scholarly journals Multi-omic Evaluation of Metabolic Alterations in Multiple Sclerosis Identifies Shifts in Aromatic Amino Acid Metabolism

2021 ◽  
Author(s):  
Kathryn C. Fitzgerald ◽  
Matthew D. Smith ◽  
Elias S. Sotirchos ◽  
Michael D. Kornberg ◽  
Morgan Douglas ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Amino Acid ◽  
Metabolic Pathways ◽  
Aromatic Amino Acid ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
P Value ◽  
Healthy Controls ◽  
Metabolic Dysfunction ◽  
Metabolic Alterations

ABSTRACTThe circulating metabolome is a product of interactions between the genome, epigenome, exposome and microbiome. The metabolome may be altered in people with multiple sclerosis (MS); however, existing metabolomics studies were relatively small or characterized a limited number of metabolites. Herein, we performed a multi-site study profiling the circulating metabolome to obtain relative abundances for 269 metabolites in a large cohort of MS patients and healthy controls. After adjusting for batch effects and extensive quality control, we created an overall metabolic dysfunction score, defined apriori sets of metabolites using known metabolic pathways, and derived novel networks of correlated metabolites using a weighted correlation network analysis (WGCNA). We assessed whether metabolic dysfunction, individual metabolites, metabolic pathways or WGCNA-identified module scores differed between people with MS versus healthy controls (HC) after adjusting for age, sex and race using generalized estimating equations (participants could provide multiple samples). In a subset of patients, information on disability status was also available. Similar models assessed the association between metabolites and metabolite sets with measures of disability. In people with MS, we identified striking abnormalities in a WGCNA-defined module enriched in aromatic amino acid (AAA) metabolites (FDR-adjusted p-value=2.77E-18) that are also strongly associated with disability (FDR-adjusted p-value for AAA module=1.01E-4). Consistent results were obtained using apriori-defined metabolite sets or in analyses of individual metabolites. The identified abnormalities likely relate to imbalances in gut microbial metabolism of AAAs resulting in reduced production of immunomodulatory metabolites and increased production of metabotoxins (indole acetate, phenylacetylglutamine, p-cresol sulfate, p-cresol glucuronide). Single cell RNA sequencing data analysis demonstrated altered AAA metabolism in CSF and blood derived monocyte cell populations, while treatment of human peripheral blood mononuclear cells with AAA-derived metabotoxins resulted in increased production of tumor necrosis factor-α. We identify novel metabolic alterations in people with MS potentially contributing to disease pathophysiology.

scholarly journals Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models

2017 ◽  
Vol 114 (40) ◽  
pp. 10713-10718 ◽  
Author(s):  
Egle Cekanaviciute ◽  
Bryan B. Yoo ◽  
Tessel F. Runia ◽  
Justine W. Debelius ◽  
Sneha Singh ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Gut Bacteria ◽  
The Body ◽  
Healthy Controls ◽  
Peripheral Blood Mononuclear ◽  
Cell Functions ◽  
Multiple Sclerosis Patients

The gut microbiota regulates T cell functions throughout the body. We hypothesized that intestinal bacteria impact the pathogenesis of multiple sclerosis (MS), an autoimmune disorder of the CNS and thus analyzed the microbiomes of 71 MS patients not undergoing treatment and 71 healthy controls. Although no major shifts in microbial community structure were found, we identified specific bacterial taxa that were significantly associated with MS. Akkermansia muciniphila and Acinetobacter calcoaceticus, both increased in MS patients, induced proinflammatory responses in human peripheral blood mononuclear cells and in monocolonized mice. In contrast, Parabacteroides distasonis, which was reduced in MS patients, stimulated antiinflammatory IL-10–expressing human CD4+CD25+ T cells and IL-10+FoxP3+ Tregs in mice. Finally, microbiota transplants from MS patients into germ-free mice resulted in more severe symptoms of experimental autoimmune encephalomyelitis and reduced proportions of IL-10+ Tregs compared with mice “humanized” with microbiota from healthy controls. This study identifies specific human gut bacteria that regulate adaptive autoimmune responses, suggesting therapeutic targeting of the microbiota as a treatment for MS.

scholarly journals Multi-omic evaluation of metabolic alterations in multiple sclerosis identifies shifts in aromatic amino acid metabolism

2021 ◽  
Vol 2 (10) ◽  
pp. 100424
Author(s):  
Kathryn C. Fitzgerald ◽  
Matthew D. Smith ◽  
Sol Kim ◽  
Elias S. Sotirchos ◽  
Michael D. Kornberg ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Amino Acid ◽  
Aromatic Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Metabolic Alterations ◽  
Aromatic Amino Acid Metabolism

scholarly journals COVID-19 Severity Potentially Modulated by Cardiovascular-Disease-Associated Immune Dysregulation

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1018
Author(s):  
Abby C. Lee ◽  
Grant Castaneda ◽  
Wei Tse Li ◽  
Chengyu Chen ◽  
Neil Shende ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Expression Profiles ◽  
Immune Dysregulation ◽  
Left Ventricular ◽  
Recurrent Event ◽  
Healthy Controls ◽  
Sequencing Data ◽  
Peripheral Blood Mononuclear

Patients with underlying cardiovascular conditions are particularly vulnerable to severe COVID-19. In this project, we aimed to characterize similarities in dysregulated immune pathways between COVID-19 patients and patients with cardiomyopathy, venous thromboembolism (VTE), or coronary artery disease (CAD). We hypothesized that these similarly dysregulated pathways may be critical to how cardiovascular diseases (CVDs) exacerbate COVID-19. To evaluate immune dysregulation in different diseases, we used four separate datasets, including RNA-sequencing data from human left ventricular cardiac muscle samples of patients with dilated or ischemic cardiomyopathy and healthy controls; RNA-sequencing data of whole blood samples from patients with single or recurrent event VTE and healthy controls; RNA-sequencing data of human peripheral blood mononuclear cells (PBMCs) from patients with and without obstructive CAD; and RNA-sequencing data of platelets from COVID-19 subjects and healthy controls. We found similar immune dysregulation profiles between patients with CVDs and COVID-19 patients. Interestingly, cardiomyopathy patients display the most similar immune landscape to COVID-19 patients. Additionally, COVID-19 patients experience greater upregulation of cytokine- and inflammasome-related genes than patients with CVDs. In all, patients with CVDs have a significant overlap of cytokine- and inflammasome-related gene expression profiles with that of COVID-19 patients, possibly explaining their greater vulnerability to severe COVID-19.

scholarly journals P003 Metabolomics for improved patient stratification in inflammatory bowel disease: Characterisation of the ulcerative colitis metabolome

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S130-S131
Author(s):  
J Diab ◽  
T Hansen ◽  
R Goll ◽  
H Stenlund ◽  
E Jensen ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Ulcerative Colitis ◽  
Amino Acid ◽  
Metabolic Pathways ◽  
Personalised Medicine ◽  
Healthy Controls ◽  
Patient Stratification ◽  
Metabolomic Profile ◽  
Metabolic Signature ◽  
Treatment Naïve

Abstract Background The onset of ulcerative colitis (UC) is characterised by a dysregulated mucosal immune response triggered by several genetic and environmental factors in the context of host-microbe interaction. This complexity makes UC ideal for metabolomic studies to unravel the disease pathobiology and to improve the patient stratification strategies toward personalised medicine. This study aims to explore the mucosal metabolomic profile in treatment-naïve and deep remission UC patients, and to define the metabolic signature of UC. Methods Treatment-naive UC patients (n = 18), UC patients in deep remission (n = 10), and healthy volunteers (n = 14) were recruited. Mucosa biopsies were collected during colonoscopy. The UC activity and the state of deep remission were assessed by endoscopy, histology, and by measuring TNF gene expression. Metabolomic analysis was performed by combined gas chromatography coupled to time-of-flight mass spectrometry (GC-TOF-MS) and ultra-high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS). In total, 177 metabolites from 50 metabolic pathways were identified. Results Multivariate data analysis revealed a distinct metabolomic profile in inflamed mucosa taken from treatment- naïve UC patients compared with non-inflamed mucosa taken from UC remission patients and healthy controls. The mucosal metabolome in UC remission patients differed to a lesser extent from the healthy controls. The most prominent metabolome changes among the study groups were in lysophosphatidylcholine, acylcarnitine, and amino acid profiles. Several metabolic pathways were perturbed, ranging from amino acid metabolism (such as tryptophan metabolism, and alanine, aspartate and glutamate metabolism) to antioxidant defence pathway (glutathione pathway). Furthermore, the pathway analysis revealed a disruption in the long-and short-chain fatty acid (LCFA and SCFA) metabolism, namely linoleic metabolism and butyrate metabolism. Conclusion The mucosal metabolomic profiling revealed a metabolic signature during the onset of UC, and reflected the homeostatic disturbance in the gut. The altered metabolic pathways highlight the importance of system biology approaches to identify key drivers of IBD pathogenesis which prerequisite personalised treatment.

scholarly journals Changes in Amino Acid and Acylcarnitine Plasma Profiles for Distinguishing Patients with Multiple Sclerosis from Healthy Controls

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Marat F. Kasakin ◽  
Artem D. Rogachev ◽  
Elena V. Predtechenskaya ◽  
Vladimir J. Zaigraev ◽  
Vladimir V. Koval ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Amino Acid ◽  
Discriminant Analysis ◽  
Clinical Decision ◽  
Partial Least Square ◽  
Least Square ◽  
Control Group ◽  
Healthy Controls ◽  
Linear Discriminant ◽  
Tandem Mass Spectrometric

McDonald criteria and magnetic resonance imaging (MRI) are used for the diagnosis of multiple sclerosis (MS); nevertheless, it takes a considerable amount of time to make a clinical decision. Amino acid and fatty acid metabolic pathways are disturbed in MS, and this information could be useful for diagnosis. The aim of our study was to find changes in amino acid and acylcarnitine plasma profiles for distinguishing patients with multiple sclerosis from healthy controls. We have applied a targeted metabolomics approach based on tandem mass-spectrometric analysis of amino acids and acylcarnitines in dried plasma spots followed by multivariate statistical analysis for discovery of differences between MS (n=16) and control (n=12) groups. It was found that partial least square discriminant analysis yielded better group classification as compared to principal component linear discriminant analysis and the random forest algorithm. All the three models detected noticeable changes in the amino acid and acylcarnitine profiles in the MS group relative to the control group. Our results hold promise for further development of the clinical decision support system.

Cytokine analysis in multiple sclerosis by competitive RT - PCR: A decreased expression of IL-10 and an increased expression of TNF-α in chronic progression

1999 ◽  
Vol 5 (5) ◽  
pp. 342-348 ◽  
Author(s):  
Wen-Xin Huang ◽  
Ping Huang ◽  
Hans Link ◽  
Jan Hillert
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Mononuclear Cells ◽  
Interleukin 4 ◽  
Cytokine Gene Expression ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Cytokine Analysis ◽  
Autoimmune Attack

Multiple sclerosis (MS) is an inflammatory, demyelinating disease that is specific to the central nervous system. Cytokines are thought to be key mediators of the autoimmune attack against central nervous system myelin in MS. To investigate the involvement of cytokines in MS, the mRNA levels of interferon gamma (IFN-g), tumor necrosis factor alpha (TNF-a), interleukin-4 (IL-4) and interleukin-10 (IL-10) in peripheral blood mononuclear cells without stimulation in vitro were quantified by a competitive reverse transcription polymerase chain reaction technique. The level of IL-10 specific mRNA was significantly decreased in 47 MS patients compared with 42 healthy controls (P50.0001). TNF-a was significantly increased in MS patients compared with healthy controls (P=0.014), especially in the patients with chronic progressive MS (P=0.0003). Thus we conclude that there are significant in vivo alterations in cytokine gene expression in the periphery in MS.

Systemic upregulation of CD40 and CD40 ligand mRNA expression in multiple sclerosis

2000 ◽  
Vol 6 (2) ◽  
pp. 61-65 ◽  
Author(s):  
Wen-Xin Huang ◽  
Ping Huang ◽  
Jan Hillert
Keyword(s):  
Multiple Sclerosis ◽  
Mononuclear Cells ◽  
Cd40 Ligand ◽  
Autoimmune Response ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Peripheral Blood Mononuclear ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Organ Specific

It is increasingly clear that the CD40 and CD40 ligand (CD40L) receptor-ligand pair mediates a crucial activation signal in both cell-mediated and humoral immune responses. Here, we detected mRNA levels of CD40 and CD40L in non-stimulated peripheral blood mononuclear cells in 46 patients with multiple sclerosis (MS) and 46 healthy controls by a competitive RT-PCR procedure allowing quantification without previous culture or antigenic stimulation. The levels of CD40 and CD40L mRNA were markedly increased in MS patients (P <0.0001) compared with healthy controls. There was no difference between clinical MS subgroups or stage of disease. Our findings indicate that, although MS is an organ specific disorder an increased signaling via the CD40 and CD40L pathway may be present at the systemic level. The nature of this upregulation, whether primary or secondary to the organ-specific autoimmune response, is yet to be determined. Since interference with CD40/CD40L is an effective way to interfere with autoimmune model diseases such as experimental autoimmune encephalomyelitis, it may be relevant to investigate further the role of these molecules in the pathogenesis of MS.

scholarly journals Decoding the Complex Crossroad of Tryptophan Metabolic Pathways

2022 ◽  
Vol 23 (2) ◽  
pp. 787
Author(s):  
Giada Mondanelli ◽  
Claudia Volpi ◽  
Ciriana Orabona
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Metabolic Pathways ◽  
Aromatic Amino Acid ◽  
Living Cells ◽  
Cellular Homeostasis

Among the 20 amino acids needed for protein synthesis, Tryptophan (Trp) is an aromatic amino acid fundamental not only for the synthesis of the major components of living cells (namely, the proteins), but also for the maintenance of cellular homeostasis [...]

scholarly journals Structural and functional connectomes in people with multiple sclerosis

2020 ◽  
Author(s):  
Ceren Tozlu ◽  
Keith Jamison ◽  
Susan Gauthier ◽  
Amy Kuceyeski
Keyword(s):  
Multiple Sclerosis ◽  
Functional Mri ◽  
Imaging Modality ◽  
Structural Connectivity ◽  
Receiver Operating Curve ◽  
Ensemble Prediction ◽  
P Value ◽  
Lesion Volume ◽  
Healthy Controls ◽  
Functional Connectome

One of the challenges in multiple sclerosis is that lesion volume does not correlate with symptom severity. Advanced techniques such as diffusion and functional MRI allow imaging of the brain's connectivity networks, which may provide better insight as to brain-behavior relationships in impairment and compensation in multiple sclerosis. We aim to build machine learning models based on structural and functional connectomes to classify a) healthy controls versus people with multiple sclerosis and b) impaired versus not impaired people with multiple sclerosis. We also aim to identify the most important imaging modality for both classification tasks, and, finally, to investigate which brain regions' connectome measures contribute most to the classification. Fifteen healthy controls (age=43.6 ± 8.6, 53% female) and 76 people with multiple sclerosis (age: 45.2 ± 11.4 years, 65% female, disease duration: 12.2 ± 7.2 years) were included. Twenty-three people with multiple sclerosis were considered impaired, with an Expanded Disability Status Scale of 2 or higher. Subjects underwent MRI scans that included anatomical, diffusion and resting-state functional MRI. Random Forest models were constructed using structural and static/dynamic functional connectome measures independently; single modality models were then combined for an ensemble prediction. The accuracy of the models was assessed by the area under the receiver operating curve. Models that included structural connectomes significantly outperformed others when classifying healthy controls and people with multiple sclerosis, having a median accuracy of 0.86 (p-value<0.05, corrected). Models that included dynamic functional connectome metrics significantly outperformed others when distinguishing people with multiple sclerosis by impairment level, having a median accuracy of 0.63 (p-value<0.05, corrected). Structural connectivity between subcortical, somatomotor, and visual networks was most damaged by multiple sclerosis. For the classification of patients with multiple sclerosis into impairment severity groups, the most discriminatory metric was dwell time in a dynamic functional connectome state characterized by strong connectivity between and among somatomotor and visual networks. These results suggest that damage to the structural connectome, particularly in the subcortical, visual, and somatomotor networks, is a hallmark of multiple sclerosis, and, furthermore, that increased functional coordination between these same regions may be related to severity of motor disability in multiple sclerosis. The use of multi-modal connectome imaging has the potential to shed light on mechanisms of disease and compensation in multiple sclerosis, thus enabling more accurate prognoses and possibly the development of novel therapeutics.

scholarly journals Biochemical and Immunological Characterization of MP65, a Major Mannoprotein Antigen of the Opportunistic Human PathogenCandida albicans

2000 ◽  
Vol 68 (2) ◽  
pp. 694-701 ◽  
Author(s):  
Maria J. Gomez ◽  
Bruno Maras ◽  
Alessandra Barca ◽  
Roberto La Valle ◽  
Donatella Barra ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Synthetic Peptides ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Amino Acid Sequences ◽  
Antigenic Determinants ◽  
Cell Mediated Immunity ◽  
Antigenic Peptides

ABSTRACT In the search of the antigenic determinants of a 65-kDa mannoprotein (MP65) of Candida albicans, tryptic fragments of immunoaffinity-purified MP65 preparations were tested for their ability to induce lymphoproliferation of human peripheral blood mononuclear cells (PBMC). Five major peptides (T1 to T5) were shown to induce a vigorous proliferation of PBMC from the majority of the eight healthy human subjects tested. With the use of synthetic peptides, critical amino acid sequences of the two most immunoactive (T1 and T2) peptides were determined. Similar to what was found for the MP65 molecule, no PBMC multiplication was induced by the antigenic peptides in cultures of naive cord blood cells. The amino acid sequence analysis of tryptic and chymotryptic peptides of MP65 demonstrated a substantial homology with the deduced sequences of two cell wall proteins ofSaccharomyces cerevisiae, encoded by the genesYRM305C and YGR279C. However, the antigenic peptides were those showing the least similarity with the corresponding regions of the above proteins. In particular, the lymphoproliferation-inducing sequence of the T1 peptide scored only 20% identity with the homologous regions of S. cerevisiaeproteins. Besides disclosing the amino acid sequence of MP65, this study provides an initial characterization of some of its antigenic determinants, as well as of synthetic peptides of potential use to detect specific immune responses against MP65, a major target of anticandidal cell-mediated immunity in humans.

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