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Gut Microbes 2024Metformin is widely used for treating type 2 diabetes mellitus (T2D). However, the efficacy of metformin monotherapy is highly variable within the human population....
Metformin is widely used for treating type 2 diabetes mellitus (T2D). However, the efficacy of metformin monotherapy is highly variable within the human population. Understanding the potential indirect or synergistic effects of metformin on gut microbiota composition and encoded functions could potentially offer new insights into predicting treatment efficacy and designing more personalized treatments in the future. We combined targeted metabolomics and metagenomic profiling of gut microbiomes in newly diagnosed T2D patients before and after metformin therapy to identify potential pre-treatment biomarkers and functional signatures for metformin efficacy and induced changes in metformin therapy responders. Our sequencing data were largely corroborated by our metabolic profiling and identified that pre-treatment enrichment of gut microbial functions encoding purine degradation and glutamate biosynthesis was associated with good therapy response. Furthermore, we identified changes in glutamine-associated amino acid (arginine, ornithine, putrescine) metabolism that characterize differences in metformin efficacy before and after the therapy. Moreover, metformin Responders' microbiota displayed a shifted balance between bacterial lipidA synthesis and degradation as well as alterations in glutamate-dependent metabolism of N-acetyl-galactosamine and its derivatives (e.g. CMP-pseudaminate) which suggest potential modulation of bacterial cell walls and human gut barrier, thus mediating changes in microbiome composition. Together, our data suggest that glutamine and associated amino acid metabolism as well as purine degradation products may potentially condition metformin activity via its multiple effects on microbiome functional composition and therefore serve as important biomarkers for predicting metformin efficacy.
Topics: Humans; Metformin; Gastrointestinal Microbiome; Diabetes Mellitus, Type 2; Amino Acids; Male; Middle Aged; Female; Purines; Bacteria; Biomarkers; Hypoglycemic Agents; Aged; Adult; Treatment Outcome; Metabolomics
PubMed: 38868903
DOI: 10.1080/19490976.2024.2361491 -
Frontiers in Genetics 2024Inborn errors of metabolism (IEMs) are uncommon. Although some studies have explored the distribution and characteristics of IEMs in newborns, the impact of these...
Inborn errors of metabolism (IEMs) are uncommon. Although some studies have explored the distribution and characteristics of IEMs in newborns, the impact of these disorders on hospitalized newborns remains unclear. In this study, we gathered data from 21,840 newborn patients admitted for various medical conditions at the Children's Hospital of Chongqing Medical University from January 2017 and December 2022. Liquid chromatography-tandem mass spectrometry (LC-MS/MS), gas chromatography-mass spectrometry (GC-MS/MS), and genetic analysis were used to elucidate the disease spectrum, incidence rate, and genetic characteristics of IEMs in hospitalized newborns. The results revealed that the incidence of IEMs in hospitalized newborns was 1/377 (58/21,840), with a higher incidence in full-term infants (1/428) than in premature infants (1/3,120). Among the diagnosed genetic metabolic diseases, organic acid metabolism disorders (1/662), amino acid metabolism disorders (1/950), and fatty acid oxidation disorders (1/10,920) were the most prevalent. Methylmalonic acidemia (MMA), especially the isolated form, emerged as the most common IEM, while neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and ornithine transcarbamylase deficiency (OTCD) were prevalent in premature infants. Of the 58 confirmed cases of IEMs, 72 variants were identified, of which 31.94% (23/72) had not been reported previously. This study contributes to understanding the incidence and clinical features of IEMs in hospitalized newborns, offering more efficient strategies for screening and diagnosing these disorders.
PubMed: 38863445
DOI: 10.3389/fgene.2024.1395988 -
BioRxiv : the Preprint Server For... Jun 2024Tau protein aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer's disease, frontotemporal dementia (FTD) and progressive supranuclear...
Tau protein aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer's disease, frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP), spurring development of tau-lowering therapeutic strategies. Here, we report fully human bifunctional anti-tau-PEST intrabodies that bind the mid-domain of tau to block aggregation and degrade tau via the proteasome using the ornithine decarboxylase (ODC) PEST degron. They effectively reduced tau protein in human iPSC-derived cortical neurons in 2D cultures and 3D organoids, including those with the disease-associated tau mutations R5L, N279K, R406W, and V337M. Anti-tau-hPEST intrabodies facilitated efficient ubiquitin-independent proteolysis, in contrast to tau-lowering approaches that rely on the cell's ubiquitination system. Importantly, they counteracted the proteasome impairment observed in V337M patient-derived cortical neurons and significantly improved neuronal survival. By serial mutagenesis, we created variants of the PEST degron that achieved graded levels of tau reduction. Moderate reduction was as effective as high reduction against tau V337M-induced neural cell death.
PubMed: 38854137
DOI: 10.1101/2024.05.28.596248 -
BioRxiv : the Preprint Server For... May 2024Metabolic adaptations in response to changes in energy supply and demand are essential for survival. The mitochondrial calcium uniporter coordinates metabolic...
Metabolic adaptations in response to changes in energy supply and demand are essential for survival. The mitochondrial calcium uniporter coordinates metabolic homeostasis by regulating TCA cycle activation, mitochondrial fatty acid oxidation and cellular calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial metabolic pathways has remained unexplored. Here, we investigate the metabolic consequences of uniporter loss- and gain-of-function, and identify a key transcriptional regulator that mediates these effects. Using gene expression profiling and proteomic, we find that loss of uniporter function increases the expression of proteins in the branched-chain amino acid (BCAA) catabolism pathway. Activity is further augmented through phosphorylation of the enzyme that catalyzes this pathway's committed step. Conversely, in the liver cancer fibrolamellar carcinoma (FLC)-which we demonstrate to have high mitochondrial calcium levels- expression of BCAA catabolism enzymes is suppressed. We also observe uniporter-dependent suppression of the transcription factor KLF15, a master regulator of liver metabolic gene expression, including those involved in BCAA catabolism. Notably, loss of uniporter activity upregulates KLF15, along with its transcriptional target ornithine transcarbamylase (OTC), a component of the urea cycle, suggesting that uniporter hyperactivation may contribute to the hyperammonemia observed in FLC patients. Collectively, we establish that FLC has increased mitochondrial calcium levels, and identify an important role for mitochondrial calcium signaling in metabolic adaptation through the transcriptional regulation of metabolism.
PubMed: 38853984
DOI: 10.1101/2024.05.27.596106 -
BioRxiv : the Preprint Server For... May 2024is a commensal bacterium in the gastrointestinal tract (GIT) of humans and other organisms. also causes infections in root canals, wounds, the urinary tract, and on...
is a commensal bacterium in the gastrointestinal tract (GIT) of humans and other organisms. also causes infections in root canals, wounds, the urinary tract, and on heart valves. metabolizes arginine through the arginine deiminase (ADI) pathway, which converts arginine to ornithine and releases ATP, ammonia, and CO. arginine metabolism also affects virulence of other pathogens during co-culture. may encounter elevated levels of arginine in the GIT or the oral cavity, where arginine is used as a dental therapeutic. Little is known about how responds to growth in arginine in the absence of other bacteria. To address this, we used RNAseq and additional assays to measure growth, gene expression, and biofilm formation in OG1RF grown in arginine. We demonstrate that arginine decreases biofilm production and causes widespread differential expression of genes related to metabolism, quorum sensing, and polysaccharide synthesis. Growth in arginine also increases aggregation of and promotes decreased susceptibility to the antibiotics ampicillin and ceftriaxone. This work provides a platform for understanding of how the presence of arginine in biological niches affects physiology and virulence of surrounding microbes.
PubMed: 38853917
DOI: 10.1101/2024.05.30.596650 -
Food Chemistry May 2024White tea stored for various times have different flavors. However, the mechanism of flavor conversion remains elusive. Flavonoids and amino acids are two typical flavor...
White tea stored for various times have different flavors. However, the mechanism of flavor conversion remains elusive. Flavonoids and amino acids are two typical flavor components in tea. Herein, the contents of 46 flavonoids and 40 amino acids were measured in white tea (Shoumei) stored for 1, 3, 5 and 7 years, respectively. L-tryptophan, L-ornithine and L-theanine contribute to the refreshing taste of Shoumei 1 and 3. Quercetin, rutin and hesperidin contribute to aging charm and grain aroma of Shoumei 5 and 7. 306 bacterial OTUs and 268 fungal OTUs core microbiota existed in all samples. Interestingly, white teas contained higher richness of fungi than bacteria. The correlation analysis showed that the cooperation with bacteria and fungi may result in the flavonoids and amino acids composition changes in white teas during storage. Overall, this study provides new insights into flavor conversion of white tea during storage.
PubMed: 38843719
DOI: 10.1016/j.foodchem.2024.139932 -
Hepatology Communications Jun 2024Patients with pediatric cirrhosis-sepsis (PC-S) attain early mortality. Plasma bacterial composition, the cognate metabolites, and their contribution to the...
BACKGROUND
Patients with pediatric cirrhosis-sepsis (PC-S) attain early mortality. Plasma bacterial composition, the cognate metabolites, and their contribution to the deterioration of patients with PC-S to early mortality are unknown. We aimed to delineate the plasma metaproteome-metabolome landscape and identify molecular indicators capable of segregating patients with PC-S predisposed to early mortality in plasma, and we further validated the selected metabolite panel in paired 1-drop blood samples using untargeted metaproteomics-metabolomics by UHPLC-HRMS followed by validation using machine-learning algorithms.
METHODS
We enrolled 160 patients with liver diseases (cirrhosis-sepsis/nonsepsis [n=110] and noncirrhosis [n=50]) and performed untargeted metaproteomics-metabolomics on a training cohort of 110 patients (Cirrhosis-Sepsis/Nonsepsis, n=70 and noncirrhosis, n=40). The candidate predictors were validated on 2 test cohorts-T1 (plasma test cohort) and T2 (1-drop blood test cohort). Both T1 and T2 had 120 patients each, of which 70 were from the training cohort.
RESULTS
Increased levels of tryptophan metabolites and Salmonella enterica and Escherichia coli-associated peptides segregated patients with cirrhosis. Increased levels of deoxyribose-1-phosphate, N5-citryl-d-ornithine, and Herbinix hemicellulolytic and Leifsonia xyli segregated patients with PC-S. MMCN-based integration analysis of WMCNA-WMpCNA identified key microbial-metabolic modules linked to PC-S nonsurvivors. Increased Indican, Staphylobillin, glucose-6-phosphate, 2-octenoylcarnitine, palmitic acid, and guanidoacetic acid along with L. xyli, Mycoplasma genitalium, and Hungateiclostridium thermocellum segregated PC-S nonsurvivors and superseded the liver disease severity indices with high accuracy, sensitivity, and specificity for mortality prediction using random forest machine-learning algorithm.
CONCLUSIONS
Our study reveals a novel metabolite signature panel capable of segregating patients with PC-S predisposed to early mortality using as low as 1-drop blood.
Topics: Humans; Male; Female; Liver Cirrhosis; Child; Metabolomics; Adolescent; Sepsis; Biomarkers; Child, Preschool; Machine Learning; Metabolome; Bacterial Proteins
PubMed: 38836842
DOI: 10.1097/HC9.0000000000000440 -
Italian Journal of Pediatrics Jun 2024Lysinuric protein intolerance (LPI) is a multi-organ metabolic disorder characterized by the imbalance in absorption and excretion of cationic amino acids like lysine,...
BACKGROUND
Lysinuric protein intolerance (LPI) is a multi-organ metabolic disorder characterized by the imbalance in absorption and excretion of cationic amino acids like lysine, ornithine and arginine. Infants with LPI typically present with recurrent vomiting, poor growth, interstitial lung disease or renal impairment. The early onset of pulmonary alveolar proteinosis (PAP) has been reported to be associated with a severe form of LPI. Treatment of PAP most commonly consists of whole-lung lavage (WLL) and in autoimmune PAP, granulocyte-macrophage colony stimulating factor (GM-CSF) administration. Nevertheless, GM-CSF therapy in LPI-associated PAP has not been scientifically justified.
CASE PRESENTATION
We describe the case of an 8-month-old infant presenting with respiratory failure due to LPI associated with PAP, who was twice treated with WLL; firstly, while on veno-venous ECMO assistance and then by the use of a selective bronchial blocker. After the two treatments with WLL, she was weaned from daytime respiratory support while on initially subcutaneous, then on inhaled GM-CSF therapy.
CONCLUSIONS
This case supports the notion that GM-CSF therapy might be of benefit in patients with LPI-associated PAP. Further studies are needed to clarify the exact mechanism of GM-CSF in patients with LPI-associated PAP.
Topics: Humans; Pulmonary Alveolar Proteinosis; Granulocyte-Macrophage Colony-Stimulating Factor; Infant; Female; Bronchoalveolar Lavage; Amino Acid Metabolism, Inborn Errors
PubMed: 38831374
DOI: 10.1186/s13052-024-01677-y -
Frontiers in Microbiology 2024Sepsis is commonly associated with a sudden impairment of brain function, thus leading to significant rates of illness and mortality. The objective of this research was...
BACKGROUND
Sepsis is commonly associated with a sudden impairment of brain function, thus leading to significant rates of illness and mortality. The objective of this research was to integrate microbiome and metabolome to reveal the mechanism of microbiota-hippocampus-metabolites axis dysfunction in a mouse model of sepsis.
METHODS
A mouse model of sepsis was established via cecal ligation and puncture. The potential associations between the composition of the gut microbiota and metabolites in the hippocampus of mice with sepsis were investigated by combining 16S ribosomal RNA gene sequencing and ultra-high-performance liquid chromatography tandem mass spectrometry.
RESULTS
A total of 140 differential metabolites were identified in the hippocampal tissues of mice with sepsis when compared to those of control mice. These differential metabolites in mice with sepsis were not only associated with autophagy and serotonergic synapse, but also involved in the metabolism and synthesis of numerous amino acids. At the phylum level, the abundance of was increased, while that of () was decreased in mice with sepsis. At the genus level, the abundance of was increased, while that of was decreased in mice with sepsis. The ()/ (F/B) ratio was decreased in mice with sepsis when compared to that of control mice. Furthermore, the F/B ratio was positively correlated with 5'-methylthioadenosine, PC (18:3(9Z,12Z,15Z)/18:0) and curdione, and negatively correlated with indoxylsulfuric acid, corticosterone, kynurenine and ornithine.
CONCLUSION
Analysis revealed a reduction in the F/B ratio in mice with sepsis, thus contributing to the disturbance of 5'-methylthioadenosine, curdione, PC (18:3(9Z,12Z,15Z)/18:0), corticosterone, ornithine, indoxylsulfuric acid and kynurenine; eventually, these changes led to hippocampus dysfunction. Our findings provide a new direction for the management of sepsis-induced hippocampus dysfunction.
PubMed: 38827158
DOI: 10.3389/fmicb.2024.1302907 -
World Journal of Hepatology May 2024Metabolic-dysfunction associated steatotic liver disease (MASLD) is a hepatic manifestation of metabolic syndrome. Studies suggest ornithine aspartate (LOLA) as drug...
BACKGROUND
Metabolic-dysfunction associated steatotic liver disease (MASLD) is a hepatic manifestation of metabolic syndrome. Studies suggest ornithine aspartate (LOLA) as drug therapy.
AIM
To analyze the influence of LOLA intake on gut microbiota using a nutritional model of MASLD.
METHODS
Adult male Sprague Dawley rats were randomized into three groups: Control (10 rats fed with a standard diet), MASLD (10 rats fed with a high-fat and choline-deficient diet), and LOLA (10 rats receiving 200 mg/kg/d LOLA, after the 16 week receiving high-fat and choline-deficient diet). After 28 wk of the experiment, animals were euthanized, and feces present in the intestine were collected. Following fecal DNA extraction, the V4 region of the 16S rRNA gene was amplified followed by sequencing in an Ion S5™ system.
RESULTS
Alpha and beta diversity metrics were comparable between MASLD and LOLA. 3 OTUs were differentially abundant between MASLD and LOLA, which belong to the species , , and . The functional prediction provided two different metabolic profiles between MASLD and LOLA. The 9 pathways differentially abundant in MASLD are related to a change in energy source, adenosine/purine nucleotides degradation as well as guanosine and adenosine deoxyribonucleotides biosynthesis. The 14 pathways differentially abundant in LOLA are associated with four major metabolic functions primarily influenced by L-aspartate, including tricarboxylic acid cycle pathways, purine/guanosine nucleotides biosynthesis, pyrimidine ribonucleotides biosynthesis and salvage as well as lipid IVA biosynthesis.
CONCLUSION
Although LOLA had no influence on alpha and beta diversity in this nutritional model of MASLD, it was associated with changes in specific gut microbes and their related metabolic pathways.
PubMed: 38818297
DOI: 10.4254/wjh.v16.i5.832