RESUMEN
The consumption of complementary foods can bring about diarrhea and intestinal barrier dysfunction in infants. In this study, three different Lactobacillus strains combined with L-tryptophan (Trp) were administered to rat pups with complementary foods. Complementary food feeding caused inflammatory cell infiltration, crypt structure irregularity and goblet cell reduction in the colon tissues of the rat pups. However, the oral administration of Trp combined with Lactiplantibacillus plantarum DPUL-S164 or Limosilactobacillus reuteri DPUL-M94 significantly restored the pathological changes in the colon tissues and inhibited the expression of pro-inflammatory cytokines in the colon and ileum of the rat pups. M94 or S164 combined with Trp intervention could promote the expression of cell differentiation genes and tight junction proteins, and restore the intestinal barrier damage caused by complementary foods in rat pups by activating the aryl hydrocarbon receptors (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In addition, the indole-3-lactic acid (ILA), indole-3-propionic acid (IPA), or indole-3-carbaldehyde (I3C) level in the cecal contents of the rat pups increased after intervention of Trp combined with S164 or M94, which may account for the amelioration of intestinal barrier damage in rat pups administered with complementary foods. Furthermore, S164 or M94 combined with Trp intervention up-regulated the relative abundance of f_Lactobacillaceae, f_Akkermansiaceae, g_Lactobacillus, and g_Akkermansia in the intestinal tract of the rat pups. In conclusion, S164 or M94 combined with Trp intervention can ameliorate complementary food-induced intestinal barrier damage and gut flora disorder in rat pups by producing ILA, IPA, or I3C, which are AhR ligands.
Asunto(s)
Indoles , Mucosa Intestinal , Ratas Sprague-Dawley , Triptófano , Animales , Ratas , Indoles/farmacología , Triptófano/farmacología , Triptófano/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Lactobacillus , Probióticos/farmacología , Probióticos/administración & dosificación , Colon/metabolismo , Colon/microbiología , Colon/patología , Masculino , Limosilactobacillus reuteri , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Receptores de Hidrocarburo de Aril/metabolismo , Íleon/metabolismo , Íleon/microbiología , Íleon/efectos de los fármacosRESUMEN
Approximately two-thirds of patients with asthma, a common inflammatory airway disease, are thought to present with allergies. Probiotics and tryptophan metabolites are becoming increasingly important in treating allergic asthma. This study aimed to identify potential probiotic strains and tryptophan metabolites that could alleviate asthma symptoms. Based on in vitro fermentation experiments, we evaluated variations in probiotic capacity to metabolize tryptophan. Of the eight tested strains, Bifidobacterium animalis subsp. lactis CCFM1274 produced relatively high levels of indole-3-carboxaldehyde (I3C). A mouse model of allergic asthma was established by oral administration of ovalbumin (OVA) and was subjected to oral administration of probiotics. The results demonstrated that treatment with CCFM1274 reduced the tendency for body weight loss and mortality in OVA-induced asthmatic mice. Ingestion of CCFM1274 improved the infiltration of perivascular and peribronchial inflammatory cells in the lung sections stained with hematoxylin and eosin (H&E). This outcome was accompanied by a reduction in the serum levels of OVA-specific immunoglobulin E (OVA-sIgE) and in the levels of IL-10 and IL-17 in the bronchoalveolar lavage fluid (BALF). The linear discriminant analysis effect size (LEfSe) of the gut microbiota showed that CCFM1274 increased the relative abundance of Bifidobacterium. In conclusion, CCFM1274 remodeled intestinal tryptophan metabolism in mice and contributed to the improvement of allergic asthma.
Asunto(s)
Asma , Bifidobacterium animalis , Microbioma Gastrointestinal , Ratones Endogámicos BALB C , Probióticos , Triptófano , Animales , Triptófano/metabolismo , Asma/tratamiento farmacológico , Ratones , Probióticos/farmacología , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Ovalbúmina , Modelos Animales de Enfermedad , Inmunoglobulina E , Líquido del Lavado Bronquioalveolar/química , Intestinos/microbiología , Humanos , Indoles/farmacologíaRESUMEN
5-Hydroxytryptophan (5-HTP), a precursor of the neurotransmitter serotonin in mammals, has demonstrated efficacy in treating various diseases such as depression, fibromyalgia and obesity. However, conventional biosynthesis methods of 5-HTP are limited by low yield and high reagent and process costs. In this study, the strain C1T7-S337A/F318Y with optimized promoter distribution was obtained, and the 5-HTP yield was 60.30â¯% higher than that of the initial strain. An efficient fermentation process for 5-HTP synthesis was developed using strain C1T7-S337A/F318Y with whey powder as a substrate for cell growth and inducer production. Shake flask fermentation experiments yielded 1.302â¯g/L 5-HTP from 2.0â¯g/L L-tryptophan (L-Trp), surpassing the whole-cell biocatalysis by 42.86â¯%. Scale-up to a 5â¯L fermenter further increased the yield to 1.649â¯g/L. This fermentation strategy substantially slashed reagent cost by 95.39â¯%, providing a more economically viable and environmentally sustainable route for industrial biosynthesis of 5-HTP. Moreover, it contributes to the broader utilization of whey powder in various industries.
Asunto(s)
5-Hidroxitriptófano , Escherichia coli , Fermentación , Suero Lácteo , 5-Hidroxitriptófano/metabolismo , Suero Lácteo/metabolismo , Escherichia coli/metabolismo , Escherichia coli/genética , Escherichia coli/crecimiento & desarrollo , Triptófano/metabolismo , Reactores Biológicos/microbiologíaRESUMEN
Type 2 diabetes (T2D) is potentially linked to disordered tryptophan metabolism that attributes to the intricate interplay among diet, gut microbiota, and host physiology. However, underlying mechanisms are substantially unknown. Comparing the gut microbiome and metabolome differences in mice fed a normal diet (ND) and high-fat diet (HFD), we uncover that the gut microbiota-dependent tryptophan metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) is present at lower concentrations in mice with versus without insulin resistance. We further demonstrate that the microbial transformation of tryptophan into 5-HIAA is mediated by Burkholderia spp. Additionally, we show that the administration of 5-HIAA improves glucose intolerance and obesity in HFD-fed mice, while preserving hepatic insulin sensitivity. Mechanistically, 5-HIAA promotes hepatic insulin signaling by directly activating AhR, which stimulates TSC2 transcription and thus inhibits mTORC1 signaling. Moreover, T2D patients exhibit decreased fecal levels of 5-HIAA. Our findings identify a noncanonical pathway of microbially producing 5-HIAA from tryptophan and indicate that 5-HIAA might alleviate the pathogenesis of T2D.
Asunto(s)
Dieta Alta en Grasa , Microbioma Gastrointestinal , Resistencia a la Insulina , Hígado , Diana Mecanicista del Complejo 1 de la Rapamicina , Receptores de Hidrocarburo de Aril , Transducción de Señal , Triptófano , Proteína 2 del Complejo de la Esclerosis Tuberosa , Animales , Dieta Alta en Grasa/efectos adversos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Triptófano/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Receptores de Hidrocarburo de Aril/metabolismo , Hígado/metabolismo , Humanos , Proteína 2 del Complejo de la Esclerosis Tuberosa/metabolismo , Proteína 2 del Complejo de la Esclerosis Tuberosa/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/microbiología , Masculino , Ratones Endogámicos C57BL , Obesidad/metabolismo , Obesidad/microbiología , Factores de Transcripción con Motivo Hélice-Asa-Hélice BásicoRESUMEN
The mechanism connecting gut microbiota to appetite regulation is not yet fully understood. This study identifies specific microbial community and metabolites that may influence appetite regulation. In the initial phase of the study, mice were administered a broad-spectrum antibiotic cocktail (ABX) for 10 days. The treatment significantly reduced gut microbes and disrupted the metabolism of arginine and tryptophan. Consequently, ABX-treated mice demonstrated a notable reduction in feed consumption. The hypothalamic expression levels of CART and POMC, two key anorexigenic factors, were significantly increased, while orexigenic factors, such as NPY and AGRP, were decreased. Notably, the levels of appetite-suppressing hormone cholecystokinin in the blood were significantly elevated. In the second phase, control mice were maintained, while the ABX-treated mice received saline, probiotics, and short-chain fatty acids (SCFAs) for an additional 10 days to restore their gut microbiota. The microbiota reconstructed by probiotic and SCFA treatments were quite similar, while microbiota of the naturally recovering mice demonstrated greater resemblance to that of the control mice. Notably, the abundance of Akkermansia and Bacteroides genera significantly increased in the reconstructed microbiota. Moreover, microbiota reconstruction corrected the disrupted arginine and tryptophan metabolism and the abnormal peripheral hormone levels caused by ABX treatment. Among the groups, SCFA-treated mice had the highest feed intake and NPY expression. Our findings indicate that gut microbes, especially Akkermansia, regulate arginine and tryptophan metabolism, thereby influencing appetite through the microbe-gut-brain axis.
Asunto(s)
Microbioma Gastrointestinal , Metaboloma , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Masculino , Ratones Endogámicos C57BL , Antibacterianos/farmacología , Triptófano/metabolismo , Apetito/efectos de los fármacos , Probióticos/farmacología , Arginina/farmacología , Arginina/metabolismo , Hipotálamo/metabolismo , Regulación del Apetito/fisiología , Ácidos Grasos Volátiles/metabolismoRESUMEN
BACKGROUND: In mammals, amino acid metabolism has evolved to control immune responses. Tryptophan (Trp) is the rarest essential amino acid found in food and its metabolism has evolved to be a primary regulatory node in the control of immune responses. Celiac disease (CeD) is a developed immunological condition caused by gluten intolerance and is linked to chronic small intestine enteropathy in genetically predisposed individuals. Dendritic cells (DCs), serving as the bridge between innate and adaptive immunities, can influence immunological responses in CeD through phenotypic alterations. OBJECTIVE: This review aims to highlight the connection between Trp metabolism and tolerogenic DCs, and the significance of this interaction in the pathogenesis of CeD. RESULTS: It is been recognized that various DC subtypes contribute to the pathogenesis of CeD. Tolerogenic DCs, in particular, are instrumental in inducing immune tolerance, leading to T-reg differentiation that helps maintain intestinal immune tolerance against inflammatory responses in CeD patients and those with other autoimmune disorders. T-regs, a subset of T-cells, play a crucial role in maintaining intestinal immunological homeostasis by regulating the activities of other immune cells. Notably, Trp metabolism, essential for T-reg function, facilitates T-reg differentiation through microbiota-mediated degradation and the kynurenine pathway. CONCLUSION: Therefore, alterations in Trp metabolism could potentially influence the immune response in CeD, affecting both the development of the disease and the persistence of symptoms despite adherence to a gluten-free diet.
Asunto(s)
Enfermedad Celíaca , Células Dendríticas , Tolerancia Inmunológica , Triptófano , Humanos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Triptófano/metabolismo , Enfermedad Celíaca/inmunología , Enfermedad Celíaca/metabolismo , Animales , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
The aim of this study was to investigate the overall effects of phototherapy on biopterin (BH4), neopterin (BH2), tryptophan (Trp), and behavioral neuroinflammatory reaction in patients with post-stroke depression. There involved a total of 100 hospitalized patients with post-stroke depression at our hospital from February 2021 to December 2022. The participants enrolled were randomly assigned to either the control group or the experimental group. The control group received routine treatment, including medication and psychological support, while the experimental group received 30 min of phototherapy daily for 8 weeks. All participantsvoluntarily participated in the study and provided informed consent. Baseline characteristics of the patients were statistically analyzed. The severity of depressive symptoms was evaluated using the hamilton depression scale (HAMD) and the beck depression inventory (BDI). Levels of amino acid neurotransmitters, including gamma-aminobutyric acid (GABA), aspartic acid (Asp), and glutamic acid (Glu), were measured using radioimmunoassay. Plasma levels of neuroinflammatory factors, such as TNF-α, IL-6, and IL-1ß were, determined using ELISA. Plasma levels of BH4, BH2, and Trp were detected by HPLC. Levels of SOD, GPx, CAT, and MDA in plasma were measured using corresponding kits and colorimetry. Quality of life was assessed using the SF-36 scale. There were no differences in baseline characteristic between the two groups (P > 0.05). The HAMD and BDI scores in the experimental group were lower than those in the control group (P < 0.05), indicating phototherapy could reduce the severity of post-stroke depression. The levels of GABA, Glu, and Asp in both groups significantly increased after treatment compared to their respective levels before treatment (P < 0.01).The levels of GABA in the experimental group were higher than those in the control group (P < 0.01),while the levels of Glu, and Asp were lower than those in the control group (P < 0.01). The plasma levels of TNF-α, IL-6, and IL-1ß in the experimental group were evidently lower than those in the control group (P < 0.05). Moreover, the levels of BH4 and Trp in experimental group were significantly higher than those in the control group (P < 0.05), while the levelsof BH2 in the experimental group were significantly lower than the control group (P < 0.05). Additionally, the levels of SOD, GPx, and CAT in the experimental group were evidently higher than those in the control group (P < 0.05), whereas the levels of MDA in the experimental group were significantly lower than control group (P < 0.05). The experimental group showed higher scores in physical function, mental health, social function, and overall health compared to the control group (P < 0.05). Phototherapy exerted a profound impact on the metabolism of BH4, BH2, and Trp, as well as on behavioral neuroinflammatory reactions and the quality of life in patients suffering from post-stroke depression. Through its ability to optimize the secretion and synthesis of neurotransmitters, phototherapy effectively regulated neuroinflammatory reactions, improved biochemical parameters, enhancedantioxidant capacity, and alleviated depressive symptoms. As a result, phototherapy was considered a valuable adjuvant therapeutic approach for patients with post-stroke depression.
Asunto(s)
Biopterinas , Depresión , Neopterin , Fototerapia , Accidente Cerebrovascular , Triptófano , Humanos , Neopterin/sangre , Triptófano/sangre , Triptófano/metabolismo , Femenino , Masculino , Persona de Mediana Edad , Depresión/terapia , Depresión/etiología , Depresión/sangre , Anciano , Fototerapia/métodos , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/psicología , Biopterinas/análogos & derivados , Enfermedades Neuroinflamatorias/terapia , Enfermedades Neuroinflamatorias/etiologíaRESUMEN
Indigo, as a water-soluble non-azo colorant, is widely used in textile, food, pharmaceutical and other industrial fields. Currently, indigo is primarily synthesized by chemical methods, which causes environmental pollution, potential safety hazards, and other issues. Therefore, there is an urgent need to find a safer and greener synthetic method. In this study, a dual-enzyme cascade pathway was constructed with the tryptophan synthase (tryptophanase, EcTnaA) from Escherichia coli and flavin-dependent monooxygenase (flavin-dependent monooxygenase, MaFMO) from Methylophaga aminisulfidivorans to synthesize indigo with L-tryptophan as substrate. A recombinant strain EM-IND01 was obtained. The beneficial mutant MaFMOD197E was obtained by protein engineering of the rate-limiting enzyme MaFMO. MaFMOD197E showed the specific activity and kcat/Km value 2.36 times and 1.34 times higher than that of the wild type, respectively. Furthermore, MaFMOD197E was introduced into the strain EM-IND01 to construct the strain EM-IND02. After the fermentation conditions were optimized, the strain achieved the indigo titer of (1 288.59±7.50) mg/L, the yield of 0.86 mg/mg L-tryptophan, and the productivity of 26.85 mg/(L·h) in a 5 L fermenter. Protein engineering was used to obtain mutants with increased MaFMO activity in this study, which laid a foundation for industrial production of indigo.
Asunto(s)
Escherichia coli , Carmin de Índigo , Triptófano , Carmin de Índigo/metabolismo , Triptófano/metabolismo , Triptófano/biosíntesis , Escherichia coli/genética , Escherichia coli/metabolismo , Ingeniería de Proteínas , Triptofanasa/genética , Triptofanasa/metabolismo , Triptófano Sintasa/metabolismo , Triptófano Sintasa/genética , Fermentación , Oxigenasas/genética , Oxigenasas/metabolismoRESUMEN
Kynurenine pathway inhibition reverses deficits in Alzheimer's mouse models.
Asunto(s)
Enfermedad de Alzheimer , Indolamina-Pirrol 2,3,-Dioxigenasa , Quinurenina , Animales , Humanos , Ratones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Modelos Animales de Enfermedad , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Quinurenina/metabolismo , Triptófano/metabolismoRESUMEN
Human tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are two important targets in cancer immunotherapy. Extensive research has led to a large number of potent IDO inhibitors; in addition, 52 structures of IDO in complex with inhibitors with a wide array of chemical scaffolds have been documented. In contrast, progress in the development of TDO inhibitors has been limited. Only four structures of TDO in complex with competitive inhibitors that compete with the substrate L-tryptophan for binding to the active site have been reported to date. Here we systematically evaluated the structures of TDO in complex with competitive inhibitors with three types of pharmacophores, imidazo-isoindole, indole-tetrazole, and indole-benzotriazole. The comparative assessment of the protein-inhibitor interactions sheds new light into the structure-based design of enzyme-selective inhibitors.
Asunto(s)
Inhibidores Enzimáticos , Indolamina-Pirrol 2,3,-Dioxigenasa , Triptófano Oxigenasa , Humanos , Triptófano Oxigenasa/antagonistas & inhibidores , Triptófano Oxigenasa/metabolismo , Triptófano Oxigenasa/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/química , Relación Estructura-Actividad , Indoles/química , Indoles/farmacología , Indoles/metabolismo , Modelos Moleculares , Tetrazoles/química , Tetrazoles/farmacología , Tetrazoles/metabolismo , Triptófano/química , Triptófano/metabolismo , Imidazoles/química , Imidazoles/farmacología , Imidazoles/metabolismo , Unión ProteicaRESUMEN
Introduction: Tryptophan metabolism is strongly associated with immunosuppression and may influence lung adenocarcinoma prognosis as well as tumor microenvironment alterations. Methods: Sequencing datasets were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. Two different clusters were identified by consensus clustering, and prognostic models were established based on differentially expressed genes (DEGs) in the two clusters. We investigated differences in mutational landscapes, enrichment pathways, immune cell infiltration, and immunotherapy between high- and low-risk scoring groups. Single-cell sequencing data from Bischoff et al. were used to identify and quantify tryptophan metabolism, and model genes were comprehensively analyzed. Finally, PTTG1 was analyzed at the pan-cancer level by the pan-TCGA cohort. Results: Risk score was defined as an independent prognostic factor for lung adenocarcinoma and was effective in predicting immunotherapy response in patients with lung adenocarcinoma. PTTG1 is one of the key genes, and knockdown of PTTG1 in vitro decreases lung adenocarcinoma cell proliferation and migration and promotes apoptosis and down-regulation of tryptophan metabolism regulators in lung adenocarcinoma cells. Discussion: Our study revealed the pattern and molecular features of tryptophan metabolism in lung adenocarcinoma patients, established a model of tryptophan metabolism-associated lung adenocarcinoma prognosis, and explored the roles of PTTG1 in lung adenocarcinoma progression, EMT process, and tryptophan metabolism.
Asunto(s)
Adenocarcinoma del Pulmón , Inmunoterapia , Neoplasias Pulmonares , Triptófano , Humanos , Triptófano/metabolismo , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/mortalidad , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/terapia , Pronóstico , Inmunoterapia/métodos , Regulación Neoplásica de la Expresión Génica , Femenino , Masculino , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Transcriptoma , Persona de Mediana Edad , Perfilación de la Expresión Génica , Microambiente Tumoral/inmunología , Microambiente Tumoral/genéticaRESUMEN
Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer's disease (AD), with recent proteomic studies highlighting disrupted glial metabolism in AD. We report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN), rescues hippocampal memory function in mouse preclinical models of AD by restoring astrocyte metabolism. Activation of astrocytic IDO1 by amyloid ß and tau oligomers increases KYN and suppresses glycolysis in an aryl hydrocarbon receptor-dependent manner. In amyloid and tau models, IDO1 inhibition improves hippocampal glucose metabolism and rescues hippocampal long-term potentiation in a monocarboxylate transporter-dependent manner. In astrocytic and neuronal cocultures from AD subjects, IDO1 inhibition improved astrocytic production of lactate and uptake by neurons. Thus, IDO1 inhibitors presently developed for cancer might be repurposed for treatment of AD.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Astrocitos , Glucosa , Glucólisis , Hipocampo , Indolamina-Pirrol 2,3,-Dioxigenasa , Quinurenina , Neuronas , Animales , Humanos , Masculino , Ratones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Astrocitos/metabolismo , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Glucosa/metabolismo , Glucólisis/efectos de los fármacos , Hipocampo/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Quinurenina/metabolismo , Ácido Láctico/metabolismo , Potenciación a Largo Plazo , Memoria/efectos de los fármacos , Transportadores de Ácidos Monocarboxílicos/metabolismo , Neuronas/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Proteínas tau/metabolismo , Triptófano/metabolismoRESUMEN
Chronic immune activation promotes tuberculosis (TB) reactivation in the macaque Mycobacterium tuberculosis (M. tuberculosis)/SIV coinfection model. Initiating combinatorial antiretroviral therapy (cART) early lowers the risk of TB reactivation, but immune activation persists. Studies of host-directed therapeutics (HDTs) that mitigate immune activation are, therefore, required. Indoleamine 2,3, dioxygenase (IDO), a potent immunosuppressor, is one of the most abundantly induced proteins in NHP and human TB granulomas. Inhibition of IDO improves immune responses in the lung, leading to better control of TB, including adjunctive to TB chemotherapy. The IDO inhibitor D-1 methyl tryptophan (D1MT) is, therefore, a bona fide TB HDT candidate. Since HDTs against TB are likely to be deployed in an HIV coinfection setting, we studied the effect of IDO inhibition in M. tuberculosis/SIV coinfection, adjunctive to cART. D1MT is safe in this setting, does not interfere with viral suppression, and improves the quality of CD4+ and CD8+ T cell responses, including reconstitution, activation and M. tuberculosis-specific cytokine production, and access of CD8+ T cells to the lung granulomas; it reduces granuloma size and necrosis, type I IFN expression, and the recruitment of inflammatory IDO+ interstitial macrophages (IMs). Thus, trials evaluating the potential of IDO inhibition as HDT in the setting of cART in M. tuberculosis/HIV coinfected individuals are warranted.
Asunto(s)
Coinfección , Indolamina-Pirrol 2,3,-Dioxigenasa , Macaca mulatta , Mycobacterium tuberculosis , Síndrome de Inmunodeficiencia Adquirida del Simio , Triptófano , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Animales , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Coinfección/tratamiento farmacológico , Coinfección/inmunología , Triptófano/metabolismo , Triptófano/análogos & derivados , Tuberculosis/inmunología , Tuberculosis/tratamiento farmacológico , Virus de la Inmunodeficiencia de los Simios/inmunología , Modelos Animales de Enfermedad , Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/complicaciones , Antirretrovirales/uso terapéutico , Antirretrovirales/farmacología , Masculino , Pulmón/inmunología , Pulmón/patología , Humanos , Linfocitos T CD4-Positivos/inmunologíaRESUMEN
Essential amino acids (EAA) and microRNAs (miRs) control biological activity of a cell. Whether EAA regulates the activity of miR has never been demonstrated. Here, as proof-of-concept, a tryptophan (Trp, an EAA) complex containing Argonaute 2 (Ago2) and miRs including miR-193a (Trp/Ago2/miR-193a) is identified. Trp binds miR-193a-3p and interacts with Ago2. Trp/Ago2/miR-193a increases miR-193a-3p activity via enhancing Argonaute 2 (Ago2) RNase activity. Other miRs including miR-103 and miR-107 in the Trp complex enhance miR-193a activity by targeting the same genes. Mechanistically, the Trp/Ago2/miR-193a complex interacts with Trp-binding pockets of the PIWI domain of Ago2 to enhance Ago2 mediated miR activity. This newly formed Ago2/Trp/miR-193a-3p complex is more efficient than miR-193a-3p alone in inhibiting the expression of targeted genes and inhibiting colon cancer liver metastasis. The findings show that Trp regulates miR activity through communication with the RNA-induced silencing complexes (RISC), which provides the basis for tryptophan based miR therapy.
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Proteínas Argonautas , Neoplasias del Colon , Neoplasias Hepáticas , MicroARNs , Complejo Silenciador Inducido por ARN , Triptófano , Triptófano/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Humanos , Proteínas Argonautas/metabolismo , Proteínas Argonautas/genética , Complejo Silenciador Inducido por ARN/metabolismo , Complejo Silenciador Inducido por ARN/genética , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Neoplasias del Colon/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Ratones , Animales , Línea Celular Tumoral , Modelos Animales de EnfermedadRESUMEN
Neurodevelopmental disorders are rapidly increasing in prevalence and have been linked to various environmental risk factors. Mounting evidence suggests a potential role of vitamin D in child neurodevelopment, though the causal mechanisms remain largely unknown. Here, we investigate how vitamin D deficiency affects children's communication development, particularly in relation to Autism Spectrum Disorder (ASD). We do so by developing an integrative network approach that combines metabolomic profiles, clinical traits, and neurodevelopmental data from a pediatric cohort. Our results show that low levels of vitamin D are associated with changes in the metabolic networks of tryptophan, linoleic, and fatty acid metabolism. These changes correlate with distinct ASD-related phenotypes, including delayed communication skills and respiratory dysfunctions. Additionally, our analysis suggests the kynurenine and serotonin sub-pathways may mediate the effect of vitamin D on early life communication development. Altogether, our findings provide metabolome-wide insights into the potential of vitamin D as a therapeutic option for ASD and other communication disorders.
Asunto(s)
Trastorno del Espectro Autista , Deficiencia de Vitamina D , Vitamina D , Humanos , Vitamina D/metabolismo , Niño , Trastorno del Espectro Autista/metabolismo , Femenino , Masculino , Deficiencia de Vitamina D/metabolismo , Preescolar , Metaboloma , Redes y Vías Metabólicas/efectos de los fármacos , Metabolómica/métodos , Triptófano/metabolismo , Trastornos del Neurodesarrollo/metabolismo , Trastornos del Neurodesarrollo/etiologíaRESUMEN
Neonatal respiratory distress syndrome (NRDS) is one of the most severe respiratory disorders in preterm infants (PTIs) due to immature lung development. To delineate the serum metabolic alterations and gut microbiota variations in NRDS and assess their implications on neonatal development, we enrolled 13 NRDS neonates and 12 PTIs and collected fecal and serum specimens after birth. Longitudinal fecal sampling was conducted weekly for a month in NRDS neonates. NRDS neonates were characterized by notably reduced gestational ages and birth weights and a higher rate of asphyxia at birth relative to PTIs. Early postnatal disturbances in tryptophan metabolism were evident in the NRDS group, concomitant with elevated relative abundance of Haemophilus, Fusicatenibacter, and Vibrio. Integrative multiomics analyses revealed an inverse relationship between tryptophan concentrations and Blautia abundance. At one-week old, NRDS neonates exhibited cortisol regulation anomalies and augmented hepatic catabolism. Sequential microbial profiling revealed distinct gut microbiota evolution in NRDS subjects, characterized by a general reduction in potentially pathogenic bacteria. The acute perinatal stress of NRDS leads to mitochondrial compromise, hormonal imbalance, and delayed gut microbiota evolution. Despite the short duration of NRDS, its impact on neonatal development is significant and requires extended attention.
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Heces , Microbioma Gastrointestinal , Recien Nacido Prematuro , Síndrome de Dificultad Respiratoria del Recién Nacido , Humanos , Recién Nacido , Síndrome de Dificultad Respiratoria del Recién Nacido/microbiología , Síndrome de Dificultad Respiratoria del Recién Nacido/metabolismo , Heces/microbiología , Femenino , Masculino , Edad Gestacional , Triptófano/metabolismo , Triptófano/sangre , Hidrocortisona/sangreRESUMEN
Indole serves as a signaling molecule that could regulate different bacterial physiological processes, including antibiotic resistance through biofilm formation and drug efflux pump activity. In Escherichia coli, indole is produced through the tryptophan pathway, which involves three permeases (Mtr, AroP, and TnaB) that can transport the amino acid tryptophan. Although these permeases play distinct roles in the secretion of indole biosynthesis, their impact on multidrug resistance mediated by indole remaines unclear. This study was designed to investigate the connection between the tryptophan transport system and antibiotic resistance by constructing seven gene deletion mutants from E. coli MG1655 (wild type). Our result showed that deletion of the aroP or tnaB gene led to increased antibiotic resistance as evaluated by MICs for different antibiotics. Efflux activity test results revealed that the increased antibiotic resistance was related with the AcrAB-Tolc drug efflux pump in the mutants. The transcriptome analysis further demonstrated that decreased susceptibility to kanamycin and ampicillin in E. coli was accompanied by reduced accumulation of reactive oxygen species and decreased motility. These findings highlight the substantial influence of the tryptophan transport system on antibiotic resistance in E. coli, which is crucial for developing strategies against antibiotic resistance in bacterial infections.
Asunto(s)
Antibacterianos , Proteínas de Escherichia coli , Escherichia coli , Pruebas de Sensibilidad Microbiana , Triptófano , Escherichia coli/genética , Escherichia coli/efectos de los fármacos , Escherichia coli/metabolismo , Triptófano/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Antibacterianos/farmacología , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Eliminación de Gen , Farmacorresistencia Bacteriana Múltiple/genética , Transporte Biológico , Farmacorresistencia Bacteriana/genética , Especies Reactivas de Oxígeno/metabolismo , Ampicilina/farmacología , Silenciador del Gen , Kanamicina/farmacología , Sistemas de Transporte de Aminoácidos/genética , Sistemas de Transporte de Aminoácidos/metabolismo , Regulación Bacteriana de la Expresión Génica , Proteínas PortadorasRESUMEN
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.
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Encéfalo , Dieta Alta en Grasa , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , FN-kappa B , Estrés Oxidativo , Ácido Quínico , Transducción de Señal , Triptófano , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Triptófano/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Masculino , Estrés Oxidativo/efectos de los fármacos , Ácido Quínico/análogos & derivados , Ácido Quínico/farmacología , Ácido Quínico/metabolismo , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/prevención & control , Quinasa I-kappa B/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/prevención & control , Ácidos Indolacéticos/metabolismo , Ácido Quinurénico/metabolismo , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/prevención & controlRESUMEN
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.
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Ácidos Grasos no Esterificados , Neoplasias , Triptófano , Humanos , Neoplasias/metabolismo , Triptófano/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Animales , Receptores de Hidrocarburo de Aril/metabolismo , Quinurenina/metabolismo , Hemo/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Homocisteína/metabolismoRESUMEN
AIM: Tryptophan (TRP), an essential amino acid, undergoes catabolism through various pathways. Notably, the kynurenine pathway (KP), constituting one of these pathways, exhibits a unidirectional impact on immune response and energy metabolism. Nonetheless, its influence on pain sensation is characterized by biphasic dynamics. This study aims to scrutinize the influence of the KP pathway on pain sensation, particularly within the context of pancreatic inflammation. METHODS: Our prospective case-control study involved individuals diagnosed with acute pancreatitis and a control group matched for gender and age. The patient cohort was subsequently subdivided into severe and non-severe subgroups. To assess metabolites within KP, two blood samples were collected from the patient cohort, one at the time of diagnosis and another during the recovery phase. Furthermore, for pain quantification, daily pain scores utilizing the Visual Analog Scale (VAS) were extracted from the patients' medical records. RESULTS: The study incorporated 30 patients along with an equivalent number of controls. A noticeable distinction was evident between the patient and control groups, characterized by an increase in kynurenine levels and a decrease in the tryptophan/kynurenine ratio. Throughout the process of disease recovery, a uniform decrease was observed in all KP metabolites, excluding 3-Hydroxykynurenine. Elevated levels of Kynurenic acid (KYNA) were correlated with increased pain scores. Critically, no apparent distinctions in KP metabolites were discerned concerning pain severity in patients with comorbidities characterized by neural involvement. CONCLUSION: Based on our results, the kynurenine pathway (KP) is activated in instances of acute pancreatitis. Elevated levels of KYNA were found to be associated with heightened pain scores. The operative stages within the KP responsible for pain modulation are impaired in cases characterized by neuropathy-induced pain sensation.