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The gut microbiota metabolite trimethylamine-N-oxide (TMAO)-derived from dietary phosphatidylcholine-is mechanistically linked to cardiovascular disease (CVD) and increased cardiovascular risk. This study examined the relationship between fasting plasma TMAO levels and 5-year all-cause mortality in a cohort of patients at high risk of cardiovascular events (CORE-Thailand Registry). Of the 134 patients, 123 (92%) had established cardiovascular disease, and 11 (8%) had multiple risk factors. Fasting plasma TMAO levels were measured using nuclear magnetic resonance spectroscopy. Within this prospective cohort study, the median TMAO was 3.81 μM [interquartile range (IQR) 2.89-5.50 μM], with a mean age of 65 ± 11 years; 61% were men, and 39.6% had type II diabetes. Among 134 patients, 65 (49%) were identified as the high-TMAO group (≥ 3.8 μM), and 69 (51%) were identified as the low-TMAO group (< 3.8 μM). After a median follow-up of 58.8 months, the high-TMAO group was associated with a 2.88-fold increased mortality risk. Following adjustment for traditional risk factors, high-sensitivity cardiac troponin-T, estimated glomerular filtration rate, angiotensin-converting enzyme (ACEI), or angiotensin-receptor blocker (ARB) use, the high-TMAO group remained predictive of 5-year all-cause mortality risk (the high-TMAO vs. the low-TMAO group, adjusted hazard ratio 2.73, 95% CI 1.13-6.54; P = 0.025). Among Thai patients at high risk of cardiovascular events, increased plasma TMAO levels portended greater long-term mortality risk., (© 2024. The Author(s).)

Burkholderia pseudomallei, an etiological agent of melioidosis is an environmental bacterium that can survive as an intracellular pathogen. The biofilm produced by B. pseudomallei is crucial for cellular pathogenesis of melioidosis. The purpose of this investigation is to explore the role of biofilm in survival of B. pseudomallei during encounters with Acanthamoeba sp. using B. pseudomallei H777 (a biofilm wild type), M10 (a biofilm defect mutant) and C17 (a biofilm-complemented strain). The results demonstrated similar adhesion to amoebae by both the biofilm wild type and biofilm mutant strains. There was higher initial internalisation, but the difference diminished after longer encounter with the amoeba. Interestingly, confocal laser scanning microscopy demonstrated that pre-formed biofilm of B. pseudomallei H777 and C17 were markedly more persistent in the face of Acanthamoeba sp. grazing than that of M10. Metabolomic analysis revealed a significant increased level of 8-O-4'-diferulic acid, a superoxide scavenger metabolite, in B. pseudomallei H777 serially passaged in Acanthamoeba sp. The interaction between B. pseudomallei with a free-living amoeba may indicate the evolutionary pathway that enables the bacterium to withstand superoxide radicals in intracellular environments. This study supports the hypothesis that B. pseudomallei biofilm persists under grazing by amoebae and suggests a strategy of metabolite production that turns this bacterium from saprophyte to intracellular pathogen., (© 2023. Springer Nature Limited.)

The detection of pre-extensively (pre-XDR) and extensively drug-resistant tuberculosis (XDR-TB) is challenging. Drug-susceptibility tests for some anti-TB drugs, especially ethambutol (ETH) and ethionamide (ETO), are problematic due to overlapping thresholds to differentiate between susceptible and resistant phenotypes. We aimed to identify possible metabolomic markers to detect Mycobacterium tuberculosis (Mtb) strains causing pre-XDR and XDR-TB. The metabolic patterns of ETH- and ETO-resistant Mtb isolates were also investigated. Metabolomics of 150 Mtb isolates (54 pre-XDR, 63 XDR-TB and 33 pan-susceptible; pan-S) were investigated. Metabolomics of ETH and ETO phenotypically resistant subgroups were analyzed using UHPLC-ESI-QTOF-MS/MS. Orthogonal partial least-squares discriminant analysis revealed distinct separation in all pairwise comparisons among groups. Two metabolites (meso-hydroxyheme and itaconic anhydride) were able to differentiate the pre-XDR and XDR-TB groups from the pan-S group with 100% sensitivity and 100% specificity. In comparisons of the ETH and ETO phenotypically resistant subsets, sets of increased (ETH = 15, ETO = 7) and decreased (ETH = 1, ETO = 6) metabolites specific for the resistance phenotype of each drug were found. We demonstrated the potential for metabolomics of Mtb to differentiate among types of DR-TB as well as between isolates that were phenotypically resistant to ETO and ETH. Thus, metabolomics might be further applied for DR-TB diagnosis and patient management., (© 2023. The Author(s).)

The three-dimensional multicellular spheroid (3D MCS) model has been employed in cholangiocarcinoma research as it generates 3D architecture and includes more physiological relevance with the multicellular arrangement. However, it is also essential to explain the molecular signature in this microenvironment and its structural complexity. The results indicated that poorly differentiated CCA cell lines were unable to form 3D MCS due to the lack of cell adhesion molecules with more mesenchymal marker expression. The well-differentiated CCA and cholangiocyte cell lines were able to develop 3D MCSs with round shapes, smooth perimeter, and cell adhesion molecules that led to the hypoxic and oxidative microenvironment detected. For MMNK-1, KKU-213C, and KKU-213A MCSs, the proteo-metabolomic analysis showed proteins and metabolic products altered compared to 2D cultures, including cell-cell adhesion molecules, energy metabolism-related enzymes and metabolites, and oxidative-related metabolites. Therefore, the 3D MCSs provide different physiological states with different phenotypic signatures compared to 2D cultures. Considering the 3D model mimics more physiological relevance, it might lead to an alternate biochemical pathway, targeting to improve drug sensitivity for CCA treatment., (© 2023. The Author(s).)

Black soldier fly (BSF, Hermetia illucens) is popular for its applications in animal feed, waste management and antimicrobial peptide source. The major advantages of BSF larva include their robust immune system and high nutritional content that can be further developed into more potential agricultural and medical applications. Several strategies are now being developed to exploit their fullest capabilities and one of these is the immunity modulation using bacterial challenges. The mechanism underlying metabolic responses of BSF to different bacteria has, however, remained unclear. In the current study, entometabolomics was employed to investigate the metabolic phenoconversion in response to either Escherichia coli, Staphylococcus aureus, or combined challenges in BSF larva. We have, thus far, characterised 37 metabolites in BSF larva challenged with different bacteria with the major biochemical groups consisting of amino acids, organic acids, and sugars. The distinct defense mechanism-specific metabolic phenotypes were clearly observed. The combined challenge contributed to the most significant metabolic phenoconversion in BSF larva with the dominant metabolic phenotypes induced by S. aureus. Our study suggested that the accumulation of energy-related metabolites provided by amino acid catabolism is the principal metabolic pathway regulating the defense mechanism. Therefore, combined challenge is strongly recommended for raising BSF immunity as it remarkably triggered amino acid metabolisms including arginine and proline metabolism and alanine, aspartate and glutamate metabolism along with purine metabolism and pyruvate metabolism that potentially result in the production of various nutritional and functional metabolites., (© 2021. The Author(s).)

Plasma Trimethylamine-N-oxide (TMAO), a gut microbiota metabolite from dietary phosphatidylcholine, is mechanistically linked to cardiovascular disease (CVD) and adverse cardiovascular events. We aimed to examine the relationship between plasma TMAO levels and subclinical myocardial damage using high-sensitivity cardiac troponin-T (hs-cTnT). We studied 134 patients for whom TMAO data were available from the Cohort Of patients at a high Risk of Cardiovascular Events-Thailand (CORE-Thailand) registry, including 123 (92%) patients with established atherosclerotic disease and 11 (8%) with multiple risk factors. Plasma TMAO was measured by NMR spectroscopy. In our study cohort (mean age 64 ± 8.9 years; 61% men), median TMAO was 3.81 μM (interquartile range [IQR] 2.89-5.50 μM), and median hs-cTnT was 15.65 ng/L (IQR 10.17-26.67). Older patients and those with diabetic or hypertension were more likely to have higher TMAO levels. Plasma TMAO levels correlated with those of hs-cTnT (r = 0.54; p < 0.0001) and were significantly higher in patients with subclinical myocardial damage (hs-cTnT ≥ 14 ng/L; 4.48 μM vs 2.98 μM p < 0.0001). After adjusting for traditional risk factors, elevated TMAO levels remained independently associated with subclinical myocardial damage (adjusted odds ratio [OR]: 1.58; 95% CI 1.24-2.08; p = 0.0007). This study demonstrated that plasma TMAO was an independent predictor for subclinical myocardial damage in this study population., (© 2021. The Author(s).)