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The gastrointestinal (GI) tract harbors trillions of microorganisms known to influence human health and disease, and next-generation sequencing (NGS) now enables the in-depth analysis of their diversity and functions. Although a significant amount of research has been conducted on the GI microbiome, comprehensive metagenomic datasets covering the entire tract are scarce due to cost and technical challenges. Despite the widespread use of fecal samples, integrated datasets encompassing the entire digestive process, beginning at the mouth and ending with feces, are lacking. With this study, we aimed to fill this gap by analyzing the complete metagenome of the GI tract, providing insights into the dynamics of the microbiota and potential therapeutic avenues. In this study, we delved into the complex world of the GI microbiota, which we examined in five healthy Japanese subjects. While samples from the whole GI flora and fecal samples provided sufficient bacteria, samples obtained from the stomach and duodenum posed a challenge. Using a principal coordinate analysis (PCoA), clear clustering patterns were identified; these revealed significant diversity in the duodenum. Although this study was limited by its small sample size, the flora in the overall GI tract showed unwavering consistency, while the duodenum exhibited unprecedented phylogenetic diversity. A visual heat map illustrates the discrepancy in abundance, with Fusobacteria and Bacilli dominating the upper GI tract and Clostridia and Bacteroidia dominating the fecal samples. Negativicutes and Actinobacteria were found throughout the digestive tract. This study demonstrates that it is possible to continuously collect microbiome samples throughout the human digestive tract. These findings not only shed light on the complexity of GI microbiota but also provide a basis for future research.
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Understanding the physiological changes associated with aging and the associated disease risks is essential to establish biomarkers as indicators of biological aging. This study used the NMR-measured plasma metabolome to calculate age-specific metabolite indices. In doing so, the scope of the study was deliberately simplified to capture general trends and insights into age-related changes in metabolic patterns. In addition, changes in metabolite concentrations with age were examined in detail, with the period from 55-59 to 60-64 years being a period of significant metabolic change, particularly in men, and from 45-49 to 50-54 years in females. These results illustrate the different variations in metabolite concentrations by sex and provide new insights into the relationship between age and metabolic diseases.
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Envelhecimento , Metaboloma , Metabolômica , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Metabolômica/métodos , Japão , Idoso , Envelhecimento/metabolismo , Adulto , Fatores Sexuais , Fatores Etários , Biomarcadores/sangue , Estudos de Coortes , Espectroscopia de Ressonância Magnética , População do Leste AsiáticoRESUMO
Whole blood transcriptome analysis is a valuable approachin medical research, primarily due to the ease of sample collection and the richness of the information obtained. Since the expression profile of individual genes in the analysis is influenced by medical traits and demographic attributes such as age and gender, there has been a growing demand for a comprehensive database for blood transcriptome analysis. Here, we performed whole blood RNA sequencing (RNA-seq) analysis on 576 participants stratified by age (20-30s and 60-70s) and gender from cohorts of the Tohoku Medical Megabank (TMM). A part of female segment included pregnant women. We did not exclude the globin gene family in our RNA-seq study, which enabled us to identify instances of hereditary persistence of fetal hemoglobin based on the HBG1 and HBG2 expression information. Comparing stratified populations allowed us to identify groups of genes associated with age-related changes and gender differences. We also found that the immune response status, particularly measured by neutrophil-to-lymphocyte ratio (NLR), strongly influences the diversity of individual gene expression profiles in whole blood transcriptome analysis. This stratification has resulted in a data set that will be highly beneficial for future whole blood transcriptome analysis in the Japanese population.
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Perfilação da Expressão Gênica , Transcriptoma , Humanos , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Perfilação da Expressão Gênica/métodos , Japão , Idoso , Adulto Jovem , Fatores Etários , Fatores Sexuais , Povo Asiático/genética , População do Leste AsiáticoRESUMO
Modern medicine is increasingly focused on personalized medicine, and multi-omics data is crucial in understanding biological phenomena and disease mechanisms. Each ethnic group has its unique genetic background with specific genomic variations influencing disease risk and drug response. Therefore, multi-omics data from specific ethnic populations are essential for the effective implementation of personalized medicine. Various prospective cohort studies, such as the UK Biobank, All of Us and Lifelines, have been conducted worldwide. The Tohoku Medical Megabank project was initiated after the Great East Japan Earthquake in 2011. It collects biological specimens and conducts genome and omics analyses to build a basis for personalized medicine. Summary statistical data from these analyses are available in the jMorp web database (https://jmorp.megabank.tohoku.ac.jp), which provides a multidimensional approach to the diversity of the Japanese population. jMorp was launched in 2015 as a public database for plasma metabolome and proteome analyses and has been continuously updated. The current update will significantly expand the scale of the data (metabolome, genome, transcriptome, and metagenome). In addition, the user interface and backend server implementations were rewritten to improve the connectivity between the items stored in jMorp. This paper provides an overview of the new version of the jMorp.
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Bases de Dados Genéticas , Multiômica , População , Medicina de Precisão , Humanos , Genômica/métodos , Japão , Estudos Prospectivos , População/genéticaRESUMO
BACKGROUND: In the TSUBAKI study, bardoxolone methyl significantly increased measured and estimated glomerular filtration rates (GFR) in patients with multiple forms of chronic kidney disease (CKD), including Japanese patients with type 2 diabetes and stage 3-4 CKD. Since bardoxolone methyl targets the nuclear factor erythroid 2-related factor 2 pathway, this exploratory analysis of the TSUBAKI study investigated the impact of the regulatory single nucleotide polymorphism, rs6721961, on the effects of bardoxolone methyl. METHODS: Japanese patients aged 20-79 years with type 2 diabetes and stage 3-4 CKD were randomized to bardoxolone methyl 5-15 mg/day (titrated as tolerated) or placebo for 16 weeks. Genotype frequency, clinical characteristics, renal function, and adverse events were primarily assessed. RESULTS: Of 104 patients (bardoxolone methyl n = 55, placebo n = 49); 57% were genotype C/C, 32% C/A and 12% A/A. The frequency of the A/A genotype was higher among patients with diabetic kidney disease than in the general Japanese population (~ 5%). Measured and estimated GFRs increased from baseline in all genotypes receiving bardoxolone methyl. There were no significant differences between genotypes for safety parameters, including blood pressure, bodyweight, and levels of B-type natriuretic peptide, or in the type and frequency of adverse events, suggesting that the efficacy and safety of bardoxolone methyl are unaffected by the rs6721961 polymorphism-617 (CâA) genotype. CONCLUSIONS: Our approach of combining genome analysis with clinical trials for an investigational drug provides important and useful clues for exploring the efficacy and safety of the drug. TRIAL REGISTRATION: ClinicalTrials.gov; NCT02316821.
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Ácido Oleanólico/análogos & derivados , Insuficiência Renal Crônica , Humanos , Fator 2 Relacionado a NF-E2/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/genética , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/genéticaRESUMO
The prognosis of patients with peritoneal metastases from pancreatic cancer is poor, largely due to massive ascites, which precludes systemic treatment. Two patients with a poor performance status and malignant ascites were treated with cell-free and concentrated ascites reinfusion therapy followed by combined chemotherapy with intraperitoneal paclitaxel, intravenous gemcitabine, and nab-paclitaxel. These patients achieved a survival of 19 and 36 weeks with a relatively good quality of life. Combined intraperitoneal paclitaxel and systemic chemotherapy may provide effective palliative management for some patients with peritoneal metastases from pancreatic cancer.
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With the number of samples increasing in many biobanks, one of the most pressing tasks is recording the correct relationships between information and the specimens. Genomic information is useful in determining the identity of these specimens. The Tohoku Medical Megabank Organization is running one of the largest biobanks in Japan. Here, we introduce a management system, which includes the development of a new probe set for the MassARRAY system for use during the production of proliferating T cells (T cells) and lymphoblastoid cell lines (LCLs). We selected single nucleotide variants that could be detected by next-generation sequencing and showed high resolution with â¼0.5 minor allele frequencies. After checking the set of probes against 96 samples from 48 people, we obtained no contradictory results in comparison with our genome sequence information. When we applied the set to our 3035 LCLs and 2256 T cells, the result showed 98.93% consistency with the corresponding genomic information. We surveyed the handling records of the 1.07% of samples that showed inconsistencies, and found that most had resulted from human errors (ID swapping between samples) during manual operations. After improving a few error-prone protocols, the error rate dropped to 0.47% for LCLs and 0% for T cells. Overall, the system that we developed shows high accuracy with easy and fast operability, and provides a good opportunity to improve the validation procedure to facilitate high-quality banking, especially in cases involving genomic information.
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α-Tomatine is a major saponin that accumulates in tomatoes (Solanum lycopersicum). We previously reported that α-tomatine secreted from tomato roots modulates root-associated bacterial communities, particularly by enriching the abundance of Sphingobium belonging to the family Sphingomonadaceae. To further characterize the α-tomatine-mediated interactions between tomato plants and soil bacterial microbiota, we first cultivated tomato plants in pots containing different microbial inoculants originating from three field soils. Four bacterial genera, namely, Sphingobium, Bradyrhizobium, Cupriavidus, and Rhizobacter, were found to be commonly enriched in tomato root-associated bacterial communities. We constructed a pseudo-rhizosphere system using a mullite ceramic tube as an artificial root to investigate the influence of α-tomatine in modifying bacterial communities. The addition of α-tomatine from the artificial root resulted in the formation of a concentration gradient of α-tomatine that mimicked the tomato rhizosphere, and distinctive bacterial communities were observed in the soil close to the artificial root. Sphingobium was enriched according to the α-tomatine concentration gradient, whereas Bradyrhizobium, Cupriavidus, and Rhizobacter were not enriched in α-tomatine-treated soil. The tomato root-associated bacterial communities were similar to the soil bacterial communities in the vicinity of artificial root-secreting exudates; however, hierarchical cluster analysis revealed a distinction between root-associated and pseudo-rhizosphere bacterial communities. These results suggest that the pseudo-rhizosphere device at least partially creates a rhizosphere environment in which α-tomatine enhances the abundance of Sphingobium in the vicinity of the root. Enrichment of Sphingobium in the tomato rhizosphere was also apparent in publicly available microbiota data, further supporting the tight association between tomato roots and Sphingobium mediated by α-tomatine.
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IMPORTANCE: Saponins are a group of plant specialized metabolites with various bioactive properties, both for human health and soil microorganisms. Our previous works demonstrated that Sphingobium is enriched in both soils treated with a steroid-type saponin, such as tomatine, and in the tomato rhizosphere. Despite the importance of saponins in plant-microbe interactions in the rhizosphere, the genes involved in the catabolism of saponins and their aglycones (sapogenins) remain largely unknown. Here we identified several enzymes that catalyzed the degradation of steroid-type saponins in a Sphingobium isolate from tomato roots, RC1. A comparative genomic analysis of Sphingobium revealed the limited distribution of genes for saponin degradation in our saponin-degrading isolates and several other isolates, suggesting the possible involvement of the saponin degradation pathway in the root colonization of Sphingobium spp. The genes that participate in the catabolism of sapogenins could be applied to the development of new industrially valuable sapogenin molecules.
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Sapogeninas , Saponinas , Solanum lycopersicum , Humanos , Sapogeninas/metabolismo , Esteroides , Saponinas/metabolismo , Plantas/metabolismoRESUMO
Strain C5-48T, an anaerobic intestinal bacterium that potentially accumulates acetaldehyde at levels exceeding its minimum mutagenic concentration (50 µM) in the colon and rectum, was isolated from the feces of a patient with alcoholism. The 16S rRNA gene sequence of strain C5-48T showed high similarity to the corresponding sequences of Lachnoclostridium edouardi Marseille-P3397T (95.7%) and Clostridium fessum SNUG30386T (94.7%). However, phylogenetic analysis using the sequences of the 16S rRNA, rpoB, and hsp60 genes and whole-genome analysis strongly suggested that C5-48T should be included in the genus Enterocloster. The novelty of strain C5-48T was further confirmed by comprehensive average nucleotide identity (ANI) calculations based on its whole-genome sequence, which showed appreciable ANI values with known Enterocloster species (e.g., 74.3% and 73.4% with Enterocloster bolteae WAL 16351T and Enterocloster clostridioformis ATCC 25537T, respectively). The temperature range for growth of strain C5-48T was 15-37 °C with an optimum of 37 °C. The pH range for growth was 5.5-10.5 with an optimum of 7.5. The major constituents of the cell membrane lipids of strain C5-48T were 16:0, 14:0, and 18:1 ω7c dimethyl acetal fatty acids. On the basis of the genotypic and phenotypic properties, Enterocloster alcoholdehydrogenati sp. nov. is proposed, with the type strain C5-48T (= JCM 33305T = DSM 109474T).
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Alcoolismo , Bactérias , Fezes , Bactérias/classificação , Bactérias/isolamento & purificação , Fezes/microbiologia , Alcoolismo/microbiologia , Filogenia , Sequenciamento Completo do Genoma , QuimiotaxiaRESUMO
Plant specialized metabolites (PSMs) are often stored as glycosides within cells and released from the roots with some chemical modifications. While isoflavones are known to function as symbiotic signals with rhizobia and to modulate the soybean rhizosphere microbiome, the underlying mechanisms of root-to-soil delivery are poorly understood. In addition to transporter-mediated secretion, the hydrolysis of isoflavone glycosides in the apoplast by an isoflavone conjugate-hydrolyzing ß-glucosidase (ICHG) has been proposed but not yet verified. To clarify the role of ICHG in isoflavone supply to the rhizosphere, we have isolated two independent mutants defective in ICHG activity from a soybean high-density mutant library. In the root apoplastic fraction of ichg mutants, the isoflavone glycoside contents were significantly increased, while isoflavone aglycone contents were decreased, indicating that ICHG hydrolyzes isoflavone glycosides into aglycones in the root apoplast. When grown in a field, the lack of ICHG activity considerably reduced isoflavone aglycone contents in roots and the rhizosphere soil, although the transcriptomes showed no distinct differences between the ichg mutants and wild-types (WTs). Despite the change in isoflavone contents and composition of the root and rhizosphere of the mutants, root and rhizosphere bacterial communities were not distinctive from those of the WTs. Root bacterial communities and nodulation capacities of the ichg mutants did not differ from the WTs under nitrogen-deficient conditions either. Taken together, these results indicate that ICHG elevates the accumulation of isoflavones in the soybean rhizosphere but is not essential for isoflavone-mediated plant-microbe interactions.
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Isoflavonas , Isoflavonas/química , Glycine max/genética , Glycine max/metabolismo , beta-Glucosidase/genética , beta-Glucosidase/química , Rizosfera , Glicosídeos/metabolismo , Bactérias/metabolismo , SoloRESUMO
BACKGROUND: Since dementia is preventable with early interventions, biomarkers that assist in diagnosing early stages of dementia, such as mild cognitive impairment (MCI), are urgently needed. METHODS: Multiomics analysis of amnestic MCI (aMCI) peripheral blood (n = 25) was performed covering the transcriptome, microRNA, proteome, and metabolome. Validation analysis for microRNAs was conducted in an independent cohort (n = 12). Artificial intelligence was used to identify the most important features for predicting aMCI. FINDINGS: We found that hsa-miR-4455 is the best biomarker in all omics analyses. The diagnostic index taking a ratio of hsa-miR-4455 to hsa-let-7b-3p predicted aMCI patients against healthy subjects with 97% overall accuracy. An integrated review of multiomics data suggested that a subset of T cells and the GCN (general control nonderepressible) pathway are associated with aMCI. INTERPRETATION: The multiomics approach has enabled aMCI biomarkers with high specificity and illuminated the accompanying changes in peripheral blood. Future large-scale studies are necessary to validate candidate biomarkers for clinical use.
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Disfunção Cognitiva , Demência , MicroRNAs , Humanos , Inteligência Artificial , Multiômica , Progressão da Doença , Testes Neuropsicológicos , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/genética , Disfunção Cognitiva/psicologia , BiomarcadoresRESUMO
The identification of unknown chemicals has emerged as a significant issue in untargeted metabolome analysis owing to the limited availability of purified standards for identification; this is a major bottleneck for the accumulation of reusable metabolome data in systems biology. Public resources for discovering and prioritizing the unknowns that should be subject to practical identification, as well as further detailed study of spending costs and the risks of misprediction, are lacking. As such a resource, we released databases, Food-, Plant- and Thing-Metabolome Repository (http://metabolites.in/foods, http://metabolites.in/plants, and http://metabolites.in/things, referred to as XMRs) in which the sample-specific localization of unknowns detected by liquid chromatography-mass spectrometry in a wide variety of samples can be examined, helping to discover and prioritize the unknowns. A set of application programming interfaces for the XMRs facilitates the use of metabolome data for large-scale analysis and data mining. Several applications of XMRs, including integrated metabolome and genome analyses, are presented. Expanding the concept of XMRs will accelerate the identification of unknowns and increase the discovery of new knowledge.
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Bases de Dados Factuais , Metaboloma , Metabolômica , Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Metabolômica/métodosRESUMO
Chronic consumption of excess ethanol is one of the major risk factors for colorectal cancer (CRC), and the pathogenesis of ethanol-related CRC (ER-CRC) involves ethanol-induced oxidative-stress and inflammation in the colon and rectum, as well as gut leakiness. In this study, we hypothesised that oral administration of sesaminol, a sesame lignan, lowers the risk of ER-CRC because we found that it is a strong antioxidant with very low prooxidant activity. This hypothesis was examined using a mouse model, in which 2.0% v/v ethanol was administered ad libitum for 2 weeks with or without oral gavage with sesaminol (2.5 mg per day). Oral sesaminol administration suppressed the ethanol-induced colonic lesions and the ethanol-induced elevation of the colonic levels of oxidative stress markers (8-hydroxy-2'-deoxyguanosine, malondialdehyde, and 4-hydroxyalkenals). It consistently suppressed the chronic ethanol-induced expressions of cytochrome P450-2E1 and inducible nitric oxide synthase and upregulated heme oxygenase-1 expression, probably via the nuclear factor erythroid-derived 2-like 2 pathway in the mouse colon. Oral sesaminol administration also suppressed the chronic ethanol-induced elevation of colonic inflammation marker levels, such as those of tumour necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1, probably via the nuclear factor-kappa B pathway. Moreover, it prevented the chronic ethanol-induced gut leakiness by restoring tight junction proteins, giving rise to lower plasma endotoxin levels compared with those of ethanol-administered mice. All of these results suggest that dietary supplementation of sesaminol may lower the risk of ER-CRC by suppressing each of the above-mentioned steps in ER-CRC pathogenesis.
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Colite , Dioxóis , Furanos , Lignanas , Estresse Oxidativo , 8-Hidroxi-2'-Desoxiguanosina , Administração Oral , Animais , Antioxidantes/metabolismo , Quimiocina CCL2/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Dioxóis/uso terapêutico , Endotoxinas , Etanol/efeitos adversos , Furanos/uso terapêutico , Heme Oxigenase-1/metabolismo , Inflamação/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Malondialdeído , Camundongos , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Proteínas de Junções Íntimas/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Background: Osteopenia is defined as low bone mineral density (BMD) and has been shown to be associated with outcomes of patients with various cancers. The association between osteopenia and perihilar cholangiocarcinoma is unknown. The aim of this study was to evaluate osteopenia as a prognostic factor in patients with perihilar cholangiocarcinoma. Methods: A total of 58 patients who underwent surgery for perihilar cholangiocarcinoma were retrospectively analyzed. The BMD at the 11th thoracic vertebra was measured using computed tomography scan within one month of surgery. Patients with a BMD < 160 HU were considered to have osteopenia and b BMD ≥ 160 did not have osteopenia. The log-rank test was performed for survival using the Kaplan−Meier method. After adjusting for confounding factors, overall survival was assessed by Cox's proportional-hazards model. Results: The osteopenia group had 27 (47%) more females than the non-osteopenia group (p = 0.036). Median survival in the osteopenia group was 37 months and in the non-osteopenia group was 61 months (p = 0.034). In multivariable analysis, osteopenia was a significant independent risk factor associated with overall survival in patients with perihilar cholangiocarcinoma (hazard ratio 3.54, 95% confidence interval 1.09−11.54, p = 0.036), along with primary tumor stage. Conclusions: Osteopenia is associated with significantly shorter survival in patients with perihilar cholangiocarcinoma.
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ATTED-II (https://atted.jp) is a gene coexpression database for nine plant species based on publicly available RNAseq and microarray data. One of the challenges in constructing condition-independent coexpression data based on publicly available gene expression data is managing the inherent sampling bias. Here, we report ATTED-II version 11, wherein we adopted a coexpression calculation methodology to balance the samples using principal component analysis and ensemble calculation. This approach has two advantages. First, omitting principal components with low contribution rates reduces the main contributors of noise. Second, balancing large differences in contribution rates enables considering various sample conditions entirely. In addition, based on RNAseq- and microarray-based coexpression data, we provide species-representative, integrated coexpression information to enhance the efficiency of interspecies comparison of the coexpression data. These coexpression data are provided as a standardized z-score to facilitate integrated analysis with different data sources. We believe that with these improvements, ATTED-II is more valuable and powerful for supporting interspecies comparative studies and integrated analyses using heterogeneous data.
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Arabidopsis , Genes de Plantas , Arabidopsis/genética , Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica de Plantas , Redes Reguladoras de Genes , Genes de Plantas/genéticaRESUMO
Angelica archangelica L. is a traditional medicinal plant of Nordic origin that produces an unusual amount and variety of terpenoids. The unique terpenoid composition of A. archangelica likely arises from the involvement of terpene synthases (TPSs) with different specificities, none of which has been identified. As the first step in identifying TPSs responsible for terpenoid chemodiversity in A. archangelica, we produced a transcriptome catalogue using the mRNAs extracted from the leaves, tap roots, and dry seeds of the plant; 11 putative TPS genes were identified (AaTPS1-AaTPS11). Phylogenetic analysis predicted that AaTPS1-AaTPS5, AaTPS6-AaTPS10, and AaTPS11 belong to the monoterpene synthase (monoTPS), sesquiterpene synthase (sesquiTPS), and diterpene synthase clusters, respectively. We then performed in vivo enzyme assays of the AaTPSs using recombinant Escherichia coli systems to examine their enzymatic activities and specificities. Nine recombinant enzymes (AaTPS2-AaTPS10) displayed TPS activities with specificities consistent with their phylogenetics; however, AaTPS5 exhibited a strong sesquiTPS activity along with a weak monoTPS activity. We also analyzed terpenoid volatiles in the flowers, immature and mature seeds, leaves, and tap roots of A. archangelica using gas chromatography-mass spectrometry; 14 monoterpenoids and 13 sesquiterpenoids were identified. The mature seeds accumulated the highest levels of monoterpenoids, with ß-phellandrene being the most prominent. α-Pinene and ß-myrcene were abundant in all organs examined. The in vivo assay results suggest that the AaTPSs functionally identified in this study are at least partly involved in the chemodiversity of terpenoid volatiles in A. archangelica.
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To reveal gene-environment interactions underlying common diseases and estimate the risk for common diseases, the Tohoku Medical Megabank (TMM) project has conducted prospective cohort studies and genomic and multiomics analyses. To establish an integrated biobank, we developed an integrated database called "dbTMM" that incorporates both the individual cohort/clinical data and the genome/multiomics data of 157,191 participants in the Tohoku Medical Megabank project. To our knowledge, dbTMM is the first database to store individual whole-genome data on a variant-by-variant basis as well as cohort/clinical data for over one hundred thousand participants in a prospective cohort study. dbTMM enables us to stratify our cohort by both genome-wide genetic factors and environmental factors, and it provides a research and development platform that enables prospective analysis of large-scale data from genome cohorts.
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Sodium-dependent glucose cotransporters (SGLTs) have attracted considerable attention as new targets for type 2 diabetes mellitus. In the kidney, SGLT2 is the major glucose uptake transporter in the proximal tubules, and inhibition of SGLT2 in the proximal tubules shows renoprotective effects. On the other hand, SGLT1 plays a role in glucose absorption from the gastrointestinal tract, and the relationship between SGLT1 inhibition in the gut and renal function remains unclear. Here, we examined the effect of SGL5213, a novel and potent intestinal SGLT1 inhibitor, in a renal failure (RF) model. SGL5213 improved renal function and reduced gut-derived uremic toxins (phenyl sulfate and trimethylamine-N-oxide) in an adenine-induced RF model. Histological analysis revealed that SGL5213 ameliorated renal fibrosis and inflammation. SGL5213 also reduced gut inflammation and fibrosis in the ileum, which is a primary target of SGL5213. Examination of the gut microbiota community revealed that the Firmicutes/Bacteroidetes ratio, which suggests gut dysbiosis, was increased in RF and SGL5213 rebalanced the ratio by increasing Bacteroidetes and reducing Firmicutes. At the genus level, Allobaculum (a major component of Erysipelotrichaceae) was significantly increased in the RF group, and this increase was canceled by SGL5213. We also measured the effect of SGL5213 on bacterial phenol-producing enzymes that catalyze tyrosine into phenol, following the reduction of phenyl sulfate, which is a novel marker and a therapeutic target for diabetic kidney disease DKD. We found that the enzyme inhibition was less potent, suggesting that the change in the microbial community and the reduction of uremic toxins may be related to the renoprotective effect of SGL5213. Because SGL5213 is a low-absorbable SGLT1 inhibitor, these data suggest that the gastrointestinal inhibition of SGLT1 is also a target for chronic kidney diseases.
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Adenina/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/tratamento farmacológico , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Sorbitol/análogos & derivados , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Microbioma Gastrointestinal/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Insuficiência Renal/metabolismo , Sorbitol/farmacologia , Sorbitol/uso terapêuticoRESUMO
L-Canavanine, a conditionally essential non-proteinogenic amino acid analog to L-arginine, plays important roles in cell division, wound healing, immune function, the release of hormones, and a precursor for the synthesis of nitric oxide (NO). In this report, we found that the L-canavanine is released into the soil from the roots of hairy vetch (Vicia villosa) and declines several weeks after growth, while it was absent in bulk proxy. Hairy vetch root was able to exudate L-canavanine in both pots and in vitro conditions in an agar-based medium. The content of the L-canavanine in pots and agar conditions was higher than the field condition. It was also observed that the addition of L-canavanine significantly altered the microbial community composition and diversity in soil. Firmicutes and Actinobacteria became more abundant in the soil after the application of L-canavanine. In contrast, Proteobacteria and Acidobacteria populations were decreased by higher L-canavanine concentration (500 nmol/g soil). Prediction of the soil metabolic pathways using PICRUSt2 estimated that the L-arginine degradation pathway was enriched 1.3-fold when L-canavanine was added to the soil. Results indicated that carbon metabolism-related pathways were altered and the degradation of nitrogen-rich compounds (i.e., amino acids) enriched. The findings of this research showed that secretion of the allelochemical L-canavanine from the root of hairy vetch may alter the soil microbial community and soil metabolite pathways to increase the survival chance of hairy vetch seedlings. This is the first report that L-canavanine acts as an allelochemical that affects the biodiversity of soil microbial community.