PubMed

Int Immunopharmacol. 2024 Aug 10;140:112912. doi: 10.1016/j.intimp.2024.112912. Online ahead of print.ABSTRACTOBJECTIVE: Lung adenocarcinoma (LA), the most prevalent type of lung cancer, is associated with a high mortality rate, especially among patients with cancer previously infected with coronavirus disease (COVID-19). Therefore, this study aimed to explore the mechanisms by which COVID-19 exacerbates LA progression in a clinical setting.METHODS: The experiment involved collecting serum samples from three groups: a healthy control group (Con, n = 20), a lung adenocarcinoma group (LA, n = 30), and a group of lung adenocarcinoma patients with first-time COVID-19 infection (C-LA, n = 58). Metabolites were analyzed using liquid chromatography-mass spectrometry, and differentially expressed metabolites were identified through bioinformatics analysis. The concentrations of glutathione (GSH), reactive oxygen species (ROS), and copper ions (Cu2+) in the serum of patients in the Con and C-LA groups were measured. Mitochondrial morphological changes in monocytes and lymphocytes were observed using electron microscopy.RESULTS: Metabolomic analysis revealed 142 distinct metabolites, among which glutamine (Gln) expression was significantly decreased in the C-LA group. Compared to the Con group, the C-LA group showed a significant decrease in GSH and a notable increase in ROS and Cu2+. Further research revealed that the mitochondria of monocytes and lymphocytes in the C-LA group exhibited corresponding alterations indicative of cuproptosis.CONCLUSIONS: SARS-CoV-2 infection may reduce Gln levels, leading to reduced GSH levels, copper overload, and increased death of immune cells, which may further exacerbate rapid tumor development. Thus, glutamine regulation plays an important role in LA progression in patients with COVID-19 and represents a potential therapeutic target.PMID:39133954 | DOI:10.1016/j.intimp.2024.112912

Neurology. 2024 Sep 10;103(5):e209749. doi: 10.1212/WNL.0000000000209749. Epub 2024 Aug 12.ABSTRACTBACKGROUND AND OBJECTIVES: Brain MRI abnormalities and increases in neurofilament light chain (NfL) have mostly been observed in cross-sectional studies before ataxia onset in polyglutamine spinocerebellar ataxias. Our study aimed to identify longitudinal changes in biological, clinical, and/or imaging biomarkers in spinocerebellar ataxia (SCA) 2 and SCA7 carriers over 1 year.METHODS: We studied SCA2 and SCA7 carriers and controls (expansion-negative relatives) at the Paris Brain Institute. Inclusion criteria included Scale for the Assessment and Rating of Ataxia (SARA) scores between 0 and 15. Assessments at baseline, 6 months, and 12 months comprised neurologic, quality of life, orofacial motor, neuropsychological, and ophthalmologic examinations, along with gait and oculomotor recordings, brain MRI, CSF, and blood sampling. The primary outcome was the longitudinal change in these assessments over 1 year.RESULTS: We included 15 SCA2 carriers, 15 SCA7 carriers, and 10 controls between May 2020 and April 2021. At baseline, the ages were similar (41 [37, 46] for SCA2, 38 [28.5, 39.8] for SCA7, and 39.5 [31, 54.5] for controls, p = 0.78), as well the sex (p = 0.61); SARA scores were low but different (4 [1.25, 6.5] in SCA2, 2 [0, 11.5] in SCA7, and 0 in controls, p < 0.01). Pons and medulla volumes were smaller in SCAs (p < 0.05) and cerebellum volume only in SCA2 (p = 0.01). Plasma NfL levels were higher in SCA participants (SCA2: 14.2 pg/mL [11.52, 15.89], SCA7: 15.53 [13.27, 23.23]) than in controls (4.88 [3.56, 6.17], p < 0.001). After 1-year follow-up, in SCA2, there was significant pons (-144 ± 60 mm3) and cerebellum (-1,508 ± 580 mm3) volume loss and a worsening of gait assessment; in SCA7, SARA score significantly increased (+1.3 ± 0.4) and outer retinal nuclear layer thickness decreased (-15.4 ± 1.6 μm); for both SCA groups, the orofacial motor assessment significantly worsened. For preataxic and early ataxic carriers, the strongest longitudinal deterioration on outcome measures was orofacial motility in SCA2 and retinal thickness in SCA7.DISCUSSION: Despite the limitation of the small sample size, we detected annual changes in preataxic and early ataxic SCA individuals across brain MRI imaging, clinical scores, gait parameters, and retinal thickness. These parameters could serve as potential end points for future therapeutic trials in the preataxic phase.TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT04288128.PMID:39133883 | DOI:10.1212/WNL.0000000000209749

Gut Microbes. 2024 Jan-Dec;16(1):2387875. doi: 10.1080/19490976.2024.2387875. Epub 2024 Aug 12.ABSTRACTThe intestinal microbiome during infancy and childhood has distinct metabolic functions and microbial composition compared to adults. We recently published a gnotobiotic mouse model of the pre-weaning microbiome (PedsCom), which retains a pre-weaning configuration during the transition from a milk-based diet to solid foods, leads to a stunted immune system, and increases susceptibility to enteric infection. Here, we compared the phylogenetic and metabolic relationships of the PedsCom consortium to two adult-derived gnotobiotic communities, Altered Schaedler Flora and Oligo-Mouse Microbiota 12 (Oligo-MM12). We find that PedsCom contains several unique functions relative to these adult-derived mouse consortia, including differences in carbohydrate and lipid metabolism genes. Notably, amino acid degradation metabolic modules are more prevalent among PedsCom isolates, which is in line with the ready availability of these nutrients in milk. Indeed, metabolomic analysis revealed significantly lower levels of total free amino acids and lower levels of specific amino acids abundant in milk (e.g. glutamine and glutamic acid) in the intestinal contents of adult PedsCom colonized mice compared to Oligo-MM12 controls. Metabolomic analysis of pre-weaning intestinal contents also showed lower levels of amino acids that are replete in milk compared to germ-free controls. Thus, enhanced amino acid metabolism is a prominent feature of the pre-weaning microbiome that may facilitate design of early-life microbiome interventions.PMID:39133869 | DOI:10.1080/19490976.2024.2387875

J Am Soc Mass Spectrom. 2024 Aug 12. doi: 10.1021/jasms.4c00208. Online ahead of print.ABSTRACTUntargeted tandem mass spectrometry (MS/MS) is an essential technique in modern analytical chemistry, providing a comprehensive snapshot of chemical entities in complex samples and identifying unknowns through their fragmentation patterns. This high-throughput approach generates large data sets that can be challenging to interpret. Molecular Networks (MNs) have been developed as a computational tool to aid in the organization and visualization of complex chemical space in untargeted mass spectrometry data, thereby supporting comprehensive data analysis and interpretation. MNs group related compounds with potentially similar structures from MS/MS data by calculating all pairwise MS/MS similarities and filtering these connections to produce a MN. Such networks are instrumental in metabolomics for identifying novel metabolites, elucidating metabolic pathways, and even discovering biomarkers for disease. While MS/MS similarity metrics have been explored in the literature, the influence of network topology approaches on MN construction remains unexplored. This manuscript introduces metrics for evaluating MN construction, benchmarks state-of-the-art approaches, and proposes the Transitive Alignments approach to improve MN construction. The Transitive Alignment technique leverages the MN topology to realign MS/MS spectra of related compounds that differ by multiple structural modifications. Combining this Transitive Alignments approach with pseudoclique finding, a method for identifying highly connected groups of nodes in a network, resulted in more complete and higher-quality molecular families. Finally, we also introduce a targeted network construction technique called induced transitive alignments where we demonstrate effectiveness on a real world natural product discovery application. We release this transitive alignment technique as a high-throughput workflow that can be used by the wider research community.PMID:39133821 | DOI:10.1021/jasms.4c00208

PLoS One. 2024 Aug 12;19(8):e0308710. doi: 10.1371/journal.pone.0308710. eCollection 2024.ABSTRACTBACKGROUND: Late-onset breast milk jaundice (LBMJ) is a common form of hyperbilirubinemia, which can result in serious complications for newborns with persistently high bilirubin levels. The aim of this study was to investigate the differences in fecal metabolites between breastfed infants with and without LBMJ in order to elucidate potential biological mechanisms.METHODS: Biological samples were collected from 12 infants with LBMJ and 12 healthy individuals. Ultra-high performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UHPLC-Q-TOF/MS) was utilized for non-targeted determination of fecal metabolites. Principal components analysis (PCA), cluster analysis, and differential metabolite analysis were performed in both positive ion mode and negative ion mode for the two groups. Additionally, the KEGG database was employed to comprehensively analyze the pathways of differential metabolites.RESULTS: There were no significant differences in maternal and neonatal demographic characteristics between the two groups (p > 0.05). The results of PCA and cluster heat map analysis in both modes showed that there were significant differences in metabolites between the two groups. Among 751 differential metabolites (DMs) detected in positive ion mode, 720 were up-regulated in the case group while 31 were down-regulated. In negative ion mode, 1891 DMs were detected, including 817 up-regulated metabolites and 1074 down-regulated metabolites in the case group. Analysis of differential metabolic pathways showed that the DMs of the two groups were mainly annotated and enriched in Biotin metabolism, N-Glycan biosynthesis, Taurine and hypotaurine metabolism, Pyrimidine metabolism, and Pentose and glucuronate interconversions.CONCLUSION: Significant differences exist in fecal metabolites between LBMJ infants and healthy controls. The study of differential metabolic pathways provides insights into the mechanism of LBMJ.PMID:39133689 | DOI:10.1371/journal.pone.0308710

Cancer Treat Res. 2024;191:191-216. doi: 10.1007/978-3-031-55622-7_8.ABSTRACTDiet play an important role in the development of cancer. A lot of research has been done on the role of individual nutrients or phytochemicals and cancer risk. Both harmful and beneficial associations of this nutrient have been observed with cancer. However, there is an interaction of individual dietary constituents to influence disease risk. On the other hand, examining the diet as a whole as is done in dietary patterns research may produce more accurate estimates and data that can be more easily translated into dietary recommendations. Dietary patterns and cancer research are becoming increasingly common in the epidemiology literature, and novel dietary patterns are being generated at a rapid pace. However, major issues remain over whether one general "healthy" dietary pattern can be suggested for cancer prevention or whether several diets should be advocated for different forms of cancer protection. It is challenging to study typical human diet in animal model that is appropriate for cancer prevention. Some dietary patterns, such as the ketogenic diet or macronutrient composition alteration, have been investigated more extensively in animal models than in humans in terms of cancer prevention, and bigger human observational studies are now needed to advise dietary guidelines. The question of whether to adapt nutritional guidelines to population subgroups based on susceptibility factors (for example, family history, sex, age, other lifestyle factors or comorbidities, metabolomics signatures, or microbiota-based profiles) is still open and will be crucial in moving the field forward.PMID:39133409 | DOI:10.1007/978-3-031-55622-7_8

Anim Biotechnol. 2024 Nov;35(1):2388704. doi: 10.1080/10495398.2024.2388704. Epub 2024 Aug 12.ABSTRACTThe flavour, tenderness and juiciness of the beef are all impacted by the composition of the intramuscular fat (IMF), which is a key determinant of beef quality. Thus, enhancing the IMF composition of beef cattle has become a major area of research. Consequently, the aim of this paper was to provide insight and synthesis into the emerging technologies, nutritional practices and management strategies to improve IMF composition in beef cattle. This review paper examined the current knowledge of management techniques and nutritional approaches relevant to cattle farming in the beef industry. It includes a thorough investigation of animal handling, weaning age, castration, breed selection, sex determination, environmental factors, grazing methods, slaughter weight and age. Additionally, it rigorously explored dietary energy levels and optimization of fatty acid profiles, as well as the use of feed additives and hormone implant techniques with their associated regulations. The paper also delved into emerging technologies that are shaping future beef production, such as genomic selection methods, genome editing techniques, epigenomic analyses, microbiome manipulation strategies, transcriptomic profiling approaches and metabolomics analyses. In conclusion, a holistic approach combining genomic, nutritional and management strategies is imperative for achieving targeted IMF content and ensuring high-quality beef production.PMID:39133095 | DOI:10.1080/10495398.2024.2388704

Lab Chip. 2024 Aug 12. doi: 10.1039/d4lc00269e. Online ahead of print.ABSTRACTThe interactions of proteins, membranes, nucleic acid, and metabolites shape a cell's phenotype. These interactions are stochastic, and each cell develops differently, making it difficult to synchronize cell populations. Consequently, studying biological processes at the single- or few-cell level is often necessary to avoid signal dilution below the detection limit or averaging over many cells. We have developed a method to study metabolites and proteins from a small number of or even a single adherent eukaryotic cell. Initially, cells are lysed by short electroporation and aspirated with a microcapillary under a fluorescent microscope. The lysate is placed on a carrier slide for further analysis using liquid-chromatography mass spectrometry (LC-MS) and/or reverse-phase protein (RPPA) approach. This method allows for a correlative measurement of (i) cellular structures and metabolites and (ii) cellular structures and proteins on the single-cell level. The correlative measurement of cellular structure by light-microscopy, metabolites by LC-MS, and targeted protein detection by RPPA was possible on the few-cell level. We discuss the method, potential applications, limitations, and future improvements.PMID:39132885 | DOI:10.1039/d4lc00269e

J Agric Food Chem. 2024 Aug 12. doi: 10.1021/acs.jafc.4c05187. Online ahead of print.ABSTRACTSprouting of stored oilseeds due to improper storage can lead to quality defects of cold-pressed oils obtained from them. This study aimed to evaluate the effect of seed sprouting on volatile organic compounds (VOCs), aroma-active compounds, and the content of nonvolatile metabolites in cold-pressed false flax oil obtained from sprouted seeds. In this study, 88 unique VOCs were detected in sprouted oils, whereas only 42 were found in the control oils. The control oils were characterized by a higher abundance of alcohols, while all other groups of compounds were associated with sprouted seeds. The formation of many VOCs was reflected in changes in the nonvolatile precursors. Fifteen aroma-active compounds were identified in sprouted oil, with five compounds playing a significant role (FD ≥ 128) in aroma formation. The presented approach allowed identification of differences caused by seed sprouting, resulting in oils with a much stronger aroma and a richer profile of VOCs due to intensive metabolic changes. The origin of many VOCs can be explained by alterations in the content of nonvolatile metabolites.PMID:39132846 | DOI:10.1021/acs.jafc.4c05187

Ren Fail. 2024 Dec;46(2):2387429. doi: 10.1080/0886022X.2024.2387429. Epub 2024 Aug 12.ABSTRACTObjectives: To investigate the role of the intestinal flora and metabolites in the development of hyperuricemic renal injury in chronic kidney disease (CKD).Methods: Unilaterally nephrectomized mice were fed with adenine and potassium oxonate for 9 weeks. HE staining combined with plasma biochemical indicators was used to evaluate renal pathological and functional changes. We conducted 16S rRNA sequencing and untargeted metabolomics on feces and plasma samples to reveale changes in intestinal microbiota and metabolites.Result: Our analysis revealed significant differences in 15 bacterial genera, with 7 being upregulated and 8 being downregulated. Furthermore, metabolomic analysis revealed changes in the distribution of amino acid and biotin metabolites in basic metabolic pathways in both feces and serum. Specifically, differentially abundant metabolites in feces were associated primarily with histidine metabolism; the biosynthesis of phenylalanine, tyrosine, and tryptophan; and tyrosine metabolism. In plasma, the differentially abundant metabolites were involved in multiple metabolic pathways, including aminoacyl-tRNA biosynthesis; glycine, serine, and threonine amino acid metabolism; valine, leucine, and isoleucine biosynthesis; tyrosine biosynthesis and metabolism; biotin metabolism; and taurine and hypotaurine metabolism. Furthermore, correlation analysis revealed that Akkermansia, UCG-005, Lachnospiraceae_NK4A136_group, Lactococcus, and Butymonas were associated with various differentially abundant metabolites as well as renal function, oxidative stress, and mitophagy. The changes in the intestinal flora observed in hyperuricemia may lead to imbalances in amino acid and biotin metabolism in both the intestine and host, ultimately affecting oxidative stress and mitophagy in mice and accelerating the progression of CKD.Conclusion: Our findings provide insights into a potential pathogenic mechanism by which hyperuricemia exacerbates renal injury in mice with renal insufficiency. Understanding these pathways may offer new therapeutic strategies for managing hyperuricemic renal injury in CKD patients.PMID:39132829 | DOI:10.1080/0886022X.2024.2387429

medRxiv [Preprint]. 2024 Jul 30:2024.07.29.24311176. doi: 10.1101/2024.07.29.24311176.ABSTRACTStudying relationships between longitudinal changes in omics variables and risks of events requires specific methodologies for joint analyses of longitudinal and time-to-event outcomes. We applied two such approaches (joint models [JM], stochastic process models [SPM]) to longitudinal metabolomics data from the Long Life Family Study focusing on understudied associations of longitudinal changes in lysophosphatidylcholines (LPC) with mortality and aging-related outcomes (23 LPC species, 5,790 measurements of each in 4,011 participants, 1,431 of whom died during follow-up). JM analyses found that higher levels of the majority of LPC species were associated with lower mortality risks, with the largest effect size observed for LPC 15:0/0:0 (hazard ratio: 0.715, 95% CI (0.649, 0.788)). SPM applications to LPC 15:0/0:0 revealed how the association found in JM reflects underlying aging-related processes: decline in robustness to deviations from optimal LPC levels, better ability of males' organisms to return to equilibrium LPC levels (which are higher in females), and increasing gaps between the optimum and equilibrium levels leading to increased mortality risks with age. Our results support LPC as a biomarker of aging and related decline in robustness/resilience, and call for further exploration of factors underlying age-dynamics of LPC in relation to mortality and diseases.PMID:39132492 | PMC:PMC11312646 | DOI:10.1101/2024.07.29.24311176

Front Behav Neurosci. 2024 Jul 25;18:1397284. doi: 10.3389/fnbeh.2024.1397284. eCollection 2024.ABSTRACTDietary phospholipids (PLs) are promising supplements that are commonly found as natural food ingredients and emulsifier additives. The present study aimed to evaluate the effect of major PLs found in food supplements on social behavior in mice. In this study, the effect of short-term high dietary PL content was studied in terms of social odor discrimination and social interactions with male and female intruders in male mice. We used odor discrimination and habituation tests to demonstrate that PL-fed male mice tend to lose preference toward female odor and fail to discriminate against socially significant scents. At the same time, test animals recognize non-social odors. We also found that PL affected the social behavior of the test males, who tend to behave indiscriminately toward male and female intruders during direct contact. Brain metabolomic profiling revealed no major changes in the intermediary metabolism or neurotransmitter biosynthesis. At the same time, intranasal PL application resembled the effects of dietary supplementation. These data suggest that certain PL might suppress pheromone perception in the olfactory system and affect the sense of socially important odor cues.PMID:39132447 | PMC:PMC11310928 | DOI:10.3389/fnbeh.2024.1397284

Front Microbiol. 2024 Jul 25;15:1279536. doi: 10.3389/fmicb.2024.1279536. eCollection 2024.ABSTRACTINTRODUCTION: Cistanche salsa (C.A.Mey.) G. Beck is a perennial holoparasitic herb recognized for its medicinal properties, particularly in kidney-tonifying and laxative treatments. Despite its therapeutic potential, little is known about the endophyte communities inhabiting C. salsa and its host plants, and how these microorganisms may impact the production and accumulation of metabolites in C. salsa.METHODS: We conducted a dual analysis focusing on metabolomics of wild C. salsa and microbiome characterization of both C. salsa and its host plant, Kalidium foliatum (Pall.) Moq. The metabolomics analysis revealed variations in metabolite composition across different parts of C. salsa. Additionally, the microbiome analysis involved studying endophytic bacteria and fungi, comparing their community structures between parasitic C. salsa and its host plant.RESULTS: Significant variations in metabolite composition were observed through metabolomic profiling, which identified 93 secondary metabolites and 398 primary metabolites across various parts of C. salsa. Emphasis was placed on differences in metabolite composition within the flowers. Microbiome analysis revealed differential community compositions of endophytic bacteria between the parasitic and host plants, whereas differences in endophytic fungi were less pronounced. Certain endophytes, such as Bacteroidota, Proteobacteria, Ascomycota, and Basidiomycota, were associated with the production of specific secondary metabolites in C. salsa, including the plant-specific compound salsaside.DISCUSSION: Our findings highlight the intricate relationship between C. salsa and its endophytic microbiota, suggesting a potential role of these microorganisms in modulating the biosynthesis of bioactive compounds. The differential preferences of endophytic bacteria and fungi across various microenvironments within the parasitic plant system underscore the complexity of these interactions. Further elucidation of these dynamics could enhance our understanding of C. salsa's medicinal properties and its ecological adaptations as a holoparasitic herb.PMID:39132140 | PMC:PMC11312099 | DOI:10.3389/fmicb.2024.1279536

Front Microbiol. 2024 Jul 26;15:1379064. doi: 10.3389/fmicb.2024.1379064. eCollection 2024.ABSTRACTBACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a type of liver metabolic syndrome. Employing multi-omics analyses encompassing the microbiome, metabolome and transcriptome is crucial for comprehensively elucidating the biological processes underlying NAFLD.METHODS: Hepatic tissue, blood and fecal samples were obtained from 9 NAFLD model mice and 8 normal control mice. Total fecal microbiota DNA was extracted, and 16S rRNA was amplified, to analyze alterations in the gut microbiota (GM) induced by NAFLD. Subsequently, diagnostic strains for NAFLD were screened, and their functional aspects were examined. Differential metabolites and differentially expressed genes were also screened, followed by enrichment analysis. Correlations between the differential microbiota and metabolites, as well as between the DEGs and differential metabolites were studied. A collinear network involving key genes-, microbiota-and metabolites was constructed.RESULTS: Ileibacterium and Ruminococcaceae, both belonging to Firmicutes; Olsenella, Duncaniella and Paramuribaculum from Bacteroidota; and Bifidobacterium, Coriobacteriaceae_UCG_002 and Olsenella from Actinobacteriota were identified as characteristic strains associated with NAFLD. Additionally, differentially expressed metabolites were predominantly enriched in tryptophan, linoleic acid and methylhistidine metabolism pathways. The functions of 2,510 differentially expressed genes were found to be associated with disease occurrence. Furthermore, a network comprising 8 key strains, 14 key genes and 83 key metabolites was constructed.CONCLUSION: Through this study, we conducted a comprehensive analysis of NAFLD alterations, exploring the gut microbiota, genes and metabolites of the results offer insights into the speculated biological mechanisms underlying NAFLD.PMID:39132138 | PMC:PMC11310135 | DOI:10.3389/fmicb.2024.1379064

Front Microbiol. 2024 Jul 26;15:1433716. doi: 10.3389/fmicb.2024.1433716. eCollection 2024.ABSTRACTPlant parasitic nematodes (PPNs) pose a significant threat to global crop productivity, causing an estimated annual loss of US $157 billion in the agriculture industry. While synthetic chemical nematicides can effectively control PPNs, their overuse has detrimental effects on human health and the environment. Biocontrol agents (BCAs), such as bacteria and fungi in the rhizosphere, are safe and promising alternatives for PPNs control. These BCAs interact with plant roots and produce extracellular enzymes, secondary metabolites, toxins, and volatile organic compounds (VOCs) to suppress nematodes. Plant root exudates also play a crucial role in attracting beneficial microbes toward infested roots. The complex interaction between plants and microbes in the rhizosphere against PPNs is mostly untapped which opens new avenues for discovering novel nematicides through multi-omics techniques. Advanced omics approaches, including metagenomics, transcriptomics, proteomics, and metabolomics, have led to the discovery of nematicidal compounds. This review summarizes the status of bacterial and fungal biocontrol strategies and their mechanisms for PPNs control. The importance of omics-based approaches for the exploration of novel nematicides and future directions in the biocontrol of PPNs are also addressed. The review highlighted the potential significance of multi-omics techniques in biocontrol of PPNs to ensure sustainable agriculture.PMID:39132133 | PMC:PMC11316259 | DOI:10.3389/fmicb.2024.1433716

Gastro Hep Adv. 2022 Jul 1;1(4):666-677. doi: 10.1016/j.gastha.2022.03.007. eCollection 2022.ABSTRACTBACKGROUND AND AIMS: Gastrointestinal (GI) dysmotility is a common and debilitating clinical manifestation in patients with mitochondrial DNA (mtDNA)-related disease with no curative and few effective symptomatic therapies. A low-residue diet (LRD) has been shown to be effective at reducing bowel urgency, pain, and distension in functional GI-related conditions. We assessed tolerability and effects of an LRD on bowel habits in patients with mtDNA-related disease.METHODS: This was a 12-week single-arm pilot study in patients with genetically determined primary mtDNA-related disease, meeting the ROME III constipation criteria. The co-primary outcomes were tolerability of an LRD (<10 g fiber per day) assessed by food diaries and changes in stool frequency and consistency. The secondary outcomes included GI symptoms, disease burden, laxatives, physical activity levels, colonic transit time using radiopaque markers, gut microbiome (patients and controls), and metabolomics. The gut microbiome of the mtDNA-related disease patients was compared against controls for observational purpose only.RESULTS: Twenty-eight patients were enrolled, and 24 completed the LRD intervention. The LRD was well tolerated with a mean fold change of -34% in dietary fiber (5.3 ± 10.4 grams) per day (P = .03, confidence interval = 0.7-9.9) with no adverse events. The proportion of stool samples with normal stool consistency increased from 36% to 49% (P = .01); GI symptoms and laxative use were reduced. However, the LRD did not change stool frequency, stool output, and colonic transit time. The gut microbiome was significantly different between patients and controls but was not modulated by the dietary intervention.CONCLUSION: The LRD in patients with mtDNA-related mitochondrial disease and significant constipation is well tolerated and a promising treatment for alleviating GI symptoms. These positive findings should be confirmed in a randomized controlled trial.ClinicalTrials.gov Identifier: NCT03388528.PMID:39132075 | PMC:PMC11307892 | DOI:10.1016/j.gastha.2022.03.007

Curr Res Food Sci. 2024 Jul 14;9:100805. doi: 10.1016/j.crfs.2024.100805. eCollection 2024.ABSTRACTAs a multi-factorial disease, obesity has become one of the major health problems in the world, and it is still increasing rapidly. Konjac supplementation, as a convenient dietary therapy, has been shown to be able to regulate gut microbiota and improve obesity. However, the specific mechanism by which konjac improves obesity through gut microbiota remains to be studied. In this study, a high-fat diet (HFD) was used to induce a mouse obesity model, and 16S rDNA sequencing and an untargeted metabolomics were used to investigate the impact of konjac on gut microbiota and gut metabolites in HFD-induced obese mice. The results show that konjac can reduce the body weight, adipose tissue weight, and lipid level of high-fat diet induced obese mice by changing the gut microbiota structure and gut metabolic profile. Association analysis revealed that konjac supplementation induced changes in gut microbiota, resulting in the up-regulation of 7-dehydrocholesterol and trehalose 6-phosphate, as well as the down-regulation of glycocholic acid and ursocholic acid within the Secondary bile acid biosynthesis pathway, ultimately leading to improvements in obesity. Among them, g_Acinetobacter (Greengene ID: 911888) can promote the synthesis of 7-dehydrocholesterol by synthesizing ERG3. g_Allobaculum (Greengene ID: 271516) and g_Allobaculum (Greengene ID: 259370) can promote the breakdown of trehalose 6-phosphate by synthesizing glvA. Additionally, the down-regulation of glycocholic acid and ursocholic acid may be influenced by the up-regulation of Lachnospiraceae_NK4A136_group. In conclusion, konjac exerts an influence on gut metabolites through the regulation of gut microbiota, thereby playing a pivotal role in alleviating obesity induced by a high-fat diet.PMID:39131951 | PMC:PMC11315163 | DOI:10.1016/j.crfs.2024.100805

J Pharm Anal. 2024 Jul;14(7):100944. doi: 10.1016/j.jpha.2024.01.012. Epub 2024 Feb 3.ABSTRACTEvaluating toxicity and decoding the underlying mechanisms of active compounds are crucial for drug development. In this study, we present an innovative, integrated approach that combines air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI), time-of-flight secondary ion mass spectrometry (ToF-SIMS), and spatial metabolomics to comprehensively investigate the nephrotoxicity and underlying mechanisms of nitidine chloride (NC), a promising anti-tumor drug candidate. Our quantitive AFADESI-MSI analysis unveiled the region specific of accumulation of NC in the kidney, particularly within the inner cortex (IC) region, following single and repeated dose of NC. High spatial resolution ToF-SIMS analysis further allowed us to precisely map the localization of NC within the renal tubule. Employing spatial metabolomics based on AFADESI-MSI, we identified over 70 discriminating endogenous metabolites associated with chronic NC exposure. These findings suggest the renal tubule as the primary target of NC toxicity and implicate renal transporters (organic cation transporters, multidrug and toxin extrusion, and organic cation transporter 2 (OCT2)), metabolic enzymes (protein arginine N-methyltransferase (PRMT) and nitric oxide synthase), mitochondria, oxidative stress, and inflammation in NC-induced nephrotoxicity. This study offers novel insights into NC-induced renal damage, representing a crucial step towards devising strategies to mitigate renal damage caused by this compound.PMID:39131801 | PMC:PMC11314895 | DOI:10.1016/j.jpha.2024.01.012

Gastro Hep Adv. 2022 Mar 30;1(3):359-374. doi: 10.1016/j.gastha.2021.12.008. eCollection 2022.ABSTRACTBACKGROUND AND AIMS: There is clinical interest in the sustainability or otherwise of prebiotic, microbial, and antibiotic treatments to both prevent and treat inflammatory bowel diseases. This study examined the role of antibiotic manipulation of the gut microbiome to treat spontaneous and induced murine models of colitis.METHODS: Symptomatic, histological, molecular, and microbial ecology and bioinformatic readouts were used to study the effect of a 10-day antibiotic cocktail and then follow-up over 2 months in the spontaneous Winnie colitis mouse preclinical model of ulcerative colitis and also the indirect antibiotic and Winnie microbiotic gavage effects in an acute dextran sodium sulfate-induced colitis model in wild-type mice.RESULTS: The antibiotics elicited a striking reduction in both colitis symptoms and blinded histological colitis scores, together with a convergence of the microbial taxonomy of the spontaneous colitis and wild-type control mice, toward a taxonomic phenotype usually considered to be dysbiotic. The improvement in colitis was sustained over the following 8 weeks although the microbial taxonomy changed. In vitro, fecal waters from the antibiotic-treated colitis and wild-type mice suppressed the inflammatory tenor of colonic epithelial cells, and gavaged cecal slurries from these mice moderated the acute induced colitis.CONCLUSION: The results clearly show the possibility of a sustained remission of colitis by microbial manipulation, which is relevant to clinical management of inflammatory bowel diseases. The beneficial effects appeared to depend on the microbial metabolome rather than its taxonomy.PMID:39131681 | PMC:PMC11307790 | DOI:10.1016/j.gastha.2021.12.008

bioRxiv [Preprint]. 2024 Jul 29:2024.07.29.605643. doi: 10.1101/2024.07.29.605643.ABSTRACTDisruptions in microbial metabolite interactions due to gut microbiome dysbiosis and metabolomic shifts may contribute to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and other immune-related conditions. The aryl hydrocarbon receptor (AhR), activated upon binding various tryptophan metabolites, modulates host immune responses. This study investigates whether the metabolic diversity-the concentration distribution-of bacterial indole pathway metabolites can differentiate bacterial strains and classify ME/CFS samples. A fast targeted liquid chromatography-parallel reaction monitoring method at a rate of 4 minutes per sample was developed for large-scale analysis. This method revealed significant metabolic differences in indole derivatives among B. uniformis strains cultured from human isolates. Principal component analysis identified two major components (PC1, 68.9%; PC2, 18.7%), accounting for 87.6% of the variance and distinguishing two distinct B. uniformis clusters. The metabolic difference between clusters was particularly evident in the relative contributions of indole-3-acrylate and indole-3-aldehyde. We further measured concentration distributions of indole derivatives in ME/CFS by analyzing fecal samples from 10 patients and 10 healthy controls using the fast targeted metabolomics method. An AdaBoost-LOOCV model achieved moderate classification success with a mean LOOCV accuracy of 0.65 (Control: precision of 0.67, recall of 0.60, F1-score of 0.63; ME/CFS: precision of 0.64, recall of 0.7000, F1-score of 0.67). These results suggest that the metabolic diversity of indole derivatives from tryptophan degradation, facilitated by the fast targeted metabolomics and machine learning, is a potential biomarker for differentiating bacterial strains and classifying ME/CFS samples. Mass spectrometry datasets are accessible at the National Metabolomics Data Repository (ST002308, DOI: 10.21228/M8G13Q; ST003344, DOI: 10.21228/M8RJ9N; ST003346, DOI: 10.21228/M8RJ9N).PMID:39131327 | PMC:PMC11312560 | DOI:10.1101/2024.07.29.605643