Roberta Pintus

Fetal programming of neuropsychiatric disorders

Starting from the Developmental Origins of Health and Disease (DOHaD) hypotheses proposed by David Barker, namely fetal programming, in the past years, there is a growing evidence of the major role played by epigenetic factors during the intrauterine life and the perinatal period. Furthermore, it has been assessed that these factors can affect the health status in infancy and even in adulthood. In this review, we focus our attention on the fetal programming of the brain, analyzing the most recent literature concerning the epigenetic factors that can influence the development of neuropsychiatric disorders such as bipolar disorders, major depressive disorders, and schizophrenia. The perinatal epigenetic factors have been divided in two main groups: maternal factors and fetal factors. The maternal factors include diet, smoking, alcoholism, hypertension, malnutrition, trace elements, stress, diabetes, substance abuse, and exposure to environmental toxicants, while the fetal factors include hypoxia/asphyxia, placental insufficiency, prematurity, low birth weight, drugs administered to the mother or to the baby, and all factors causing intrauterine growth restriction. A better comprehension of the possible mechanisms underlying the pathogenesis of these diseases may help researchers and clinicians develop new diagnostic tools and treatments to offer these patients a tailored medical treatment strategy to improve their quality of life. Birth Defects Research (Part C) 108:207-223, 2016.

Metabolomics in necrotizing enterocolitis: the state of the art

ABSTRACT Introduction: Necrotizing enterocolitis (NEC) is a serious inflammation of the bowel that most often affects premature infants. The exact cause of NEC is still poorly understood but investigators believe that these different factors can play an important role: prematurity and immaturity of the intestine of the preterm newborns, differences in the intestinal bacterial colonization and an abnormal immune response. Since the early symptoms of NEC are often rather non-specific, the diagnosis of NEC can be difficult. Therefore, the search for diagnostic biomarkers for NEC remains warranted. This review focuses on the results of recent metabolomics investigations on NEC, providing important contributions to the understanding of the biochemical process characterizing this disease. Areas covered: Only a few metabolomics applications of NEC are reported in the literature. The metabolic pathway principally altered in NEC patients is suggested to be linked to the carbohydrates metabolism and the role of gluconate as a predictive marker for this pathology is investigated. Expert commentary: Biomarkers are crucial as a confident diagnostic tool to make NEC therapy more efficient. Although only a few metabolomics studies have been performed in NEC research, this technique proved to be helpful to understand the pathophysiological mechanisms of this disease.

Urinary metabolomic analysis to identify preterm neonates exposed to histological chorioamnionitis: A pilot study

Objective Chorioamnionitis is a leading cause of preterm birth worldwide, with higher incidence at lower gestational ages. An early and reliable diagnosis of histological chorioamnionitis (HCA) in preterm infants may be helpful in guiding postnatal management, especially the administration of prophylactic antibiotics to prevent early-onset sepsis. The main aim of this study was to investigate metabolomic analysis of urines collected in the first 24 hours of life as diagnostic tool of HCA. Methods Gestational age-, birth weight-, delivery mode- and sex- matched (1:2) preterm neonates (< 35 weeks’ gestation) born to mothers with or without HCA were enrolled from an observational study. Gas chromatography-mass spectrometry (GC-MS)-based metabolomic analysis was performed on urine samples non-invasively collected in the first 24 hours of life. Univariate analysis, partial least square discriminant analysis (PLS-DA) and its associated variable importance in projection (VIP) score were performed. The most affected metabolic pathways were examined by Metabolite Sets Enrichment Analysis (MSEA). Results Fifteen cases (mean GA 30.2 ± 3.8 weeks, mean BW 1415 ± 471.9 grams) and 30 controls (mean GA 30.2 ± 2.9 weeks, mean BW 1426 ± 569.8 grams) were enrolled. Following univariate analysis, 29 metabolites had a significantly different concentration between cases and controls. The supervised PLS-DA model confirmed a separation between the two groups. Only gluconic acid, an oxidation product of glucose, was higher in cases than in controls. All other VIP metabolites were more abundant in the control group. Glutamate metabolism, mitochondrial electron transport chain, citric acid cycle, galactose metabolism, and fructose and mannose degradation metabolism were the most significantly altered pathways (P < 0.01). Conclusions For the first time, urinary metabolomics was able to discriminate neonates born to mothers with and without HCA. The identification of specifically altered metabolic pathways may be helpful in understanding metabolic derangement following chorioamnionitis.

Metabolomics and Cardiology: Toward the Path of Perinatal Programming and Personalized Medicine

Heart diseases are one of the leading causes of death in Western Countries and tend to become chronic, lowering the quality of life of the patients and ending up in a massive cost for the Health Systems and the society. Thus, there is a growing interest in finding new technologies that would allow the physician to effectively treat and prevent cardiac illnesses. Metabolomics is one of the new “omics” sciences enabling creation of a photograph of the metabolic state of an individual exposed to different environmental factors and pathologies. This review analyzed the most recent literature about this technology and its application in cardiology in order to understand the metabolic shifts that occur even before the manifestation of these pathologies to find possible early predictive biomarkers. In this way, it could be possible to find better treatments, ameliorate the patients quality of life, and lower the death rate. This technology seems to be so promising that several industries are trying to set up kits to immediately assess the metabolites variations in order to provide a faster diagnosis and the best treatment specific for that patient, offering a further step toward the path of the development of a tailored medicine.

Urinary 1H-NMR Metabolomics in the First Week of Life Can Anticipate BPD Diagnosis

Despite the advancements in medical knowledge and technology, the etiopathogenesis of bronchopulmonary dysplasia (BPD) is not yet fully understood although oxidative stress seems to play a role, leading to a very demanding management of these patients by the neonatologist. In this context, metabolomics can be useful in understanding, diagnosing, and treating this illness since it is one of the newest omics science that analyzes the metabolome of an individual through the investigation of biological fluids such as urine and blood. In this study, 18 patients admitted to the Neonatal Intensive Care Unit of the Cagliari University Hospital were enrolled. Among them, 11 patients represented the control group and 7 patients subsequently developed BPD. A sample of urine was collected from each patient at 7 days of life and analyzed through 1H-NMR coupled with multivariate statistical analysis. The discriminant metabolites between the 2 groups noted were alanine, betaine, trimethylamine-N-oxide, lactate, and glycine. Utilizing metabolomics, it was possible to detect the urinary metabolomics fingerprint of neonates in the first week of life who subsequently developed BPD. Future studies are needed to confirm these promising results suggesting a possible role of microbiota and oxidative stress, and to apply this technology in clinical practice.

Clinical Metabolomics in Neonatology: From Metabolites to Diseases

Today, disorders that affect the newborn remain a challenge for physicians because of the enigmatic pathophysiology and difficulties in treating such delicate patients. Metabolomics, the “omics” science that studies the metabolome, namely the metabolites present in biological fluids, such as saliva, blood, sweat, and breast milk in a given time or condition, can be useful in helping neonatologists to prevent, diagnose, and treat diseases affecting the neonate, especially those with higher mortality rates. Since it is a relatively new technology, studies of its application in neonatology are limited. The aims of this review are to present metabolomics data on relevant neonatal disorders and to identify and discuss the most important 5 metabolites and their clinical significance rather than focusing on each disorder. The preliminary data are promising but further studies on metabolomics in neonatology are needed together with the standardization of results before their application in clinical practice.

Urinary metabolomics in term newborns delivered spontaneously or with cesarean section: preliminary data

Introduction: In the last years the uncritical attitude towards cesarean section (CS) has been associated with the fast emergence of ‘modern’ diseases such as early pediatric obesity, asthma, type 2 diabetes mellitus and dermatitis. Increasing evidence shows that babies born at term by vaginal delivery (VD) have a different physiology at birth, with subsequent influence on adult health. In relation to these short-term physiological changes, in the present study we aimed at assessing the influence of the mode of delivery in term newborns on the first 24 hours metabolism of neonates. Material and methods: This study was carried out on urine samples from 42 patients admitted to the Neonatal Intensive Unit and Neonatal Pathology of “S. Giovanni Calibita” Hospital Fatebenefratelli (Rome, Italy). According to the type of delivery, term neonates with similar gestational age and birthweight were divided in two groups: (1) born by spontaneous VD, (2) born by elective CS. Urine samples, collected at birth by a non-invasive method, were subjected to proton Nuclear Magnetic Resonance spectroscopy. Results: CS newborns showed lower fatty acid omega oxidation, as evidenced by lower urinary excretion of dicarboxylic acids. This metabolic signature supports current evidence that babies delivered by CS have lower body temperature and perturbed thermogenesis. CS associates also with hypoglycaemia and altered endocrine profile, which linked to changes in central energy metabolic pathways (Krebs and Cori Cycles). Lung function may be reduced in infants born by CS, primarily due to delayed clearance of lung liquid, and surfactant insufficiency, which might be reflected in different urinary excretion of myo-inositol and choline – two intermediates in lung surfactant metabolism. Conclusion: Non-invasive urine metabolic phenotyping of children born by different mode of delivery provides relevant readouts to assess metabolic requirements associated with major physiological functions during this critical period of metabolic adaptation.

Exposure to tobacco smoke and low birth weight: from epidemiology to metabolomics

ABSTRACT Introduction: The exposure to tobacco smoke during pregnancy is one of the leading causes of perinatal adverse outcomes such as stillbirth, intrauterine growth restriction (IUGR), and low birth weight, but the underlying biological mechanisms are still unclear. The incidence of this phenomenon maybe largely underestimated since the evaluation is made mainly by self-assessment questionnaires rather than measuring nicotine metabolites (such as cotinine) in biological fluids. In this context metabolomics may be useful to assess the actual number of pregnant women and to highlight the pathophysiological mechanisms that lead to the abovementioned adverse outcomes. Areas covered: The aims of this review are to analyze the literature and the application of the omics sciences, such as genomics and metabolomics concerning the negative effects of smoking during pregnancy in order to give a comprehensive picture of all the study made so far and to point out the potential of metabolomics as an investigative, predictive, and diagnostic tool. Expert commentary: Metabolomics in recent years has proved an excellent tool to try to understand the problems in perinatal medicine. With the increase in the number of studies we are convinced that it can be a useful instrument of investigation in this field.

PROM and Labour Effects on Urinary Metabolome: A Pilot Study

Since pathologies and complications occurring during pregnancy and/or during labour may cause adverse outcomes for both newborns and mothers, there is a growing interest in metabolomic applications on pregnancy investigation. In fact, metabolomics has proved to be an efficient strategy for the description of several perinatal conditions. In particular, this study focuses on premature rupture of membranes (PROM) in pregnancy at term. For this project, urine samples were collected at three different clinical conditions: out of labour before PROM occurrence (Ph1), out of labour with PROM (Ph2), and during labour with PROM (Ph3). GC-MS analysis, followed by univariate and multivariate statistical analysis, was able to discriminate among the different classes, highlighting the metabolites most involved in the discrimination.