Tuesday, 9 February 2016

See a man about a horse

Gebregiworgis et al. A Urinary Metabolic Signature for Multiple Sclerosis and Neuromyelitis Optica. J Proteome Res. 2016 Feb 5;15(2):659-666. Epub 2016 Jan 27.

Abstract: Urine is a metabolite-rich biofluid that reflects the body's effort to maintain chemical and osmotic homeostasis. Clinical diagnosis routinely relies on urine samples because the collection process is easy and noninvasive. Despite these advantages, urine is an under-investigated source of biomarkers for multiple sclerosis (MS). Nuclear magnetic resonance spectroscopy (NMR) has become a common approach for analyzing urinary metabolites for disease diagnosis and biomarker discovery. For illustration of the potential of urinary metabolites for diagnosing and treating MS patients, and for differentiating between MS and other illnesses, 38 urine samples were collected from healthy controls, MS patients, and neuromyelitis optica-spectrum disorder (NMO-SD) patients and analyzed with NMR, multivariate statistics, one-way ANOVA, and univariate statistics. Urine from MS patients exhibited a statistically distinct metabolic signature from healthy and NMO-SD controls. A total of 27 metabolites were differentially altered in the urine from MS and NMO-SD patients and were associated with synthesis and degradation of ketone bodies, amino acids, propionate and pyruvate metabolism, tricarboxylic acid cycle, and glycolysis. Metabolites altered in urine from MS patients were shown to be related to known pathogenic processes relevant to MS, including alterations in energy and fatty acid metabolism, mitochondrial activity, and the gut microbiota.



Figure: Urine is a metabolite-rich biofluid that reflects the body’s effort to maintain chemical and osmotic homeostasis. Nuclear magnetic resonance spectroscopy (NMR) has become a common approach for analyzing urinary metabolites for disease diagnosis and biomarker discovery.

It's a passing joke in the group about Prof G's propensity to add urine to the list of things collected in clinical trials, stemming from his Phd where urine featured heavily. But there may now be a role for urine studies, in fact I can attest to our group having the largest collection known to man. I remember distinctly when a batch of them had broken in a chest freezer and everyone knows that as the student you're on toilet-cleaning duty! Let's just say you have to first defrost the freezer...

But what does the simple urine have to offer? In reality urine is a complex mixture and contains many metabolites; which are small (<1500 Da) end products of enzymatic reactions or protein activity that vary based on genetics, environmental stress, toxins or drugs. Thus, a disease which causes an alteration in the way the body functions is expected to have a unique metabolic profile or fingerprint. NMR metabolomics is the investigation of urine metabolites using NMR technique which allows the simultaneous detection of a number of metabolites in a complex mixture such as urine without the need for first separating them.

In this study, the authors observed alterations in the pathways involved in energy generation, specifically glycolysis and in the synthesis and degradation of ketone bodies. The brain has high energy requirements using 25% of total glucose, but also uses ketone bodies as an alternative source of energy. Thus, what we may be observing is an alteration in energy generation in MS. This feeds well into the idea that MS is linked to mitochondrial defects, which would be expected to alter energy generation. The authors also found alterations in the creatine/phosphocreatine/creatine kinase system, which is critical for maintaining energy levels in the brain, and in propionate (short chain fatty acid) metabolism, meaning that there may be some lipid dysfunction in MS. Last but not least, they report changes in hippurate, a microbial cometabolite. Propionate is also a metabolite of the gut microbiota. So we are not alone - or are we?

10 comments:

  1. Dear NDG,

    A stream of wisdom :)

    How many samples are there? Would it be possible to pump the data into a machine learning algo to see if that might spot a pattern?

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    1. The sample size in the study was small; n=8 MS, n=9 NMO, n=7 healthy controls. We've done this type of work many years back and you can get good differentiation between types of MS as well - unfortunately the work was not perused as our bright NMR physicist moved on!

      The analysis does comprise of modelling, the one used in this study is as follows: "An SUS plot was generated from the OPLS-DA models using MVAPACK to compare the MS and NMO-SD group against healthy controls. The plot visualizes the correlation between predictive components of each model and was used to identify metabolite changes unique to either the MS or the NMO-SD group."

      Clearly more research needs to be funded in this area.

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    2. Why do you need a bright physicist to run the NMR? Talk to your chemistry collaborators, they can likely do any NMR you want - provided you can convince them to work with urine samples

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  2. NDG consumption of creatine then it would be higher and consequently more excreted?
    I take creatine because practice moderate physical activity/intense and whenever I take my fatigue goes away...

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    1. In the study they found an increase in creatine and a decrease in creatinine. Generally bulk of creatine is in muscle existing as or as a phosphorylated form (phosphocreatine), the latter maintains adenosine triphosphate/diphosphate ratio and is important for short intense activities. Therefore, the ingestion of creatine may boost physical performance and this may have beneficial effects on fatigue (although this needs to be tested!).

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  3. Question - what is the change in fatty acid metabolism which occurs in people with MS?
    (please answer in simple layman's language if possible...........)

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    1. Previous research has shown an increase in the breakdown products of lipids/fatty acids in MS patients which can lead to stress injury in cells. Propionate, which I mention above is broken down from lipids and when it accumulates in can block the Kreb's cycle (this is the initial system whereby energy starts to generated in individual cells) and can also block cell growth.

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  4. Hi! In laymans terms would this not be capable of detection of MS activity or is it simply too vague a mechanism (that is if it were pursued to a logical end)?

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    1. Yes, it should be able to divide those having relapses and those having no relapses. But it's usefulness for an individual person still needs to be tested, rather than looking at a group of individuals.

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