Understanding brain energy metabolism—neuroenergetics—is becoming increasingly important as it can be identified repeatedly as the source of neurological perturbations. Within the scientific community we are seeing a shift in paradigms from the traditional neurocentric view to that of a more dynamic, integrated one where astrocytes are no longer considered as being just supportive, and activated microglia have a profound influence. Lactate is emerging as the “good guy,” contrasting its classical “bad guy” position in the now superseded medical literature. This review begins with the evolution of the concept of “lactate shuttles”; goes on to the recent shift in ideas regarding normal neuroenergetics (homeostasis)—specifically, the astrocyte–neuron lactate shuttle; and progresses to covering the metabolic implications whereby homeostasis is lost—a state of allostasis, and the function of microglia. The role of lactate, as a substrate and shuttle, is reviewed in light of allostatic stress, and beyond—in an acute state of allostatic stress in terms of physical brain trauma, and reflected upon with respect to persistent stress as allostatic overload—neurodegenerative diseases. Finally, the recently proposed astrocyte–microglia lactate shuttle is discussed in terms of chronic neuroinflammatory infectious diseases, using tuberculous meningitis as an example. The novelty extended by this review is that the directionality of lactate, as shuttles in the brain, in neuropathophysiological states is emerging as crucial in neuroenergetics.

BackgroundFibromyalgia syndrome (FMS) is a chronic pain syndrome. A plausible pathogenesis of the disease is uncertain and the pursuit of measurable biomarkers for objective identification of affected individuals is a continuing endeavour in FMS research. Our objective was to perform an explorative metabolomics study (1) to elucidate the global urinary metabolite profile of patients suffering from FMS, and (2) to explore the potential of this metabolite information to augment existing medical practice in diagnosing the disease.MethodsWe selected patients with a medical history of persistent FMS (n = 18), who described their recent state of the disease through the Fibromyalgia Impact Questionnaire (FIQR) and an in-house clinical questionnaire (IHCQ). Three control groups were used: first-generation family members of the patients (n = 11), age-related individuals without any indications of FMS or related conditions (n = 10), and healthy young (18–22 years) individuals (n = 20). All subjects were female and the biofluid under investigation was urine. Correlation analysis of the FIQR showed the FMS patients represented a well-defined disease group for this metabolomics study. Spectral analyses of urine were conducted using a 500 MHz 1H nuclear magnetic resonance (NMR) spectrometer; data processing and analyses were performed using Matlab, R, SPSS and SAS software.Results and discussionUnsupervised and supervised multivariate analyses distinguished all three control groups and the FMS patients, and significant increases in metabolites related to the gut microbiome (hippuric, succinic and lactic acids) were observed. We have developed an algorithm for the diagnosis of FMS consisting of three metabolites — succinic acid, taurine and creatine — that have a good level of diagnostic accuracy (Receiver Operating Characteristic (ROC) analysis — area under the curve 90%) and on the pain and fatigue symptoms for the selected FMS patient group.ConclusionOur data and comparative analyses indicated an altered metabolic profile of patients with FMS, analytically detectable within their urine. Validation studies may substantiate urinary metabolites to supplement information from medical assessment, tender-point measurements and FIQR questionnaires for an improved objective diagnosis of FMS.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-017-0863-9) contains supplementary material, which is available to authorized users.

Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-methylglutaconic aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-methylglutaconic aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven,

Tuberculosis meningitis (TBM) is the most severe form of extra-pulmonary tuberculosis and is particularly intense in small children; there is no universally accepted algorithm for the diagnosis and substantiation of TB infection, which can lead to delayed intervention, a high risk factor for morbidity and mortality. In this study a proton magnetic resonance (1H NMR)-based metabolomics analysis and several chemometric methods were applied to data generated from lumber cerebrospinal fluid (CSF) samples from three experimental groups: (1) South African infants and children with confirmed TBM, (2) non-meningitis South African infants and children as controls, and (3) neurological controls from the Netherlands. A total of 16 NMR-derived CSF metabolites were identified, which clearly differentiated between the controls and TBM cases under investigation. The defining metabolites were the combination of perturbed glucose and highly elevated lactate, common to some other neurological disorders. The remaining 14 metabolites of the host’s response to TBM were likewise mainly energy-associated indicators. We subsequently generated a hypothesis expressed as an “astrocyte–microglia lactate shuttle” (AMLS) based on the host’s response, which emerged from the NMR-metabolomics information. Activation of microglia, as implied by the AMLS hypothesis, does not, however, present a uniform process and involves intricate interactions and feedback loops between the microglia, astrocytes and neurons that hamper attempts to construct basic and linear cascades of cause and effect; TBM involves a complex integration of the responses from the various cell types present within the CNS, with microglia and the astrocytes as main players.Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-014-0741-z) contains supplementary material, which is available to authorized users.

Metabolomic analysis of the urinary organic acids from 39 selected children with defined respiratory chain deficiencies (RCDs) was performed using untargeted gas chromatography-mass spectrometry, revealing the presence of 255 endogenous and 46 exogenous substances. Variable reduction identified 92 variables from the endogenous substances, which could be analysed by univariate and multivariate statistical methods. Using these methods, no characteristic organic acid biomarker profile could be defined of practical value for diagnostic purposes for complex I (CI), complex III (CIII) and multiple complex (CM) deficiencies. The statistical procedures used did, however, disclose 24 metabolites that were practical highly (d > 0.75) and statistically (p < 0.05) significant for the combined and clinically closely related group of RCDs. Several of these metabolites occur in single enzyme inherited metabolic diseases, but most were not previously reported to be linked to the metabolic perturbations that are due to RCDs. Ultimately, we constructed a global metabolic profile of carbohydrate, amino acid and fatty acid catabolism, illuminating the diverse and complex biochemical consequences of these disorders. This metabolomics investigation disclosed a metabolite profile that has the potential to define an 1 extended and characteristic biosignature for RCDs and the development of a non-invasive screening procedure for these disorders.