the secretion and metabolism of serotonin in patients with unclassified irritable bowel syndrome (IBS-U). MATERIALS AND METHODS: The study included 50 healthy subjects (Controls) and 50 patients with IBS-U, diagnosed according to Rome IV Criteria of functional gastrointestinal disorders. The severity of gastrointestinal symptoms was assessed using the Gastrointestinal Symptom Rating Scale (GSRS- IBS). The quality of sleep was estimated by Insomnia Severity Index (ISI). The serum serotonin and melatonin levels and 5-hydroxyindoleacetic acid (5-HIAA) and 6-sulfatoxymelatonin (aMT6s) concentration in urine were determined with ELISA method. RESULTS: Compared to control group, patients with IBS-U had a higher serum levels (201.3 ± 37.8 vs 145.4 ± 36.9 ng/ml, p < 0.001) and lower levels of melatonin (5.86 ± 1,16 vs9.11 ±2.43 pg/ml, p < 0.001). Likewise, in IBS-U patients urinary excretion of 5-HIAA was greater, while aMT6s excretion was lower. Due to the above changes cyproheptadine (6 mg daily) or melatonin (7 mg daily) was recommended to be taken. After 12 weeks of taking cyproheptadine, the IBS symptoms disappeared in 86.6% patients, and in 20.0% of those taking melatonin. Both drugs improved sleep in equal measure. CONCLUSIONS: Increased serotonin secretion may be the cause of abdominal complaints in unclassified irritable bowel syndrome, what should be considered in its treatment.

Altered tryptophan metabolism in patients with recurrent functional abdominal pain.

The causes of functional abdominal pain are still unclear. The role of food factors in their pathogenesis has been assessed by many researches, but the obtained results are varied. AIM: The aim of present study was to evaluate metabolism of tryptophan, which is substrate for serotonin synthesis and other bioactive compounds, in patients with recurrent functional abdominal pain. MATERIALS AND METHODS: Thirty patients with recurrent abdominal pain and 30 healthy subjects were enrolled in this study. Urinary levels of tryptophan (TRP), 5-hydroxyindoleacetic acid(5-HIAA), L-kynurenine (KYN), xanthurenic acid(XA), and quinolinic acid(QA) were determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS), and related to creatinine level (mg/gCr), during active phase(day with acute pain), and silence period, which recommended optimalisation of tryptophan intake. RESULTS: 5-HIAA/TRP ratio and KYN/TRP ratio as well as QA level s were significantly higher in patients compared to control group (p<0.001). After reducing TRP consumption, the above results improved, in particular, the level of QA decreased from 6.88±1.04 mg/Cr to 4,32±0.97 mg/gCr (p<0.001). CONCLUSIONS: Altered tryptophan metabolism may affect locally-andcentrally mediated recurrent functional abdominal pain.

The clinical value of breath ammonia determination in patients with irritable bowel syndrome.

Gastrointestinal tract is the major source of ammonia (NH3). NH3 is produced by bacterial hydrolysis of urea as well as by bacterial protein deamination. The intensity of this process depends on protein intake and the amount of gut bacteria. AIM: The aim of the study was to assess the level of the fasting breath ammonia in patients with irritable bowel syndrome (IBS) in relation to the results of lactulose hydrogen breath test (LHBT) and to clinical form of this syndrome before and after 14-days rifaximin treatment at daily dose of 1200 mg. MATERIALS AND METHODS: The study was conducted in 120 subjects, including 40 healthy people (Controls, group I), 40 patients with IBS and predominant diarrhea (group II, IBS-D), and 40 patients with IBS and predominant constipation (group III, IBS-C). The lactulose breath test (LHBT) and ammonia breath test (ABT) were performed. Diagnosis of IBS was based on Rome IV Criteria. The severity of abdominal symptoms was assessed using the Gastrointestinal Symptom Rating Scale (GSRS-IBS). RESULTS: The basic level of ammonia in expired air in control group I was 5.2 ± 1.6 ppm, in group II - 20.8 ± 5.1 ppm (p< 0.001), and in group III - 10.4 ± 3.2 ppm (p< 0.001). Positive correlation was found between breath ammonia level and the results of LHBT in both groups with IBS. After 14-days rifaximin treatment at daily dose of 1200 mg the results of LHBT and breath ammonia significantly decreased in both groups. At the same time abdominal ailments subsided or significantly reduced. CONCLUSIONS: The determination of breath ammonia may be useful as biomarker of dysbiosis in patients with irritable bowel syndrome, especially in questionable results of hydrogen breath test.