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 Lactate is emerging as the ‘good guy’, contrasting its classical ‘bad guy’ position in the now superseded medical literature.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 — to a state of allostatic overload (neuropathology), in terms of physical brain trauma, and reflected upon with respect to 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.

Fibromyalgia 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. We 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. Unsupervised 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. Our 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.

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.

Mycobacterium tuberculosisinfection, which claims hundreds of thousands of lives each year, is typically characterized by the formation of tuberculous granulomas — the histopathological hallmark of tuberculosis (TB). Our knowledge of granulomas, which comprise a biologically diverse body of pro- and anti-inflammatory cells from the host immune responses, is based mainly upon examination of lungs, in both human and animal studies, but little on their counterparts from other organs of the TB patient such as the brain. The biological heterogeneity of TB granulomas has led to their diverse, relatively uncoordinated, categorization, which is summarized here. However, there is a pressing need to elucidate more fully the phenotype of the granulomas from infected patients. Newly emerging studies at the protein (proteomics) and metabolite (metabolomics) levels have the potential to achieve this. In this review we summarize the diverse nature of TB granulomas based upon the literature, and amplify these accounts by reporting on the relatively few, emerging proteomics and metabolomics studies on TB granulomas. Metabolites (for example, trimethylamine-oxide) and proteins (such as the peptide PKAp) associated with TB granulomas, and knowledge of their localizations, help us to understand the resultant phenotype. Nevertheless, more multidisciplinary ‘omics studies, especially in human subjects, are required to contribute toward ushering in a new era of understanding of TB granulomas – both at the site of infection, and on a systemic level.