Jianpi Jiedu decoction suppresses colorectal cancer growth by inhibiting M2 polarization of TAMs through the tryptophan metabolism-AhR pathway.

BACKGROUND: Traditional Chinese medicine, JianpiJiedu decoction (JPJDF), has been utilized in colorectal cancer (CRC) treatment for over forty years. The potential of JPJDF to inhibit CRC through modulation of intestinal microbiota and their metabolites remains uncertain. AIMS: This study aims to further investigate the therapeutic mechanisms of JPJDF in CRC. METHODS: CAC mouse models were developed using azoxymethane (AOM) and dextran sulfate sodium (DSS). Intestinal tissues and contents underwent 16S rRNA gene sequencing and untargeted metabolomics analysis. Serum levels of IL-1ß and TNF-α were measured using ELISA. Immunohistochemistry was utilized to assess the expression of Ki67, ZO-1, Occludin, CD68, and CD206. Furthermore, western blotting was performed to evaluate the protein expression of AhR and NF-κB. RESULTS: JPJDF inhibited colorectal tumourigenesis in AOM/DSS treated mice, while also suppressing tumor cell proliferation and upregulating the expression of tight junction proteins. The results of 16S rRNA gene sequencing analysis revealed that JPJDF altered intestinal microbiota composition by increasing the abundance of beneficial bacteria. Additionally, JPJDF reduced tryptophan metabolites, effectively alleviating inflammation and significantly restoring intestinal barrier function in CAC mice. Molecular biology experiments confirmed that JPJDF suppressed the expression levels of AhR and M2-type tumor-associated macrophages, thereby promoting anti-tumor immunity and exerting inhibitory effects on CAC growth. CONCLUSION: JPJDF can regulate the tryptophan metabolism-AhR pathway by modulating the gut microbiota, reducing intestinal inflammation, improving intestinal barrier function, enhancing anti-tumor immunity, and effectively inhibiting CAC growth.

Dysregulated tryptophan metabolism and AhR pathway contributed to CXCL10 upregulation in stable non-segmental vitiligo.

BACKGROUND: Tryptophan metabolism dysregulation has been observed in vitiligo. However, drawing a mechanistic linkage between this metabolic disturbance and vitiligo pathogenesis remains challenging. OBJECTIVE: Aim to reveal the characterization of tryptophan metabolism in vitiligo and investigate the role of tryptophan metabolites in vitiligo pathophysiology. METHODS: LC-MS/MS, dual-luciferase reporter assay, ELISA, qRT-PCR, small interfering RNA, western blotting, and immunohistochemistry were employed. RESULTS: Kynurenine pathway activation and KYAT enzyme-associated deviation to kynurenic acid (KYNA) in the plasma of stable non-segmental vitiligo were determined. Using a public microarray dataset, we next validated the activation of kynurenine pathway was related with inflammatory-related genes expression in skin of vitiligo patients. Furthermore, we found that KYNA induced CXCL10 upregulation in keratinocytes via AhR activation. Moreover, the total activity of AhR agonist was increased while the AhR concentration per se was decreased in the plasma of vitiligo patients. Finally, higher KYAT, CXCL10, CYP1A1 and lower AhR expression in vitiligo lesional skin were observed by immunohistochemistry staining. CONCLUSION: This study depicts the metabolic and genetic characterizations of tryptophan metabolism in vitiligo and proposes that KYNA, a tryptophan-derived AhR ligand, can enhance CXCL10 expression in keratinocytes.

Baitouweng decoction alleviates ulcerative colitis by regulating tryptophan metabolism through DOPA decarboxylase promotion.

Background: Baitouweng decoction (BTW) is a classic botanical drugs formula that has been widely used clinically for the treatment of gut-related disorders in China. However, its role in ameliorating ulcerative colitis (UC) remains to be explored. Purpose: The study aimed to determine the therapeutic efficacy and potential mechanism of action of BTW on dextran sodium sulfate (DSS)-induced colitis mice. Methods: In vivo: 3.5% DSS-induced experimental colitis mice were treated with BTW (Pulsatilla chinensis (Bunge) Regel, Phellodendron chinense C. K. Schneid, Coptis chinensis Franch and Fraxinus chinensis Roxb), kynurenine or DOPA decarboxylase (DDC) inhibitor (carbidopa). In vitro: Caco-2 cells were stimulated with TNF-α to activate inflammation and later treated with various concentrations of BTW and carbidopa. Model evaluation included body weight, disease activity index (DAI) score, colon length and histopathology. Cytokine levels were measured by flow cytometry. Protein levels were analyzed by proteomics and functionally annotated. The levels of tryptophan metabolites in mouse serum and colon were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Alcian Blue/Phosphate Acid Schiff (AB/PAS) staining, immunohistochemistry and western blot were used to assess the intestinal barrier function and detect the protein expression levels. Results: BTW significantly reduced the DAI, ameliorated colonic injury and regulated inflammatory cytokines in DSS-induced colitis mice. The botanical drugs formula also promoted intestinal epithelial barrier repair by enhancing the expression of the tight junction (TJ) proteins. Tryptophan metabolic signaling pathway was significantly enriched in DSS-induced UC mice, and BTW decreased the level of kynurenine, increased indole metabolites. The therapeutic effect of BTW was evidently reduced when kynurenine was given to mice. Also, BTW promoted DDC protein expression and activated the aryl hydrocarbon receptor (AHR)/IL-22 signaling pathway. Conclusion: BTW improves ulcerative colitis by promoting DDC expression, regulating the conversion of tryptophan metabolism from the kynurenine pathway to the indole metabolism pathway, thereby modulating tryptophan metabolism to increase indole metabolites, and activating AHR receptors to restore intestinal barrier function.

Intracellular Polysaccharides of Eurotium cristatum Exhibited Anticolitis Effects in Association with Gut Tryptophan Metabolism.

This study is to investigate the protective effects of Eurotium cristatum intracellular polysaccharides (ECIP) on dextran sodium sulfate (DSS)-induced ulcerative colitis (UC). The oral administration of ECIP could downregulate the disease activity index (DAI) and ameliorate the colonic shortening, immune stress, and damage caused by DSS. In addition, ECIP treatment increased the colonic contents of SCFAs including acetic, propionic, and butyric acids in UC mice. Targeted and untargeted metabolic analysis suggested that ECIP dramatically altered the tryptophan metabolism in the feces of UC mice and promoted the conversion of tryptophan into indole metabolites including indolepyruvate and indole-3-acetic acid (IAA) and indolealdehyde (IAId). Moreover, ECIP observably increased the content of colonic IL-22 and stimulated the relative concentration and relative expression of tight junction molecules in mRNA and proteins levels. Conclusively, consumption of ECIP can improve colon damage and its related effects of UC by promoting the production of IAA and IAId to reinforce intestinal barriers.

Indole Lactic Acid in Plasma and Urine: A Potential Biomarker for Chronic Kidney Disease and Inflammatory.

Purpose: We aimed to explore changes in plasma and urine indole lactic acid (ILA) levels and the relationship between inflammation and ILA in chronic kidney disease (CKD) patients and healthy people. Patients and Methods: Forty-seven CKD patients and 30 healthy individuals were included in this study. One-way ANOVA was used for variables with normal distribution and homogeneous variance. A rank-sum test was performed for non-normally distributed variables. Correlation analyses were performed using Pearson's or Spearman correlation analyses. Independent relationship between patients and CKD was analyzed using ordinal and binary logistic regressions. Receiver operating characteristic (ROC) curve was used. Results: Plasma and urine ILA levels were positively correlated (r = 0.51, P < 0.01). Plasma ILA was positively correlated with BMI, age, creatinine, BUN, triglycerides, and uric acid and negatively correlated with hemoglobin levels. Urine ILA levels were positively correlated with age, creatinine, BUN, and uric acid and negatively correlated with hemoglobin and albumin levels. Ordered logistic regression analysis showed that CKD was significantly correlated with plasma ILA (OR=4.49, P < 0.01), urinary ILA (OR=2.14,P < 0.01), urea levels (OR=1.43, P < 0.01) and hemoglobin levels (OR=0.95, P < 0.01) were significantly related. ROC curves indicated that plasma and urinary ILA were reliable predictors of CKD. CKD was correlated with plasma, urine ILA (OR=5.92, P < 0.01; OR=2.79, P < 0.01) and Hs-CRP (OR=2.45, P < 0.01). Conclusion: Plasma and urine ILA can potentially be used as biomarkers of CKD and inflammatory status.

The role of nonesterified fatty acids in cancer biology: Focus on tryptophan and related metabolism.

Plasma nonesterified fatty acids (NEFA) are elevated in cancer, because of decreased albumin levels and of fatty acid oxidation, and increased fatty acid synthesis and lipolysis. Albumin depletion and NEFA elevation maximally release albumin-bound tryptophan (Trp) and increase its flux down the kynurenine pathway, leading to increased production of proinflammatory kynurenine metabolites, which tumors use to undermine T-cell function and achieve immune escape. Activation of the aryl hydrocarbon receptor by kynurenic acid promotes extrahepatic Trp degradation by indoleamine 2,3-dioxygenase and leads to upregulation of poly (ADP-ribose) polymerase, activation of which and also of SIRT1 (silent mating type information regulation 2 homolog 1) could lead to depletion of NAD+ and ATP, resulting in cell death. NEFA also modulate heme synthesis and degradation, changes in which impact homocysteine metabolism and production of reduced glutathione and hydrogen sulphide. The significance of the interactions between heme and homocysteine metabolism in cancer biology has received little attention. Targeting Trp disposition in cancer to prevent the NEFA effects is suggested.

Quinic acid alleviates high-fat diet-induced neuroinflammation by inhibiting DR3/IKK/NF-κB signaling via gut microbial tryptophan metabolites.

With the increasing of aging population and the consumption of high-fat diets (HFD), the incidence of Alzheimer's disease (AD) has skyrocketed. Natural antioxidants show promising potential in the prevention of AD, as oxidative stress and neuroinflammation are two hallmarks of AD pathogenesis. Here, we showed that quinic acid (QA), a polyphenol derived from millet, significantly decreased HFD-induced brain oxidative stress and neuroinflammation and the levels of Aß and p-Tau. Examination of gut microbiota suggested the improvement of the composition of gut microbiota in HFD mice after QA treatment. Metabolomic analysis showed significant increase of gut microbial tryptophan metabolites indole-3-acetic acid (IAA) and kynurenic acid (KYNA) by QA. In addition, IAA and KYNA showed negative correlation with pro-inflammatory factors and AD indicators. Further experiments on HFD mice proved that IAA and KYNA could reproduce the effects of QA that suppress brain oxidative stress and inflammation and decrease the levels of of Aß and p-Tau. Transcriptomics analysis of brain after IAA administration revealed the inhibition of DR3/IKK/NF-κB signaling pathway by IAA. In conclusion, this study demonstrated that QA could counteract HFD-induced brain oxidative stress and neuroinflammation by regulating inflammatory DR3/IKK/NF-κB signaling pathway via gut microbial tryptophan metabolites.

Hericium erinaceus polysaccharides ameliorate nonalcoholic fatty liver disease via gut microbiota and tryptophan metabolism regulation in an aged laying hen model.

Polysaccharides extracted from Hericium erinaceus (HEP) exhibit hepatoprotective activity in the alleviation of non-alcoholic fatty liver disease (NAFLD); however, the mechanisms underlying whether and how HEP regulation of the gut microbiota to alleviate liver-associated metabolic disorders are not well understood. This study used an aged laying hen model to explore the mechanisms through which HEP alleviates NAFLD, with a focus on regulatory function of HEP in the gut microbiome. The results showed that HEP ameliorated hepatic damage and metabolic disorders by improving intestinal barrier function and shaping the gut microbiota and tryptophan metabolic profiles. HEP increased the abundance of Lactobacillus and certain tryptophan metabolites, including indole-3-carboxylic acid, kynurenic acid, and tryptamine in the cecum. These metabolites upregulated the expression of ZO-1 and Occludin by activating the AhR and restoring the intestinal barrier integrity. The increased intestinal barrier functions decreased LPS transferring from the intestine to the liver, inhibited hepatic LPS/TLR4/MyD88/NF-κB pathway activation, and reduced hepatic inflammatory response and apoptosis. Fecal microbiota transplantation experiments further confirmed that the hepatoprotective effect is likely mediated by HEP-altered gut microbiota and their metabolites. Overall, dietary HEP could ameliorate the hepatic damage and metabolic disorders of NAFLD through regulating the "gut-liver" axis.

PET Imaging of Neurofibromatosis Type 1 with a Fluorine-18 Labeled Tryptophan Radiotracer.

Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder. Plexiform neurofibromas (PNFs) are benign tumors commonly formed in patients with NF1. PNFs have a high incidence of developing into malignant peripheral nerve sheath tumors (MPNSTs) with a 5-year survival rate of only 30%. Therefore, the accurate diagnosis and differentiation of MPNSTs from benign PNFs are critical to patient management. We studied a fluorine-18 labeled tryptophan positron emission tomography (PET) radiotracer, 1-(2-[18F]fluoroethyl)-L-tryptophan (L-[18F]FETrp), to detect NF1-associated tumors in an animal model. An ex vivo biodistribution study of L-[18F]FETrp showed a similar tracer distribution and kinetics between the wild-type and triple mutant mice with the highest uptake in the pancreas. Bone uptake was stable. Brain uptake was low during the 90-min uptake period. Static PET imaging at 60 min post-injection showed L-[18F]FETrp had a comparable tumor uptake with [18F]fluorodeoxyglucose (FDG). However, L-[18F]FETrp showed a significantly higher tumor-to-brain ratio than FDG (n = 4, p < 0.05). Sixty-minute-long dynamic PET scans using the two radiotracers showed similar kidney, liver, and lung kinetics. A dysregulated tryptophan metabolism in NF1 mice was further confirmed using immunohistostaining. L-[18F]FETrp is warranted to further investigate differentiating malignant NF1 tumors from benign PNFs. The study may reveal the tryptophan-kynurenine pathway as a therapeutic target for treating NF1.

Identification of Gut Microbiome Signatures Associated with Indole Pathway in Tryptophan Metabolism in Patients Undergoing Hemodialysis.

Microbiota tryptophan metabolism and the biosynthesis of indole derivatives play an important role in homeostasis and pathogenesis in the human body and can be affected by the gut microbiota. However, studies on the interplay between gut microbiota and tryptophan metabolites in patients undergoing dialysis are lacking. This study aimed to identify the gut microbiota, the indole pathway in tryptophan metabolism, and significant functional differences in ESRD patients with regular hemodialysis. We performed the shotgun metagenome sequencing of stool samples from 85 hemodialysis patients. Using the linear discriminant analysis effect size (LEfSe), we examined the composition of the gut microbiota and metabolic features across varying concentrations of tryptophan and indole metabolites. Higher tryptophan levels promoted tyrosine degradation I and pectin degradation I metabolic modules; lower tryptophan levels were associated with glutamate degradation I, fructose degradation, and valine degradation modules. Higher 3-indoxyl sulfate concentrations were characterized by alanine degradation I, anaerobic fatty acid beta-oxidation, sulfate reduction, and acetyl-CoA to crotonyl-CoA. Contrarily, lower 3-indoxyl sulfate levels were related to propionate production III, arabinoxylan degradation, the Entner-Doudoroff pathway, and glutamate degradation II. The present study provides a better understanding of the interaction between tryptophan, indole metabolites, and the gut microbiota as well as their gut metabolic modules in ESRD patients with regular hemodialysis.

Unraveling the treatment effects of huanglian jiedu decoction on drug-induced liver injury based on network pharmacology, molecular docking and experimental validation.

Huanglian Jiedu Decoction (HJD) is a well-known Traditional Chinese Medicine formula that has been used for liver protection in thousands of years. However, the therapeutic effects and mechanisms of HJD in treating drug-induced liver injury (DILI) remain unknown. In this study, a total of 26 genes related to both HJD and DILI were identified, which are corresponding to a total of 41 potential active compounds in HJD. KEGG analysis revealed that Tryptophan metabolism pathway is particularly important. The overlapped genes from KEGG and GO analysis indicated the significance of CYP1A1, CYP1A2, and CYP1B1. Experimental results confirmed that HJD has a protective effect on DILI through Tryptophan metabolism pathway. In addition, the active ingredients Corymbosin, and Moslosooflavone were found to have relative strong intensity in UPLC-Q-TOF-MS/MS analysis, showing interactions with CYP1A1, CYP1A2, and CYP1B1 through molecule docking. These findings could provide insights into the treatment effects of HJD on DILI.

Association between whole grain consumption, tryptophan metabolism, and psychological distress: a secondary analysis of a randomised controlled trial.

This study aimed to investigate whether psychological distress, whole grain consumption, and tryptophan metabolism are associated in participants undergoing weight management intervention. Seventy-nine women and men (mean age 49.7 ± 9.0 years; BMI 34.2 ± 2.5 kg/m2) participated in a 7-week weight-loss period (WL), and in a 24-week weight maintenance intervention period (WM). Whole grain consumption was measured using 4-day food diaries. Psychological distress was assessed with the General Health Questionnaire-12 (GHQ), and participants were divided into three GHQ groups based on the GHQ scores before WL. Tryptophan metabolites were determined from the participants' fasting plasma using liquid chromatography-mass spectrometry. GHQ scores were not associated with the whole grain consumption. A positive association was observed between the whole grain consumption and indole propionic acid (IPA) during the WM (p = 0.033). Serotonin levels were higher after the WL in the lowest GHQ tertile (p = 0.033), while the level at the end of the WM was higher compared to other timepoints in the highest GHQ tertile (p = 0.015 and p = 0.001). This difference between groups was not statistically significant. Furthermore, levels of several tryptophan metabolites changed within the groups during the study. Tryptophan metabolism changed during the study in the whole study group, independently from the level of psychological distress. The association between whole grain consumption and IPA is possibly explained by the effects of dietary fibre on gut microbiota. This broadens the understanding of the pathways behind the health benefits associated with the intake of whole grains.

Epigallocatechin-3-gallate mitigates cadmium-induced intestinal damage through modulation of the microbiota-tryptophan-aryl hydrocarbon receptor pathway.

Early studies have shown that the gut microbiota is a critical target during cadmium exposure. The prebiotic activity of epigallocatechin-3-gallate (EGCG) plays an essential role in treating intestinal inflammation and damage. However, the exact intestinal barrier protection mechanism of EGCG against cadmium exposure remains unclear. In this experiment, four-week-old mice were exposed to cadmium (5 mg kg-1) for four weeks. Through 16 S rDNA analysis, we found that cadmium disrupted the gut microbiota and inhibited the indole metabolism pathway of tryptophan (TRP), which serves as the principal microbial production route for endogenous ligands to activate the aryl hydrocarbon receptor (AhR). Additionally, cadmium downregulated the intestinal AhR signaling pathway and harmed the intestinal barrier function. Treatment with EGCG (20 mg kg-1) and the AhR agonist 6-Formylindolo[3,2-b] carbazole (FICZ) (1 µg/d) significantly activated the AhR pathway and alleviated intestinal barrier injury. Notably, EGCG partially restored the gut microbiota and upregulated the TRP-indole metabolism pathway to increase the level of indole-related AhR agonists. Our findings demonstrate that cadmium dysregulates common gut microbiota to disrupt TRP metabolism, impairing the AhR signaling pathway and intestinal barrier. EGCG reduces cadmium-induced intestinal functional impairment by intervening in the intestinal microbiota to metabolize AhR agonists. This study offers insights into the toxic mechanisms of environmental cadmium and a potential mechanism to protect the intestinal barrier with EGCG.

Exploring the anti-migraine effects of Tianshu capsule: chemical profile, metabolic behavior, and therapeutic mechanisms.

BACKGROUND: Migraine is widely recognized as the third most prevalent medical condition globally. Tianshu capsule (TSC), derived from "Da Chuan Xiong Fang" of the Jin dynasty, is integral in the clinical treatment of migraine. However, the chemical properties and therapeutic mechanisms of TSC different portions remain unclear. PURPOSE: This study was designed to investigate the effects of TSC different portions (including small molecular TSCP-SM and polysaccharides TSC-P) on migraine and explore the underlying mechanisms. STUDY DESIGN AND METHODS: First of all, migraine rats were established by nitroglycerin injection and treated with TSC, TSC-P, and TSC-SM. ELISA, qPCR, and immunofluorescence were used to evaluate the pharmacological effects on migraine rats. Secondly, UPLC-Q/TOF-MS and GC--MS were employed to detect the components of TSC-SM. PMP-HPLC, NMR, FT-IR, UV-Vis, AFM, and SEM were used for the chemical profiling of polysaccharides. Thirdly, the metabolic behavior profile of TSC-P was characterized by oral administrated fluorescence-labeled TSC-P and detected by NIRF imaging. Finally, the anti-migraine mechanisms were explored by determining the composition of gut microbiota, analyzing colonic short-chain fatty acids (SCFAs), and examining serum tryptophan-related metabolites. RESULTS: Both small molecules (45 volatiles and 114 small molecules) and polysaccharides (including Glc, Ara, Gal, and Gal A) have exhibited effectiveness in alleviating migraine, and this efficacy is associated with reduced CGRP and iNOS levels, along with increased ß-EP expressions. Further mechanistic exploration revealed that small-molecules exhibited effectiveness in migraine treatment by exerting antioxidative actions, while polysaccharides demonstrated superior therapeutic effects in regulating 5-HT levels. By monitoring the metabolic behavior of polysaccharides with fluorescent labeling, it was observed that TSC-P exhibited poor absorption. Instead, TSC-P demonstrated its therapeutic effects by modulating the aberrations in gut microbiota (including Alloprevotella, Muribaculaceae_ge, and Ruminococcaceae_UCG-005), cecum short-chain fatty acids (such as isobutyric, isovaleric, and valeric acids), and serum tryptophan-related metabolites (including indole-3-acetamide, tryptophol, and indole-3-propionic acid). CONCLUSION: This research provides innovative insights into chemical composition, metabolic behavior, and proposed anti-migraine mechanisms of TSC from a polarity-based perspective, and pioneering an exploration focused on the polysaccharide components within TSC for the first time.

Artemisia argyi essential oil alleviates asthma by regulating 5-LOX-CysLTs and IDO-1-KYN pathways: Insights from metabolomics.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia argyi essential oil (AAEO) is a traditional herbal remedy for asthma. However, the potential effect of AAEO on asthma has not been elucidated. AIM OF THE STUDY: To investigate the protective properties of AAEO upon asthma and elucidate its mechanism. MATERIALS AND METHODS: The effects of AAEO in asthma were assessed by histology and biochemical analysis. Then, we integrated real-time reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, immunohistochemistry and metabolomics analysis to reveal its mechanism. RESULTS: In vivo, AAEO reduced the counts of white blood cells (WBCs) and cytokines in bronchoalveolar lavage fluid (BALF), ameliorated pathologic alterations in lung tissues, and inhibited secretion of OVA-sIgE and muc5ac. Metabolomics results showed that AAEO can exert therapeutic effects on asthmatic mice by regulating disordered arachidonic acid metabolism and tryptophan metabolism. Further studies shown that AAEO inhibited the expression of 5-LOX and reduced the accumulation of CysLTs in mice. Meanwhile, AAEO promoted the activity of IDO-1, facilitated the conversion of tryptophan to kynurenine, and regulated the imbalance of Treg/Th17 immunity. Immunohistochemical results showed that AAEO promoted the expression of IDO-1. RT-qPCR results showed that AAEO promoted the expression of IL-10 and Foxp3 mRNA, and inhibited the expression of IL-17A and RORγt mRNA, thus regulated the imbalance of Treg/Th17 immunity and exerted its therapeutic effects. CONCLUSION: AAEO treatment not only attenuates the clinical symptoms of asthma but is also involved in regulating lung tissue metabolism. The anti-asthmatic activity of AAEO may be achieved by reprogramming 5-LOX-CysLTs and IDO-1-KYN pathways.

Essential oils ameliorate the intestinal damages induced by nonylphenol exposure by modulating tryptophan metabolism and activating aryl hydrocarbon receptor via gut microbiota regulation.

Nonylphenol (NP) is a ubiquitous endocrine disruptor that persists in the environment and can significantly contribute to serious health hazards, particularly intestinal barrier injury. Plant essential oils (EOs) have recently gained widespread interest due to their potential for improving intestinal health. However, the precise mechanism and protective effects of EOs ameliorating the intestinal damages induced by NP exposure remain unclear. To clarify the potential mechanism and protective impact of EOs against intestinal injury induced by NP, a total of 144 one-day-old male ducks were randomly allocated to four groups: CON (basal diet), EO (basal diet + 200 mg/kg EOs), NP (basal diet + 40 mg/kg NP), and NPEO (basal diet + 200 mg/kg EOs + 40 mg/kg NP). The data revealed that NP exposure significantly damaged intestinal barrier, as evidenced by a reduction in the levels of tight junction gene expression and an increase in intestinal permeability. Additionally, it disturbed gut microbiota, as well as interfered with tryptophan (Trp) metabolism. The NP-induced disorder of Trp metabolism restrained the activation of aryl hydrocarbon receptor (AhR) and resulted in decreased the expression levels of CYP1A1, IL-22, and STAT3 genes, which were alleviated after treatment with EOs. Taken together, NP exposure resulted in impairment of the intestinal barrier function, disruption of gut microbiota, and disturbances in Trp metabolism. Dietary EOs supplementation alleviated the intestinal barrier injury induced by NP through the Trp/AhR/IL-22 signaling pathway.

Atorvastatin improved ulcerative colitis in association with gut microbiota-derived tryptophan metabolism.

AIMS: Atorvastatin is a commonly used cholesterol-lowering drug that possesses non-canonical anti-inflammatory properties. However, the precise mechanism underlying its anti-inflammatory effects remains unclear. MATERIALS AND METHODS: The acute phase of ulcerative colitis (UC) was induced using a 5 % dextran sulfate sodium (DSS) solution for 7 consecutive days and administrated with atorvastatin (10 mg/kg) from day 3 to day 7. mRNA-seq, histological pathology, and inflammatory response were determined. Intestinal microbiota alteration, tryptophan, and its metabolites were analyzed through 16S rRNA sequencing and untargeted metabolomics. KEY FINDINGS: Atorvastatin relieved the DSS-induced UC in mice, as evidenced by colon length, body weight, disease activity index score and pathological staining. Atorvastatin treatment reduced the level of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). Atorvastatin also relieved the intestinal microbiota disorder caused by UC and decreased the proliferation of pernicious microbiota such as Akkermansia and Bacteroides. Atorvastatin dramatically altered tryptophan metabolism and increased the fecal contents of tryptophan, indolelactic acid (ILA), and indole-3-acetic acid (IAA). Furthermore, atorvastatin enhanced the expression level of aryl hydrocarbon receptor (AhR) and interleukin-22 (IL-22) and further promoted the expression level of intestinal tight junction proteins, such as ZO-1 and occludin, in colitis mice. SIGNIFICANCE: These findings indicated that atorvastatin could alleviate UC by regulating intestinal flora disorders, promoting microbial tryptophan metabolism, and repairing the intestinal barrier.

Nanovesicular Mediation of the Gut-Brain Axis by Probiotics: Insights into Irritable Bowel Syndrome.

BACKGROUND: Dysbiosis, influenced by poor diet or stress, is associated with various systemic diseases. Probiotic supplements are recognized for stabilizing gut microbiota and alleviating gastrointestinal issues, like irritable bowel syndrome (IBS). This study focused on the tryptophan pathways, which are important for the regulation of serotonin levels, and on host physiology and behavior regulation. METHODS: Nanovesicles were isolated from the plasma of subjects with chronic diarrhea, both before and after 60 days of consuming a probiotic mix (Acronelle®, Bromatech S.r.l., Milan, Italy). These nanovesicles were assessed for the presence of Tryptophan 2,3-dioxygenase 2 (TDO 2). Furthermore, the probiotics mix, in combination with H2O2, was used to treat HT29 cells to explore its cytoprotective and anti-stress effect. RESULTS: In vivo, levels of TDO 2 in nanovesicles were enhanced in the blood after probiotic treatment, suggesting a role in the gut-brain axis. In the in vitro model, a typical H2O2-induced stress effect occurred, which the probiotics mix was able to recover, showing a cytoprotective effect. The probiotics mix treatment significantly reduced the heat shock protein 60 kDa levels and was able to preserve intestinal integrity and barrier function by restoring the expression and redistribution of tight junction proteins. Moreover, the probiotics mix increased the expression of TDO 2 and serotonin receptors. CONCLUSIONS: This study provides evidence for the gut-brain axis mediation by nanovesicles, influencing central nervous system function.

Urine 5-Hydroxyindoleacetic Acid Negatively Correlates with Migraine Occurrence and Characteristics in the Interictal Phase of Episodic Migraine.

Although migraine belongs to the main causes of disability worldwide, the mechanisms of its pathogenesis are poorly known. As migraine diagnosis is based on the subjective assessment of symptoms, there is a need to establish objective auxiliary markers to support clinical diagnosis. Tryptophan (TRP) metabolism has been associated with the pathogenesis of neurological and psychiatric disorders. In the present work, we investigated an association between migraine and the urine concentration of TRP and its metabolites 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QA) in 21 low-frequency episodic migraine patients and 32 controls. We chose the interictal phase as the episodic migraine patients were recruited from the outpatient clinic and had monthly migraine days as low as 1-2 in many cases. Migraine patients displayed lower urinary levels of 5-HIAA (p < 0.01) and KYNA (p < 0.05), but KYN and QA were enhanced, as compared with the controls (p < 0.05 and 0.001, respectively). Consequently, the patients were characterized by different values of the 5-HIAA/TRP, KYN/TRP, KYNA/KYN, and KYNA/QA ratios (p < 0.001 for all). Furthermore, urinary concentration of 5-HIAA was negatively correlated with Migraine Disability Assessment score and monthly migraine and monthly headache days. There was a negative correlation between Patient Health Questionnaire 9 scores assessing depression. In conclusion, the urinary 5-HIAA level may be further explored to assess its suitability as an easy-to-determine marker of migraine.

A Review of the Evidence for Tryptophan and the Kynurenine Pathway as a Regulator of Stem Cell Niches in Health and Disease.

Stem cells are ubiquitously found in various tissues and organs in the body, and underpin the body's ability to repair itself following injury or disease initiation, though repair can sometimes be compromised. Understanding how stem cells are produced, and functional signaling systems between different niches is critical to understanding the potential use of stem cells in regenerative medicine. In this context, this review considers kynurenine pathway (KP) metabolism in multipotent adult progenitor cells, embryonic, haematopoietic, neural, cancer, cardiac and induced pluripotent stem cells, endothelial progenitor cells, and mesenchymal stromal cells. The KP is the major enzymatic pathway for sequentially catabolising the essential amino acid tryptophan (TRP), resulting in key metabolites including kynurenine, kynurenic acid, and quinolinic acid (QUIN). QUIN metabolism transitions into the adjoining de novo pathway for nicotinamide adenine dinucleotide (NAD) production, a critical cofactor in many fundamental cellular biochemical pathways. How stem cells uptake and utilise TRP varies between different species and stem cell types, because of their expression of transporters and responses to inflammatory cytokines. Several KP metabolites are physiologically active, with either beneficial or detrimental outcomes, and evidence of this is presented relating to several stem cell types, which is important as they may exert a significant impact on surrounding differentiated cells, particularly if they metabolise or secrete metabolites differently. Interferon-gamma (IFN-γ) in mesenchymal stromal cells, for instance, highly upregulates rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO-1), initiating TRP depletion and production of metabolites including kynurenine/kynurenic acid, known agonists of the Aryl hydrocarbon receptor (AhR) transcription factor. AhR transcriptionally regulates an immunosuppressive phenotype, making them attractive for regenerative therapy. We also draw attention to important gaps in knowledge for future studies, which will underpin future application for stem cell-based cellular therapies or optimising drugs which can modulate the KP in innate stem cell populations, for disease treatment.