Tryptophan Catabolites Research Articles

Clostridium sporogenes-derived metabolites protect mice against colonic inflammation

ABSTRACT Gut microbiota-derived metabolites play a pivotal role in the maintenance of intestinal immune homeostasis. Here, we demonstrate that the human commensal Clostridium sporogenes possesses a specific metabolic fingerprint, consisting predominantly of the tryptophan catabolite indole-3-propionic acid (IPA), the branched-chain acids (BCFAs) isobutyrate and isovalerate and the short-chain fatty acids (SCFAs) acetate and propionate. Mono-colonization of germ-free mice with C. sporogenes (CS mice) affected colonic mucosal immune cell phenotypes, including up-regulation of Il22 gene expression, and increased abundance of transcriptionally active colonic tuft cells and Foxp3+ regulatory T cells (Tregs). In DSS-induced colitis, conventional mice suffered severe inflammation accompanied by loss of colonic crypts. These symptoms were absent in CS mice. In conventional, but not CS mice, bulk RNAseq analysis of the colon revealed an increase in inflammatory and Th17-related gene signatures. C. sporogenes-derived IPA reduced IL-17A protein expression by suppressing mTOR activity and by altering ribosome-related pathways in Th17 cells. Additionally, BCFAs and SCFAs generated by C. sporogenes enhanced the activity of Tregs and increased the production of IL-22, which led to protection from colitis. Collectively, we identified C. sporogenes as a therapeutically relevant probiotic bacterium that might be employed in patients with inflammatory bowel disease (IBD).

8743 Regulation Of Tryptophan 2,3-Dioxygenase 2 And Androgen Receptor In Triple-Negative Breast Cancer

Abstract Disclosure: L. Kuo: None. K. Lacey: None. N. Spoelstra: None. J.K. Richer: None. Background: Triple Negative Breast Cancer (TNBC) is an aggressive subtype with a peak recurrence rate within 3-5 years after initial diagnosis. Androgen receptor (AR) and Tryptophan 2,3-dioxygenase 2 (TDO2) are elevated in TNBC cells grown under anchorage-independent conditions and facilitate anoikis resistance. Several studies reported that the luminal AR subset of TNBC showed a positive enrichment of the tryptophan (TRP) catabolism pathway gene signature. Recent studies have demonstrated that aryl hydrocarbon receptor (AhR) inhibition decreases AR promoter transcriptional activity in prostate cancer. We have observed that TNBC with high AR have high levels of genes/proteins in the tryptophan catabolism pathway including the rate limiting enzyme TDO2. Hypothesis: TDO2 activity regulates AR expression through the downstream tryptophan catabolite kynurenine (KYN), which binds and activates AhR and AhR and AR may work together to promote TNBC progression. Methods: Human TNBC cell lines: MDA-MB-453, BT549, SUM159PT ​ were used in this study and the expression of TDO2 and AR were examined by immunohistochemistry (IHC) and western blot. TDO2 was stably knocked down (KD) via shRNA or overexpressed (OE) using lentivirus transduction. Mass spectrometry-based metabolomics were used to measure changes in TRP catabolite levels, and a cytokine array (R&D) was utilized to analyze conditioned media. Results: TDO2 and AR protein are positively correlated in human TNBC cell lines. Although overexpression of TDO2 did not alter AR protein expression in SUM159PT, in the human MDA-MB-453, which have high levels of AR, knockdown of TDO2 (shTDO2) reduced AR protein by 40% and production of kynurenine (KYN) was reduced by 50% (p<0.0001). This suggests that TDO2 activity, specifically KYN binding to AhR, may influence AR protein levels. Conditioned media (CM) from TDO2 OE and KD respectively increased and decreased CXCL5 and IGFBP2. Lastly, TCGA database analysis of TNBC tumors with high levels of both AhR and AR showed significantly shorter patient survival (HR=1.47, log rank p=0.046) compared to those with tumors with lower amounts of both genes. Conclusion: TDO2 and AR are positively correlated in human TNBC cell lines. Tumors with high levels of both AR and AhR result in significantly shorter survival time for TNBC patients. Knockdown of TDO2 significantly reduced KYN production and AR expression in luminal AR TNBC cell lines and future experiments will focus on the underlying mechanism behind this and whether it is dependent on KYN-mediated activation of AhR and if AhR stabilizes AR in TNBC. Presentation: 6/3/2024

8743 Regulation of Tryptophan 2,3-Dioxygenase 2 and Androgen Receptor in Triple-Negative Breast Cancer

Abstract Disclosure: L. Kuo: None. K. Lacey: None. N. Spoelstra: None. J.K. Richer: None. Background: Triple Negative Breast Cancer (TNBC) is an aggressive subtype with a peak recurrence rate within 3-5 years after initial diagnosis. Androgen receptor (AR) and Tryptophan 2,3-dioxygenase 2 (TDO2) are elevated in TNBC cells grown under anchorage-independent conditions and facilitate anoikis resistance. Several studies reported that the luminal AR subset of TNBC showed a positive enrichment of the tryptophan (TRP) catabolism pathway gene signature. Recent studies have demonstrated that aryl hydrocarbon receptor (AhR) inhibition decreases AR promoter transcriptional activity in prostate cancer. We have observed that TNBC with high AR have high levels of genes/proteins in the tryptophan catabolism pathway including the rate limiting enzyme TDO2. Hypothesis: TDO2 activity regulates AR expression through the downstream tryptophan catabolite kynurenine (KYN), which binds and activates AhR and AhR and AR may work together to promote TNBC progression. Methods: Human TNBC cell lines: MDA-MB-453, BT549, SUM159PT ​ were used in this study and the expression of TDO2 and AR were examined by immunohistochemistry (IHC) and western blot. TDO2 was stably knocked down (KD) via shRNA or overexpressed (OE) using lentivirus transduction. Mass spectrometry-based metabolomics were used to measure changes in TRP catabolite levels, and a cytokine array (R&D) was utilized to analyze conditioned media. Results: TDO2 and AR protein are positively correlated in human TNBC cell lines. Although overexpression of TDO2 did not alter AR protein expression in SUM159PT, in the human MDA-MB-453, which have high levels of AR, knockdown of TDO2 (shTDO2) reduced AR protein by 40% and production of kynurenine (KYN) was reduced by 50% (p<0.0001). This suggests that TDO2 activity, specifically KYN binding to AhR, may influence AR protein levels. Conditioned media (CM) from TDO2 OE and KD respectively increased and decreased CXCL5 and IGFBP2. Lastly, TCGA database analysis of TNBC tumors with high levels of both AhR and AR showed significantly shorter patient survival (HR=1.47, log rank p=0.046) compared to those with tumors with lower amounts of both genes. Conclusion: TDO2 and AR are positively correlated in human TNBC cell lines. Tumors with high levels of both AR and AhR result in significantly shorter survival time for TNBC patients. Knockdown of TDO2 significantly reduced KYN production and AR expression in luminal AR TNBC cell lines and future experiments will focus on the underlying mechanism behind this and whether it is dependent on KYN-mediated activation of AhR and if AhR stabilizes AR in TNBC. Presentation: 6/3/2024

Acarbose enhances the efficacy of immunotherapy against solid tumours by modulating the gut microbiota.

The crucial role of gut microbiota in shaping immunotherapy outcomes has prompted investigations into potential modulators. Here we show that oral administration of acarbose significantly increases the anti-tumour response to anti-PD-1 therapy in female tumour-bearing mice. Acarbose modulates the gut microbiota composition and tryptophan metabolism, thereby contributing to changes in chemokine expression and increased T cell infiltration within tumours. We identify CD8+ T cells as pivotal components determining the efficacy of the combined therapy. Further experiments reveal that acarbose promotes CD8+ T cell recruitment through the CXCL10-CXCR3 pathway. Faecal microbiota transplantation and gut microbiota depletion assays indicate that the effects of acarbose are dependent on the gut microbiota. Specifically, acarbose enhances the efficacy of anti-PD-1 therapy via the tryptophan catabolite indoleacetate, which promotes CXCL10 expression and thus facilitates CD8+ T cell recruitment, sensitizing tumours to anti-PD-1 therapy. The bacterial species Bifidobacterium infantis, which is enriched by acarbose, also improves response to anti-PD-1 therapy. Together, our study endorses the potential combination of acarbose and anti-PD-1 for cancer immunotherapy.

Abstract 3013: Indoleamine 2,3-dioxygenase-mediated Tryptophan Catabolism Limits Experimental Abdominal Aortic Aneurysms

Background: Indoleamine 2,3-dioxygenase (IDO) promotes immunosuppression. Genetic IDO deficiency limits angiotensin II-induced abdominal aortic aneurysms (AAAs) in hyperlipidemic mice. We investigated the influence of IDO inhibition or IDO-catabolized tryptophan catabolite on elastase-induced AAAs in normolipidemic mice. Methods: AAAs were induced in male C57B/6J mice via intra-aortic porcine pancreatic elastase (PPE) infusion. Mice were treated with IDO inhibitor 1-methyl-DL-tryptophan (MT, 2 mg/ml in drinking water), tryptophan metabolite 3-hydroxyanthranilic acid (HAA, 200 mg/kg, oral gavage), or vehicle, starting 3 days prior to PPE infusion for 17 days. AAAs were assessed via ultrasonography and histopathology at sacrifice. Results: The Figure summarizes aortic diameters and histopathology in differentially treated PPE-infused mice. Rapid aortic enlargement was noted in MT-, as compared to vehicle-treated mice following PPE infusion. AAA rupture, unusual for this model, was noted in MT-treated AAA mice. No difference was noted between groups in medial elastin degradation, smooth muscle cell depletion, or macrophage accumulation. However, mural neoangiogenesis and lymphocyte accumulation were remarkably augmented in MT-treated mice. HAA Treatment attenuated aortic enlargement in conjunction with improved medial elastin and smooth muscle cell retention and reduced aortic leukocyte accumulation and neovessels. Conclusion: IDO activity and its tryptophan metabolite HAA limit experimental AAA progression in the PPE model. These results provide further support for investigating tryptophan metabolites in clinical AAA disease suppression.

Anti-adipogenesis effect of indole-3-acrylic acid on human preadipocytes and HFD-induced zebrafish.

Obesity, defined as excessive or abnormal body fat accumulation, which could significantly increase the risk of cardiovascular disease, type 2 diabetes mellitus (T2DM) diseases and seriously affect people's quality of life. More than 2 billion people are overweight, and the incidence of obesity is increasing rapidly worldwide, it has become a widely concerned public health issue in the world. Diverse evidence show that active metabolites are involved in the pathophysiological processes of obesity. However, whether the downstream catabolite of tryptophan, 3-indole acrylic acid (IA), is involved in obesity remains unclear. We collected the samples of serum from peripheral blood of obesity and health controls, and liquid chromatography-mass spectrometry (LC-MS) was performed to identify the plasma levels of IA. Additionally, we verified the potential benefits of IA on human preadipocytes and HFD- induced zebrafish by cell viability assay, flow cytometry assay, Oil red O staining, total cholesterol (T-CHO), triglyceride (TG) and nonesterified free fatty acids (NEFA) measurements and Nile Red staining. RNA-Seq, functional analysis and western blot revealed the mechanisms underlying the function of IA. We found that the content of IA in peripheral blood serum of overweight people was significantly lower than that of normal people. In addition, supplementation with IA in zebrafish larvae induced by a high fat diet (HFD) dramatically reduced HFD induced lipid accumulation. IA had no effect on proliferation and apoptosis of preadipocytes, but significantly inhibited adipogenesis of preadipocytes by down-regulate CEBPα and PPARγ. RNA-Seq and functional analysis revealed that IA regulated the adipogenesis of preadipocytes through stimulate the phosphorylation of STAT1. Taken together, IA has been identified as a potent metabolite for the prevention or treatment of obesity.

Abstract LB426: Evidence for a role of GPR35 in IDO1-mediated tumor immune escape by regulating Hippo-YAP pathway

Abstract IDO1 is an immune checkpoint regulator and mediator of tumor immune evasion (1). The cellular and molecular mechanisms of IDO1-mediated immune suppression are not fully understood. We describe here that GPR35, the putative receptor for kynurenic acid (KYNA), a metabolite of IDO1-mediated tryptophan catabolism, couples to Hippo-YAP pathway. GPR35 activation, either by overexpression or by treatment with tryptophan metabolites resulted in Hippo inactivation and YAP-directed transcription via TEAD family of transcription factors. Recently, YAP is found to be essential for tumor immune escape. Yap1 deficiency in T-lineage-specific knockout mice, or by dosing a YAP inhibitor, impairs Treg formation and function, leading to tumor growth inhibition (2). YAP also plays an inhibitory role in CD8 T cell function, especially in activated CTL usually found in the TME [3,4]. Through medicinal chemistry design and a structure-vs-activity relationship study effort, we discovered a GPR35-selective inhibitor, here termed TMER1i. TMER1i potently blocks GPR35 in Hippo suppression and YAP activation. We showed that GPR35 is expressed in the T-cell lineage of the immune cells including naïve CD4 T cells, Treg and CD8 T cells. Treatment of purified human naïve CD4 T cells with anti-CD3/anti-CD28 under an IDO1+ TME-like culture condition in vitro induced a robust T cell activation and differentiation toward Treg phenotype, as shown previously using mouse naïve CD4 T cells by others (5). Importantly, TMER1i efficiently blocked the Treg differentiation under these conditions. When dosed in human-PBMC reconstituted NCG mice bearing HT29 tumors, TMER1i dose-dependently increased the infiltration of human CD8 T cells within tumors in a statistically significant manner, and a trending lower Treg cell infiltration, accompanied by a tumor growth inhibition. qPCR analysis of the HT29 tumors grown in the PBMC-NCG mice indicated that IDO1 was highly expressed in the tumors. These results indicated that GPR35 selective inhibitor TMER1i enhanced an anti-tumor immune activity in an IDO1+ tumor microenvironment. Taken together, these studies provided evidence for a role of GPR35 in mediating IDO1 immune suppression by regulating Hippo-YAP pathway in Treg and CTL cells in the immune system. Thus, GPR35 inhibitors have a potential to be novel immuno-therapeutic agents effective in treating patients with IDO1-positive tumors. Reference1.Munn, DH, and Mellor, AL. (2007) Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J. Clin. Invest. 117:1147-11542.Ni, X. et al. Yap is essential for Treg-mediated suppression of antitumor Immunity. Cancer Discovery 2018; 8:1026-10433.Lebid, A. et al. (2020) YAP attenuates CD8 T cell-mediated anti-tumor response. Frontiers in Immunology 11:1-84.Stampouloglou, E. et al. (2020) YAP suppresses T-cell function and infiltration in the tumor microenvironment. PLoS Biol 18(1): e30005915.Fallarino, F. et al. (2006) The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor æ-chain and induce a regulatory phenotype in naïve T cells. J Immunol 176:6752-6761 Citation Format: Hongmei He, Nam Hee Kim, Sangdon Han, Zhi Liang Chu. Evidence for a role of GPR35 in IDO1-mediated tumor immune escape by regulating Hippo-YAP pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB426.

The Kynurenine Pathway in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis of Blood Concentrations of Tryptophan and Its Catabolites.

Preliminary evidence shows that the kynurenine pathway (KP) may be altered in attention-deficit/hyperactivity disorder (ADHD). We thus conducted a systematic review and meta-analysis exploring the peripheral blood concentrations of tryptophan catabolites (TRYCATs) in people with ADHD. We searched the main electronic databases up to 7th December 2023. Standardised mean differences (SMDs) with 95% confidence intervals (95%CIs) were used to compare TRYCAT concentrations between participants with ADHD and healthy controls (HCs). We included eight studies. Random-effects meta-analyses found higher kynurenine (SMD = 0.56; 95%CI: 0.04 to 1.08; p = 0.033; I2 = 90.3%) and lower kynurenic acid (SMD = -0.33; 95%CI: -0.49 to -0.17; p < 0.001; I2 = 0%) concentrations in people with ADHD compared to HCs. Additional analyses on drug-free children with ADHD showed higher tryptophan (SMD = 0.31; 95%CI: 0.11 to 0.50; p = 0.002; I2 = 0%) and kynurenine (SMD = 0.74; 95%CI: 0.30 to 1.17; p < 0.001; I2 = 76.5%), as well as lower kynurenic acid (SMD = -0.37; 95%CI: -0.59 to -0.15; p < 0.001; I2 = 0%) blood levels, as compared to HCs. Despite some limitations, our work provides preliminary evidence on KP alterations in ADHD that may suggest decreased neuroprotection. Further research is needed to clarify the role of the KP in ADHD.

Microbial metabolites are involved in tumorigenesis and development by regulating immune responses.

The human microbiota is symbiotic with the host and can create a variety of metabolites. Under normal conditions, microbial metabolites can regulate host immune function and eliminate abnormal cells in a timely manner. However, when metabolite production is abnormal, the host immune system might be unable to identify and get rid of tumor cells at the early stage of carcinogenesis, which results in tumor development. The mechanisms by which intestinal microbial metabolites, including short-chain fatty acids (SCFAs), microbial tryptophan catabolites (MTCs), polyamines (PAs), hydrogen sulfide, and secondary bile acids, are involved in tumorigenesis and development by regulating immune responses are summarized in this review. SCFAs and MTCs can prevent cancer by altering the expression of enzymes and epigenetic modifications in both immune cells and intestinal epithelial cells. MTCs can also stimulate immune cell receptors to inhibit the growth and metastasis of the host cancer. SCFAs, MTCs, bacterial hydrogen sulfide and secondary bile acids can control mucosal immunity to influence the occurrence and growth of tumors. Additionally, SCFAs, MTCs, PAs and bacterial hydrogen sulfide can also affect the anti-tumor immune response in tumor therapy by regulating the function of immune cells. Microbial metabolites have a good application prospect in the clinical diagnosis and treatment of tumors, and our review provides a good basis for related research.

Decreased Plasma Levels of Kynurenine and Kynurenic Acid in Previously Treated and First-Episode Antipsychotic-Naive Schizophrenia Patients.

Tryptophan (TRP) catabolites exert neuroactive effects, with the plethora of evidence suggesting that kynurenic acid (KYNA), a catabolite of the kynurenine pathway (KP), acts as the regulator of glutamate and acetylcholine in the brain, contributing to the schizophrenia pathophysiology. Newer evidence regarding measures of KP metabolites in the blood of schizophrenia patients and from the central nervous system suggest that blood levels of these metabolites by no means could reflect pathological changes of TRP degradation in the brain. The aim of this study was to investigate plasma concentrations of TRP, kynurenine (KYN) and KYNA at the acute phase and remission of schizophrenia in a prospective, case-control study of highly selected and matched schizophrenia patients and healthy individuals. Our study revealed significantly decreased KYN and KYNA in schizophrenia patients (p < 0.001), irrespective of illness state, type of antipsychotic treatment, number of episodes or illness duration and no differences in the KYN/TRP ratio between schizophrenia patients and healthy individuals. These findings could be interpreted as indices that kynurenine pathway might not be dysregulated in the periphery and that other factors contribute to observed disturbances in concentrations, but as our study had certain limitations, we cannot draw definite conclusions. Further studies, especially those exploring other body compartments that participate in kynurenine pathway, are needed.

The tryptophan catabolite or kynurenine pathway in autism spectrum disorder; a systematic review and meta-analysis.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social communication and interaction, as well as rigid and unchanging interests and behaviors. Several studies have reported that activated immune-inflammatory and nitro-oxidative pathways are accompanied by depletion of plasma tryptophan (TRP), increased competing amino acid (CAAs) levels, and activation of the TRP catabolite (TRYCAT) pathway. This study aims to systematically review and meta-analyze data on peripheral TRP, CAAs, TRYCAT pathway activity, and individual TRYCATs, including kynurenine (KYN) and kynurenic acid (KA) levels, in the blood and urine of ASD patients. After extensively searching PubMed, Google Scholar, and SciFinder, a total of 25 full-text papers were included in the analysis, with a total of 6653 participants (3557 people with ASD and 3096 healthy controls). Our results indicate that blood TRP and the TRP/CAAs ratio were not significantly different between ASD patients and controls (standardized mean difference, SMD = -0.227, 95% confidence interval, CI: -0.540; 0.085, and SMD = 0.158, 95% CI: -0.042; 0.359), respectively. The KYN/TRP ratio showed no significant difference between ASD and controls (SMD = 0.001, 95% CI: -0.169; 0.171). Blood KYN and KA levels were not significantly changed in ASD. Moreover, there were no significant differences in urine TRP, KYN, and KA levels between ASD and controls. We could not establish increases in neurotoxic TRYCATs in ASD. In conclusion, this study demonstrates no abnormalities in peripheral blood TRP metabolism, indoleamine 2,3-dioxygenase enzyme (IDO) activity, or TRYCAT production in ASD. Reduced TRP availability and elevated neurotoxic TRYCAT levels are not substantial contributors to ASD's pathophysiology.

Maternal Tryptophan Catabolites and Insulin Resistance Parameters in Preeclampsia.

Preeclampsia (PE) is a pregnancy-related disorder characterized by high blood pressure and proteinuria in the third trimester. The disease is associated with many metabolic and biochemical changes. There is a need for new biomarkers for diagnosis and follow-up. The present study examined the diagnostic ability of tryptophan catabolites (TRYCATs) and insulin resistance (IR) parameters in women with PE. This case-control study recruited sixty women with preeclampsia and 60 healthy pregnant women as a control group. Serum levels of TRYCATs (tryptophan, kynurenic acid, kynurenine, and 3-hydroxykynurenine) and IR parameters (insulin and glucose) were measured by ELISA and spectrophotometric methods. The results showed that PE women have a significantly lower tryptophan level than healthy pregnant women. However, there was a significant increase in kynurenic acid, kynurenic acid/kynurenine, kynurenine/tryptophan, and 3-hydroxykynurenine levels. PE women also have a state of IR. The correlation study indicated various correlations of IR and TRYCATs with clinical data and between each other, reflecting the role of these parameters in the pathophysiology of PE. The ROC study showed that the presence of IR state, reduced tryptophan, and increased 3-HK predicted PE disease in a suspected woman with moderate sensitivities and specificities. In conclusion, the pathophysiology of PE involves a state of IR and an alteration of the TRYCAT system. These changes should be taken into consideration when PE is diagnosed or treated.

The kynurenine pathway in HIV, frailty and inflammaging.

Kynurenine (Kyn) is a circulating tryptophan (Trp) catabolite generated by enzymes including IDO1 that are induced by inflammatory cytokines such as interferon-gamma. Kyn levels in circulation increase with age and Kyn is implicated in several age-related disorders including neurodegeneration, osteoporosis, and sarcopenia. Importantly, Kyn increases with progressive disease in HIV patients, and antiretroviral therapy does not normalize IDO1 activity in these subjects. Kyn is now recognized as an endogenous agonist of the aryl hydrocarbon receptor, and AhR activation itself has been found to induce muscle atrophy, increase the activity of bone-resorbing osteoclasts, decrease matrix formation by osteoblasts, and lead to senescence of bone marrow stem cells. Several IDO1 and AhR inhibitors are now in clinical trials as potential cancer therapies. We propose that some of these drugs may be repurposed to improve musculoskeletal health in older adults living with HIV.

Metabolites for monitoring symptoms and predicting remission in patients with depression who received electroconvulsive therapy: a pilot study

The lack of biomarkers to monitor and predict the efficacy of electroconvulsive therapy (ECT) has hindered its optimal use. To establish metabolomic markers for monitoring and predicting the treatment efficacy of ECT, we comprehensively evaluated metabolite levels in patients with major depressive disorder (MDD) by performing targeted and non-targeted metabolomic analyses using plasma samples before and after the first, third, and final ECT sessions, and 3–7 days after the final session. We compared the plasma metabolomes of age- and sex-matched healthy controls (HCs). Thirteen hospitalized patients with MDD and their corresponding HCs were included in this study. We observed that patients with MDD exhibited lower levels of amino acids, including gamma-aminobutyric acid (GABA), and metabolites involved in tryptophan metabolism and the kynurenine pathway, and higher levels of cortisol at baseline. Furthermore, we investigated the relationship between metabolite levels and depression severity across seven measurement timepoints along with one correlation analysis and found that amino acids, including GABA and tryptophan catabolites, were significantly correlated with the severity of depression. Despite the exploratory nature of this study due to the limited sample size necessitating further validation, our findings suggest that the blood metabolic profile has potential as a biomarker for ECT.

Катаболиты триптофана и гены ферментов микробиома кишечника

The signaling role of tryptophan and its catabolites is well known. However, their effects on the potential microbiota metabolic activity is still poorly understood. The study was aimed to assess concordance between changes in the predicted gut microbiome enzyme-encoding gene abundance and the tryptophan catabolites. The study involved 109 healthy volunteers and 114 obese patients. Quantification of tryptophan catabolites in the feces was performed by HPLC. Bacterial DNA was extracted from fecal samples, and the 16S rRNA gene V3-V4 region was sequenced. Primary processing of the sequencing data was performed using the QIIME v.1.9.1 tool. The alleged metabolic role of microbiota members was explored via reconstruction of unobservable states using PICRUSt. The maximum number of significant correlations between the unobservable states and the predicted gut microbiome enzyme-encoding gene abundance in obese individuals was reported for indole-3-lactate. A significant correlation between indole-3-lactate and the abundance of genes encoding the enzymes involved in metabolism of fructose, amino sugars, nucleotides, amino acids, polyamines, and sulfosaccharides was revealed. It has been found that obese patients show a threefold increase in the indole-3lactate-producing microbiota. It has been shown that in obese individuals microbial population of the intestine is represented by the totally different genera and species of microorganisms. It is concluded that indole-3-lactate has a significant effect on the predicted gut microbiome enzyme-encoding gene abundance in obese patients.

Effect of whole foods on the microbial production of tryptophan-derived aryl hydrocarbon receptor agonists in growing pigs.

Effects of whole foods on the microbial production of tryptophan-derived aryl hydrocarbon receptor (AhR) ligands in the intestine were investigated in a pig model. Ileal digesta and faeces of pigs after feeding of eighteen different foods were analyzed. Indole, indole-3-propionic acid, indole-3-acetic acid, indole-3-lactic acid, kynurenine, tryptamine, and indole-3-aldehyde were identified in ileal digesta, which were also identified in faeces but at higher concentrations except indole-3-lactic acid, together with skatole, oxindole, serotonin, and indoleacrylic acid. The panel of tryptophan catabolites in ileal digesta and faeces varied across different foods. Eggs induced the highest overall concentration of catabolites in ileal digesta dominated by indole. Amaranth induced the highest overall concentration of catabolites in faeces dominated by skatole. Using a reporter cell line, we observed many faecal samples but not ileal samples retained AhR activity. Collectively, these findings contribute to food selection targeting AhR ligands production from dietary tryptophan in the intestine.

Oral administration of kynurenic acid delays the onset of type 2 diabetes in Goto-Kakizaki rats

Kynurenic acid (KYNA) is an endogenous catabolite of tryptophan that has been found to demonstrate neuroprotective properties in psychiatric disorders. Recently, accumulating data have suggested that KYNA may also play a significant role in various metabolic diseases by stimulating energy metabolism in adipose tissue and muscle. However, whether KYNA can serves as an anti-diabetes agent has yet to be studied. In this study, we investigated the potential anti-diabetic effects of administering KYNA orally through drinking water in pre-diabetic Goto-Kakizaki rats and examined how this treatment may influence energy metabolism regulation within the liver. We found that hyperglycemic Goto-Kakizaki rats showed lower plasmatic KYNA levels compared to normal rats. Oral administration of KYNA significantly delayed the onset of diabetes in Goto-Kakizaki rats compared to untreated animals. Moreover, we found that KYNA treatment significantly increased respiration exchange ratio and promoted the energy expenditure by stimulating the expression of uncoupling protein (UCP). We confirmed that KYNA stimulated the UCP expression in HepG2 cells and mouse hepatocytes at mRNA and protein levels. Our study reveals that KYNA could potentially act as an anti-diabetic agent and KYNA-induced UCP upregulation is closely associated with the regulation of energy metabolism. These results provide further evidence for the therapeutic potential of KYNA in diabetes.

Tryptophan catabolites, inflammation, and insulin resistance as determinants of chronic fatigue syndrome and affective symptoms in long COVID.

Critical COVID-19 disease is accompanied by depletion of plasma tryptophan (TRY) and increases in indoleamine-dioxygenase (IDO)-stimulated production of neuroactive tryptophan catabolites (TRYCATs), including kynurenine (KYN). The TRYCAT pathway has not been studied extensively in association with the physiosomatic and affective symptoms of Long COVID. In the present study, we measured serum TRY, TRYCATs, insulin resistance (using the Homeostatic Model Assessment Index 2-insulin resistance, HOMA2-IR), C-reactive protein (CRP), physiosomatic, depression, and anxiety symptoms in 90 Long COVID patients, 3-10 months after remission of acute infection. We were able to construct an endophenotypic class of severe Long COVID (22% of the patients) with very low TRY and oxygen saturation (SpO2, during acute infection), increased kynurenine, KYN/TRY ratio, CRP, and very high ratings on all symptom domains. One factor could be extracted from physiosomatic symptoms (including chronic fatigue-fibromyalgia), depression, and anxiety symptoms, indicating that all domains are manifestations of the common physio-affective phenome. Three Long COVID biomarkers (CRP, KYN/TRY, and IR) explained around 40% of the variance in the physio-affective phenome. The latter and the KYN/TRY ratio were significantly predicted by peak body temperature (PBT) and lowered SpO2 during acute infection. One validated latent vector could be extracted from the three symptom domains and a composite based on CRP, KYN/TRY, and IR (Long COVID), and PBT and SpO2 (acute COVID-19). In conclusion, the physio-affective phenome of Long COVID is a manifestation of inflammatory responses during acute and Long COVID, and lowered plasma tryptophan and increased kynurenine may contribute to these effects.

Tryptophan depletion sensitizes the AHR pathway by increasing AHR expression and GCN2/LAT1-mediated kynurenine uptake, and potentiates induction of regulatory T lymphocytes

BackgroundIndoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan-dioxygenase (TDO) are enzymes catabolizing the essential amino acid tryptophan into kynurenine. Expression of these enzymes is frequently observed in advanced-stage cancers and is associated...

Urolithin A Alleviates Colitis in Mice by Improving Gut Microbiota Dysbiosis, Modulating Microbial Tryptophan Metabolism, and Triggering AhR Activation

Urolithin A (UroA) is a microbial metabolite derived from ellagitannins and ellagic acid with good bioavailability. In this study, we explored the anticolitis activity of UroA and clarified the mechanism by 16S rDNA sequencing and metabonomics. UroA alleviated dextran sulfate sodium (DSS)-induced colitis in mice, characterized by a decreased disease activity index, increased colon length, and improved colonic histopathological lesions, along with inhibited phosphorylation of the mitogen-activated protein kinase signaling pathway. In addition, UroA improved gut microbiota dysbiosis and modulated the microbiota metabolome. Furthermore, targeted metabolomics focused on tryptophan catabolites showed that UroA significantly increased the production of indole-3-aldehyde (IAld) and subsequently led to increased colonic expression of aryl hydrocarbon receptor (AhR) and promoted the serum content of IL-22 in mice with colitis. Collectively, our data identified a novel anticolitis mechanism of UroA by improving gut microbiota dysbiosis, modulating microbial tryptophan metabolism, promoting IAld production, and triggering AhR/IL-22 axis activation. However, a limitation noted in this study is that these beneficial effects of UroA were found at 50 μM in vitro and 20 mg/kg in vivo, which were nonphysiological concentrations.