Search Results (21)

Tryptophan hydroxylase (Tph), the rate-limiting enzyme of serotonin (5-hydroxytryptophan; 5-HT) synthesis, exists in two isoforms, Tph1 and Tph2. Tph1 upregulates peripheral 5-HT synthesis and blood 5-HT levels, whereas Tph2 upregulates brain 5-HT synthesis. Here, we show that plasma and brain levels of tryptophan and its metabolites, including 5-HT, 5-hydroxy indoleacetic acid, indolepropionic acid, indole-3-acetic acid, kynurenine, and xanthurenic acid, are decreased in young (8-week-old) Tph1-mutant mice compared with age-matched wild-type mice. In older (7-month-old) Tph1-mutants, the decreases in tryptophan and its metabolites outside the 5-HT pathway were diminished. Although single-housed Tph1 mutants displayed age-related alterations in food intake, body weight, and plasma FGF21 levels, blood glucose levels were lower in both young and older Tph1 mutants compared with age-matched wild-type mice. These findings suggest that Tph1 regulates tryptophan and its metabolites in the plasma and brain, as well as blood glucose homeostasis. Full article

Background: Kidney transplantation is the therapy of choice for patients with advanced chronic kidney disease; however, predicting graft outcomes remains a significant challenge. Early identification of reliable biomarkers could enhance post-transplant management and improve long-term outcomes. This study aimed to identify metabolomic biomarkers within the first week after kidney transplantation that predict renal function at six months. Methods: We conducted a prospective study involving 50 adult patients who received deceased donor kidney transplants. Plasma samples collected one week after transplant were analyzed using liquid chromatography–mass spectrometry in a semi-targeted metabolomic approach. A Partial Least Squares-Discriminant Analysis (PLS-DA) model identified metabolites associated with serum creatinine > 1.5 mg/dL at six months. Metabolites were selected based on a Variable Importance in Projection (VIP) score > 1.5, which was used to optimize model performance. Results: The PLS-DA model demonstrated strong predictive performance with an area under the curve (AUC) of 0.958. The metabolites negatively associated with serum creatinine > 1.5 mg/dL were 3-methylindole, guaiacol, histidine, 3-indolepropionic acid, and α-lipoic acid. Conversely, the metabolites positively associated with worse kidney graft outcomes included homocarnosine, 5-methylcytosine, xanthosine, choline, phenylalanine, kynurenic acid, and L-kynurenine. Conclusions: Early metabolomic profiling after transplantation shows promise in predicting renal function. Identifying metabolites with antioxidant and anti-inflammatory properties, as well as those that are harmful and could be targeted therapeutically, underscores their potential clinical significance. The link between several metabolites and the tryptophan pathway suggests that further specific evaluation of this pathway is warranted. These biomarkers can enhance patient management and graft survival. Full article

Maternal nutrition during the critical period of pregnancy increases the susceptibility of offspring to the development of diseases later in life. This study aimed to analyze metabolite profiles to investigate the effect of maternal diet during pregnancy on changes in offspring plasma metabolites and to identify correlations with metabolic parameters. Pregnant Sprague-Dawley rats were exposed to under- and overnutrition compared to controls, and their offspring were fed a standard diet after birth. Plasma metabolism was profiled in offspring at 16 weeks of age using liquid chromatography–mass spectrometry (LC-MS/MS) and gas chromatography–tandem mass spectrometry (GC-MS/MS). We analyzed 80 metabolites to identify distinct metabolites and metabolic and neurodegenerative disease-associated metabolites that were sex-differentially altered in each group compared to controls (p < 0.05, VIP score > 1.0). Specifically, changes in 3-indolepropionic acid, anthranilic acid, linoleic acid, and arachidonic acid, which are involved in tryptophan and linoleic acid metabolism, were observed in male offspring and correlated with plasma leptin levels in male offspring. Our results suggest that fatty acids involved in tryptophan and linoleic acid metabolism, which are altered by the maternal diet during pregnancy, may lead to an increased risk of metabolic and neurodegenerative diseases in the early life of male offspring. Full article

The microbiome is capable of modulating the bioavailability of chemotherapy drugs, mainly due to metabolizing these agents. Multiple cytostatic bacterial metabolites were recently identified that have cytostatic effects on cancer cells. In this study, we addressed the question of whether a set of cytostatic bacterial metabolites (cadaverine, indolepropionic acid and indoxylsulfate) can interfere with the cytostatic effects of the chemotherapy agents used in the management of breast cancer (doxorubicin, gemcitabine, irinotecan, methotrexate, rucaparib, 5-fluorouracil and paclitaxel). The chemotherapy drugs were applied in a wide concentration range to which a bacterial metabolite was added in a concentration within its serum reference range, and the effects on cell proliferation were assessed. There was no interference between gemcitabine, irinotecan, methotrexate or rucaparib and the bacterial metabolites. Nevertheless, cadaverine and indolepropionic acid modulated the Hill coefficient of the inhibitory curve of doxorubicin and 5-fluorouracil. Changes to the Hill coefficient implicate alterations to the kinetics of the binding of the chemotherapy agents to their targets. These effects have an unpredictable significance from the clinical or pharmacological perspective. Importantly, indolepropionic acid decreased the IC₅₀ value of paclitaxel, which is a potentially advantageous combination. Full article

Representatives of the genus Bifidobacterium are widely used as probiotics to modulate the gut microbiome and alleviate various health conditions. The action mechanisms of probiotics rely on their direct effect on the gut microbiota and the local and systemic effect of its metabolites. The main purpose of this animal experiment was to assess the biosafety of the Bifidobacterium longum strain BIOCC1719. Additional aims were to characterise the influence of the strain on the intestinal microbiota and the effect on several health parameters of the host during 15- and 30-day oral administration of the strain to mice. The strain altered the gut microbial community, thereby altering luminal short-chain fatty acid metabolism, resulting in a shift in the proportions of acetic, butyric, and propionic acids in the faeces and serum of the test group mice. Targeted metabolic profiling of serum revealed the possible ability of the strain to positively affect the hosts’ amino acids and bile acids metabolism, as the cholic acid, deoxycholic acid, aspartate, and glutamate concentration were significantly higher in the test group. The tendency to increase anti-inflammatory polyamines (spermidine, putrescine) and neuroprotective 3-indolepropionic acid metabolism and to lower uremic toxins (P-cresol-SO₄, indoxyl-SO₄) was registered. Thus, B. longum BIOCC1719 may exert health-promoting effects on the host through modulation of the gut microbiome and the host metabolome via inducing the production of health-promoting bioactive compounds. The health effects of the strain need to be confirmed in clinical trials with human volunteers. Full article

Ploidy breeding is one of the important approaches for persimmon (Diospyros kaki Thunb.) genetic improvement, and vegetative growth of seedlings is the basis for subsequent fruit development. Therefore, the physiological characteristics and transcriptional differences of seedling growth traits in different ploidy persimmon germplasm were studied in this study, which provided a theoretical basis for fruit evaluation and breeding of new polyploid persimmon varieties. Nonuploid and its full-sib hexaploid seedlings obtained from endosperm culture were used as materials. By observing plant phenotype, leaf tissue section, endogenous hormone content, and transcriptome sequencing, the phenotype and physiological characteristics of different ploidy Persimmon seedlings were compared, as well as the differences in transcription levels. (1) Compared with hexaploid seedlings, the nonuploid were more robust and compact, and the leaves were obviously thicker. The cell size of leaf veins and parenchyma were significantly different between the different ploidy plants. (2) The contents of Salicylic Acid (SA), Jasmonic Acid (JA), gibberellin A1 (GA1), gibberellin A3 (GA3) and Indole-3-acetic acid (IAA) in nonuploid leaves were significantly higher than those in hexaploid leaves, while the contents of cytokinin trans-zeanoside (Tzt) and dihydrozeanoside (DZR), N6-isopentenyladenine (iP) and Jasmonoyl-L-isoleucine (JA-ILE) in nonuploid leaves were significantly lower than those in hexaploid leaves. (3) A total of 5796 differentially expressed genes were identified in nonuploid and hexaploid leaves. These differentially expressed genes were mainly related to photosynthesis, plant-pathogen interaction, etc. Among them, YUCCA genes, GA3ox genes, and IPT genes related to hormone synthesis were significantly differentially expressed in the nonuploid and hexaploid leaves. It is speculated that it may be the key regulatory gene that leads to the difference in IAA, gibberellin (GA), and indolepropionic acid (IPA) levels in the nonuploid and the hexaploid. The growth traits of the new Persimmon germplasms with different ploidy were significantly different. The nonuploid plants were shorter and more compact, and the leaves were larger and thicker. These traits were closely related to the content of endogenous hormones, and the balance of endogenous hormones was affected by gene expression. In addition, based on the biological processes involved in hormones and differentially expressed genes, it is speculated that the nonuploid may be superior to the hexaploid in terms of resistance. Full article

There has been a growing interest in studying the communication of gut microbial metabolites between the gut and the liver as liver fibrosis progresses. Although 3-Indolepropionic acid (IPA) is regarded as a clinically valuable gut metabolite for the treatment of certain chronic diseases, the effects of oral administration of IPA on hepatic fibrosis in different animal models have been conflicting. While some mechanisms have been proposed to explain these contradictory effects, the direct impact of IPA on hepatic fibrosis remains unclear. In this study, we found that IPA could directly activate LX-2 human hepatic stellate cells in vitro. IPA upregulated the expression of fibrogenic marker genes and promoted the features associated with HSCs activation, including proliferation and contractility. IPA also increased reactive oxygen species (ROS) in mitochondria and the expression of inflammation-related genes in LX-2 cells. However, when a ROS-blocking agent was used, these effects were reduced. p38 and JNK, the downstream signaling cascades of ROS, were found to be required for the activation of LX-2 induced by IPA. These findings suggest that IPA can directly activate hepatic stellate cells through ROS-induced JNK and p38 signaling pathways. Full article

Background: A mechanistic understanding of the effects of dietary treatment in irritable bowel syndrome (IBS) is lacking. Our aim was therefore to investigate how fermentable oligo- di-, monosaccharides, and polyols (FODMAPs) and gluten affected gut microbiota and circulating metabolite profiles, as well as to investigate potential links between gut microbiota, metabolites, and IBS symptoms. Methods: We used data from a double-blind, randomized, crossover study with week-long provocations of FODMAPs, gluten, and placebo in participants with IBS. To study the effects of the provocations on fecal microbiota, fecal and plasma short-chain fatty acids, the untargeted plasma metabolome, and IBS symptoms, we used Random Forest, linear mixed model and Spearman correlation analysis. Results: FODMAPs increased fecal saccharolytic bacteria, plasma phenolic-derived metabolites, 3-indolepropionate, and decreased isobutyrate and bile acids. Gluten decreased fecal isovalerate and altered carnitine derivatives, CoA, and fatty acids in plasma. For FODMAPs, modest correlations were observed between microbiota and phenolic-derived metabolites and 3-indolepropionate, previously associated with improved metabolic health, and reduced inflammation. Correlations between molecular data and IBS symptoms were weak. Conclusions: FODMAPs, but not gluten, altered microbiota composition and correlated with phenolic-derived metabolites and 3-indolepropionate, with only weak associations with IBS symptoms. Thus, the minor effect of FODMAPs on IBS symptoms must be weighed against the effect on microbiota and metabolites related to positive health factors. Full article

Heat stress is an increasingly significant abiotic stress factor affecting crop yield and quality. This study aims to uncover the regulatory mechanism of sweet corn response to heat stress by integrating transcriptome and metabolome analyses of seedlings exposed to normal (25 °C) or high temperature (42 °C). The transcriptome results revealed numerous pathways affected by heat stress, especially those related to phenylpropanoid processes and photosynthesis, with 102 and 107 differentially expressed genes (DEGs) identified, respectively, and mostly down-regulated in expression. The metabolome results showed that 12 or 24 h of heat stress significantly affected the abundance of metabolites, with 61 metabolites detected after 12 h and 111 after 24 h, of which 42 metabolites were detected at both time points, including various alkaloids and flavonoids. Scopoletin-7-o-glucoside (scopolin), 3-indolepropionic acid, acetryptine, 5,7-dihydroxy-3′,4′,5′-trimethoxyflavone, and 5,6,7,4′-tetramethoxyflavanone expression levels were mostly up-regulated. A regulatory network was built by analyzing the correlations between gene modules and metabolites, and four hub genes in sweet corn seedlings under heat stress were identified: RNA-dependent RNA polymerase 2 (RDR2), UDP-glucosyltransferase 73C5 (UGT73C5), LOC103633555, and CTC-interacting domain 7 (CID7). These results provide a foundation for improving sweet corn development through biological intervention or genome-level modulation. Full article

The microbial metabolite indolepropionic acid (IPA) and related indolic metabolites, including indolecarboxylic acid (ICA), indolelactic acid (ILA), indoleacetic acid (IAA), indolebutyric acid (IBA), indoxylsulfate (ISO4), and indole, were determined in human plasma, plasma ultrafiltrate (UF), and saliva. The compounds were separated on a 150 × 3 mm column of 3 μm Hypersil C18 eluted with a mobile phase of 80% pH 5 0.01 M sodium acetate containing 1.0 g/L of tert-butylammonium chloride/20% acetonitrile and then detected fluorometrically. Levels of IPA in human plasma UF and of ILA in saliva are reported for the first time. The determination of IPA in plasma UF enables the first report of free plasma IPA, the presumed physiologically active pool of this important microbial metabolite of tryptophan. Plasma and salivary ICA and IBA were not detected, consistent with the absence of any prior reported values. Observed levels or limits of detection for other indolic metabolites usefully supplement limited prior reports. Full article

To improve the efficiency of chromium (Cr) phytoextraction by Leersia hexandra Swartz, the effects of mowing on Cr accumulation in L. hexandra were investigated using hydroponic experiments. Mowing heights (0, 5, and 10 cm), mowing interval (30, 60, 90 and 120 days), and mowing frequencies (1, 2, and 3 times) were optimized. Mowing at 10 cm above roots significantly increased shoot biomass of L. hexandra (32.9 g/pot). The 90 days mowing interval achieved the highest shoot biomass (62.8 g/pot). The shoot biomass with thrice mowing (67.0 g/pot) was higher than those with one and twice mowing, as well as no mowing (CK). The increases in biomass might ascribe to the changes in endogenous hormone balance by mowing. Proper mowing significantly increased contents of Gibberellin 3 (GA3), 6-Benzylaminopurine (6-BA), 6-Kinetin (6-KT), and trans-Zeatin-riboside (TZR) in leaves, and 3-Indolepropionic acid (IPA) in stems, but decreased Jasmonic acid (JA) in the leaves and stems, thereby enhancing the regeneration of plant. The enhancement of plant regeneration resulted in the increases of biomass and Cr accumulation. Compared to CK, the optimal mowing method (10 cm, 90 days, 3 times) increased shoot biomass and Cr accumulation by 91.4% and 36.0%, respectively. These findings suggested that proper mowing had application potential to promote efficiency of Cr phytoextraction by L. hexandra. Full article

An intricate relationship between gut microbiota, diet, and the human body has recently been extensively investigated. Gut microbiota and gut-derived metabolites, especially, tryptophan derivatives, modulate metabolic and immune functions in health and disease. One of the tryptophan derivatives, indolepropionic acid (IPA), is increasingly being studied as a marker for the onset and development of metabolic disorders, including type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). The IPA levels heavily depend on the diet, particularly dietary fiber, and show huge variations among individuals. We suggest that these variations could partially be explained using genetic variants known to be associated with specific diseases such as T2D. In this narrative review, we elaborate on the beneficial effects of IPA in the mitigation of T2D and NAFLD, and further study the putative interactions between IPA and well-known genetic variants (TCF7L2, FTO, and PPARG), known to be associated with the risk of T2D. We have investigated the long-term preventive value of IPA in the development of T2D in the Finnish prediabetic population and the correlation of IPA with phytosterols in obese individuals from an ongoing Kuopio obesity surgery study. The diversity in IPA-linked mechanisms affecting glucose metabolism and liver fibrosis makes it a unique small metabolite and a promising candidate for the reversal or management of metabolic disorders, mainly T2D and NAFLD. Full article

The metabolites produced by the gut microbiota have been reported as crucial agents against obesity; however, their key targets have not been revealed completely in complex microbiome systems. Hence, the aim of this study was to decipher promising prebiotics, probiotics, postbiotics, and more importantly, key target(s) via a network pharmacology approach. First, we retrieved the metabolites related to gut microbes from the gutMGene database. Then, we performed a meta-analysis to identify metabolite-related targets via the similarity ensemble approach (SEA) and SwissTargetPrediction (STP), and obesity-related targets were identified by DisGeNET and OMIM databases. After selecting the overlapping targets, we adopted topological analysis to identify core targets against obesity. Furthermore, we employed the integrated networks to microbiota–substrate–metabolite–target (MSMT) via R Package. Finally, we performed a molecular docking test (MDT) to verify the binding affinity between metabolite(s) and target(s) with the Autodock 1.5.6 tool. Based on holistic viewpoints, we performed a filtering step to discover the core targets through topological analysis. Then, we implemented protein–protein interaction (PPI) networks with 342 overlapping target, another subnetwork was constructed with the top 30% degree centrality (DC), and the final core networks were obtained after screening the top 30% betweenness centrality (BC). The final core targets were IL6, AKT1, and ALB. We showed that the three core targets interacted with three other components via the MSMT network in alleviating obesity, i.e., four microbiota, two substrates, and six metabolites. The MDT confirmed that equol (postbiotics) converted from isoflavone (prebiotics) via Lactobacillus paracasei JS1 (probiotics) can bind the most stably on IL6 (target) compared with the other four metabolites (3-indolepropionic acid, trimethylamine oxide, butyrate, and acetate). In this study, we demonstrated that the promising substate (prebiotics), microbe (probiotics), metabolite (postbiotics), and target are suitable for obsesity treatment, providing a microbiome basis for further research. Full article

The microbial-derived metabolite, 3-indolepropionic acid (3-IPA), has been intensely studied since its origins were discovered in 2009; however, 3-IPA’s role in immunosuppression has had limited attention. Untargeted metabolomic analyses of T-cell exhaustion and immunosuppression, represented by dysfunctional under-responsive CD8⁺ T cells, reveal a potential role of 3-IPA in these responses. T-cell exhaustion was examined via infection of two genetically related mouse strains, DBA/1J and DBA/2J, with lymphocytic choriomeningitis virus (LCMV) Clone 13 (Cl13). The different mouse strains produced disparate outcomes driven by their T-cell responses. Infected DBA/2J presented with exhausted T cells and persistent infection, and DBA/1J mice died one week after infection from cytotoxic T lymphocytes (CTLs)-mediated pulmonary failure. Metabolomics revealed over 70 metabolites were altered between the DBA/1J and DBA/2J models over the course of the infection, most of them in mice with a fatal outcome. Cognitive-driven prioritization combined with statistical significance and fold change were used to prioritize the metabolites. 3-IPA, a tryptophan-derived metabolite, was identified as a high-priority candidate for testing. To test its activity 3-IPA was added to the drinking water of the mouse models during LCMV Cl13 infection, with the results showing that 3-IPA allowed the mice to survive longer. This negative immune-modulation effect might be of interest for the modulation of CTL responses in events such as autoimmune diseases, type I diabetes or even COVID-19. Moreover, 3-IPA’s bacterial origin raises the possibility of targeting the microbiome to enhance CTL responses in diseases such as cancer and chronic infection. Full article

Large population-based studies investigating the association of physical activity (PA) with the metabolite signature contribute significantly to the understanding of the effects of PA on metabolic pathways associated with the risk of type2 diabetes. Our study included 8749 Finnish men without diabetes at baseline recruited from the Metabolic Syndrome in Men (METSIM) cohort. We used a questionnaire to measure leisure-time PA. Metabolites were measured in 7271 men as a part of Metabolon’s untargeted Discovery HD4 platform using ultrahigh-performance liquid chromatography–tandem mass spectrometry. We found 198 metabolites significantly associated with PA. Several of these metabolites were novel including especially steroids, amino acids, imidazoles, carboxylic acids, and hydroxy acids. Increased PA was significantly associated with high levels of choline plasmalogens, lysophosphatidylcholines, polyunsaturated fatty acids, carotenoids, long chain acylcarnitines, imidazoles, bilirubins, aryl sulfates, hydroxy acids, indolepropionate, and indolelactate. Several of these metabolites have been previously associated with a decreased risk of type 2 diabetes and with a healthy diet. Our population-based study shows that the metabolite signature of increased PA includes multiple metabolic pathways and is associated with better adherence to a healthy lifestyle. Full article