Immuno-Metabolic Modulation of Liver Oncogenesis by the Tryptophan Metabolism.
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ABSTRACT:
SUBMITTER: Trezeguet V
PROVIDER: S-EPMC8700200 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundImmunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis. Although an important link between intestinal metabolites and immune activity is widely established, the metabolic profile of IgAN is still poorly understood, which severely limits the mechanistic studies and therapy of IgAN.MethodsThe diversity of intestinal flora and relative abundance of metabolites in IgAN patients and healthy subjects were measured by 16s ribosomal RNA gene sequencing combined with liquid chromatography tandem-mass spectrometry. The levels of serum Gd-IgA1, IL-6, IL-10, IL-22, and TNF-a were tested by ELISA. We employed the tryptophan-targeted UHPLC-MRM-MS approach to assess the content of tryptophan metabolites quantitatively.ResultsIntestinal fatty acid levels, mainly unsaturated fatty acids, were observed to be dramatically decreased in IgAN patients. Disorders in linoleic acid and arachidonic acid metabolism, metabolic imbalances of anti-/pro- inflammatory fatty acid metabolites, and intestinal AhR signaling deficiency might reflect the damage of the intestinal mucosal barrier in IgAN patients. In addition, we found that high levels of Gd-IgA1, IL-22, and TNF-α were associated with the activity of the tryptophan-kynurenine metabolic pathway, as well as lower levels of 3-indolepropionic acid. 3-indolepropionic acid, kynurenine, and indoleacrylic acid had synergistic effects on regulating immuno-inflammatory responses in IgAN patients.ConclusionsThe metabolic characteristic of fatty acids and tryptophan in the intestinal system is disturbed in IgAN patients, leading to active immune-inflammatory reactions.
| S-EPMC8850467 | biostudies-literature
Project description:Kawasaki disease (KD) is a childhood vasculitis disease that is difficult to diagnose, and there is an urgent need for the identification of accurate and specific biomarkers. Here, we aimed to investigate metabolic alterations in patients with KD to determine novel diagnostic and prognostic biomarkers for KD. To this end, we performed untargeted metabolomics and found that several metabolic pathways were significantly enriched, including amino acid, lipid, and tryptophan metabolism, the latter of which we focused on particularly. Tryptophan-targeted metabolomics was conducted to explore the role of tryptophan metabolism in KD. The results showed that Trp and indole acetic acid (IAA) levels markedly decreased, and that l-kynurenine (Kyn) and kynurenic acid (Kyna) levels were considerably higher in patients with KD than in healthy controls. Changes in Trp, IAA, Kyn, and Kyna levels in a KD coronary arteritis mouse model were consistent with those in patients with KD. We further analyzed public single-cell RNA sequencing data of patients with KD and revealed that their peripheral blood mononuclear cells showed Aryl hydrocarbon receptor expression that was remarkably higher than that of healthy children. These results suggest that the Trp metabolic pathway is significantly altered in KD and that metabolic indicators may serve as novel diagnostic and therapeutic biomarkers for KD.
| S-EPMC10192854 | biostudies-literature
Project description:Cell encapsulation provides a three-dimensional support by incorporating isolated cells into microcapsules with the goal of simultaneously maintaining cell survival and function, as well as providing active transport for a bioreactor in vitro similarly to that observed in vivo. However, the biotra-nsformation and metabolic functions of the encapsulated cells are not satisfactory for clinical applications. For this purpose, in this study, hepatoma-derived Huh7 cells/C3A cells were treated with 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), an endogenous non-toxic ligand for aryl hydrocarbon receptor, in monolayer cultures and on microspheres. The mRNA and protein levels, as well as the metabolic activities of drug metabolizing enzymes, albumin secretion and urea synthesis were determined. When the Huh7 and C3A cells cultured in a monolayer on two?dimensional surfaces, ITE enhanced the protein levels and the metabolic activities of the major cytochrome P450 (CYP450) enzymes, CYP1A1, CYP1A2, CYP3A4 and CYP1B1, and slightly increased albumin secretion and urea synthesis. Moreover, when cultured on microspheres, ITE also substantially increased the protein levels and metabolic activities of CYP1A1, CYP1A2, CYP3A4 and CYP1B1 in both liver cell lines. On the whole, our findings indicate that ITE enhances the enzymatic activities of major CYP450 enzymes and the metabolic functions of liver cells cultured in monolayer or on microspheres, indicating that it may be utilized to improve the functions of hepatocytes. Thus, it may be used in the future for the treatment of liver diseases.
| S-EPMC5179183 | biostudies-literature
Project description:Cancer is a disease characterized by unrestrained cellular proliferation. In order to sustain growth, cancer cells undergo a complex metabolic rearrangement characterized by changes in metabolic pathways involved in energy production and biosynthetic processes. The relevance of the metabolic transformation of cancer cells has been recently included in the updated version of the review "Hallmarks of Cancer", where dysregulation of cellular metabolism was included as an emerging hallmark. While several lines of evidence suggest that metabolic rewiring is orchestrated by the concerted action of oncogenes and tumor suppressor genes, in some circumstances altered metabolism can play a primary role in oncogenesis. Recently, mutations of cytosolic and mitochondrial enzymes involved in key metabolic pathways have been associated with hereditary and sporadic forms of cancer. Together, these results demonstrate that aberrant metabolism, once seen just as an epiphenomenon of oncogenic reprogramming, plays a key role in oncogenesis with the power to control both genetic and epigenetic events in cells. In this review, we discuss the relationship between metabolism and cancer, as part of a larger effort to identify a broad-spectrum of therapeutic approaches. We focus on major alterations in nutrient metabolism and the emerging link between metabolism and epigenetics. Finally, we discuss potential strategies to manipulate metabolism in cancer and tradeoffs that should be considered. More research on the suite of metabolic alterations in cancer holds the potential to discover novel approaches to treat it.
| S-EPMC4656121 | biostudies-literature
Project description:Heart failure (HF) is associated with metabolic changes that cause a progressive impairment of cardiac and skeletal muscle high-energy phosphate production. As a consequence of the impaired cardiac metabolism, other processes are activated in the failing heart that further exacerbate the progression of HF. The reduced production of high-energy phosphates has important implications for both systole and diastole in HF with both preserved and reduced left ventricular function. The aim of this review is to summarise the state-of-the-art on metabolic therapy in HF with a particular focus on trimetazidine. Metabolic agents optimise cardiac substrate metabolism without exerting negative haemodynamic effects. In particular, as studies with metabolic agents modulating cardiac metabolism have consistently demonstrated, this approach is effective in improving symptoms, functional capacity and prognosis in people with HF when added to optimal medical therapy. Therefore, the modulation of cardiac metabolism is an important therapeutic approach to the treatment of HF, especially in patients where it is of ischaemic or metabolic origin. Although further studies are needed, metabolic agents might be a new, effective strategy for the treatment of HF.
| S-EPMC6125709 | biostudies-literature
Project description:Tryptophan is catabolized by gut microorganisms resulting in a wide range of metabolites implicated in both beneficial and adverse host effects. How gut microbial tryptophan metabolism is directed towards indole, associated with chronic kidney disease, or towards protective indolelactic acid (ILA) and indolepropionic acid (IPA) is unclear. Here we used in vitro culturing and animal experiments to assess gut microbial competition for tryptophan and the resulting metabolites in a controlled three-species defined community and in complex undefined human faecal communities. The generation of specific tryptophan-derived metabolites was not predominantly determined by the abundance of tryptophan-metabolizing bacteria, but rather by substrate-dependent regulation of specific metabolic pathways. Indole-producing Escherichia coli and ILA- and IPA-producing Clostridium sporogenes competed for tryptophan within the three-species community in vitro and in vivo. Importantly, fibre-degrading Bacteroides thetaiotaomicron affected this competition by cross-feeding monosaccharides to E. coli. This inhibited indole production through catabolite repression, thus making more tryptophan available to C. sporogenes, resulting in increased ILA and IPA production. The fibre-dependent reduction in indole was confirmed using human faecal cultures and faecal-microbiota-transplanted gnotobiotic mice. Our findings explain why consumption of fermentable fibres suppresses indole production but promotes the generation of other tryptophan metabolites associated with health benefits.
| S-EPMC11306097 | biostudies-literature
Project description:Glucose hypometabolism in the pre-clinical stage of Alzheimer's disease (AD) has been primarily associated with the APOE ɛ4 genotype, rather than fibrillar β-amyloid. In contrast, aberrant patterns of metabolic connectivity are more strongly related to β-amyloid burden than APOE ɛ4 status. A major limitation of previous studies has been the dichotomous classification of subjects as amyloid-positive or amyloid-negative. Dichotomous treatment of a continuous variable, such as β-amyloid, potentially obscures the true relationship with metabolism and reduces the power to detect significant changes in connectivity. In the present work, we assessed alterations of glucose metabolism and metabolic connectivity as continuous function of β-amyloid burden using positron emission tomography scans from the Alzheimer's Disease Neuroimaging Initiative study. Modeling β-amyloid as a continuous variable resulted in better model fits and improved power compared to the dichotomous model. Using this continuous model, we found that both APOE ɛ4 genotype and β-amyloid burden are strongly associated with glucose hypometabolism at early stages of Alzheimer's disease. We also determined that the cumulative effects of β-amyloid deposition result in a particular pattern of altered metabolic connectivity, which is characterized by global, synchronized hypometabolism at early stages of the disease process, followed by regionally heterogeneous, progressive hypometabolism.
| S-EPMC5363668 | biostudies-literature
Project description:BackgroundBerberine is an isoquinoline alkaloid compound derived from many herbs, which has been used extensively to improve liver function. But action mechanism of its hepatoprotection in alcoholic liver disease (ALD) is far from being clear.AimTo investigate the underlying mechanism of berberine's therapeutic effect on ALD associated with gut microbiota-immune system axis.MethodAn animal model fed with ethanol that mimics drinking pattern ideally in ALD patients was established. Liver function was evaluated by biochemical test and histological examination. Immune cells were detected by flow cytometry and feces samples were collected for 16S rRNA gene amplicon sequencing.ResultsWe first reported the promising beneficial effect of berberine on ameliorating acute-on-chronic alcoholic hepatic damage and explored the underlying mechanism involving gut microbiota-immune system axis. Notably, berberine activated a population with immune suppressive function, defined as granulocytic- myeloid-derived suppressor cell (G-MDSC)-like population, in the liver of mice with alleviating alcohol-induced hepatic injury. Berberine remarkably enhanced the increase of G-MDSC-like cells in blood and liver and decreased cytotoxic T cells correspondingly. Suppression of G-MDSC-like population significantly attenuated the protective effect of berberine against alcohol. Berberine activated IL6/STAT3 signaling in in vitro culture of G-MSDCs-like population, while inhibition of STAT3 activity attenuated the activation of this population by berberine. Moreover, berberine changed the overall gut microbial community, primarily increased the abundance of Akkermansia muciniphila. Of note, depletion of gut microbiota abolished the inducing effect of berberine on G-MDSC-like population, and attenuated its hepatoprotective effect against alcohol in mice, suggesting intestinal flora might be involved in mediating the expansion of this protective population.ConclusionCollectively, this study delivered insight into the role of immunosuppressive response in ALD, and facilitated the understanding of the pharmacological effects and action mechanisms of berberine.
| S-EPMC7438809 | biostudies-literature
Project description:Current research depicts specific modes of immunity and energy metabolism as being interrelated at the molecular, cellular, organ and organism level. Hence, whereas M2 (alternatively-activated) macrophages dominate insulin-sensitive adipose tissue in the lean, M1-skewed (classically-activated) macrophages accumulate in parallel to adiposity in the obese, and promote inflammation and insulin resistance, that is, meta-inflammation. The latest frontier of immuno-metabolism explores the coregulation of energy metabolism and immune function within hematopoietic cells. M1-skewed macrophages are sustained in edematous, hypoxic tissues by anaerobic glycolysis, whereas mitochondrial biogenesis and respiration dominates in M2 cells. We review the underlying mechanisms and the consequences of the transition from M2 to M1 predominance in adipose tissue, as well as the extracellular signals and transcription factors that control macrophage phenotypes and impose distinct metabolic modes.
| S-EPMC3253544 | biostudies-literature
Project description:BackgroundThe infantile spasms syndrome is an early-onset epileptic encephalopathy presenting in the first 2 years of life, often with severe developmental consequences. The role of the gut microbiota and metabolism in infantile spasms remains unexplored.MethodsEmploying a brain injury neonatal rat model of infantile spasms intractable to anticonvulsant medication treatments, we determined how the ketogenic diet and antibiotics affected specific microbial communities and the resultant circulating factors that confer spasms protection in the infantile spasms model. To confirm a role of kynurenine metabolism pathway in spasms protection, indoleamine 2,3-dioxygenase 1 was pharmacologically inhibited and comprehensive metabolomics was applied.FindingsWe show that antibiotics reduced spasms and improved the effectiveness of the ketogenic diet when given in combination. Examination of the gut microbiota and metabolomics showed the downregulation of indoleamine 2,3-dioxygenase 1 and upregulation of hippocampal kynurenic acid, a metabolite with antiepileptic effects. To further test the involvement of indoleamine 2,3-dioxygenase 1, a specific antagonist 1-methyltryptophan and minocycline, an antibiotic and inhibitor of kynurenine formation from tryptophan, were administered, respectively. Both treatments were effective in reducing spasms and elevating hippocampal kynurenic acid. A fecal microbiota transplant experiment was then performed to examine the contribution of the gut microbiota on spasm mitigation. Transplant of feces of ketogenic diet animals into normal diet animals was effective in reducing spasms.InterpretationThese results highlight the importance of tryptophan-kynurenine metabolism in infantile spasms and provide evidence for new-targeted therapies such as indoleamine 2,3-dioxygenase 1 inhibition or microbiota manipulation to promote kynurenic acid production as a strategy to reduce spasms in infantile spasms.FundingThis study was funded by the Alberta Children's Hospital Research Institute and the Owerko Centre.
| S-EPMC8883001 | biostudies-literature