Dietary restrictions modulate the gut microbiota: Implications for health and disease.

The health benefits of carefully restricting the energy intake in a strategic manner whilst avoiding malnutrition are widely discussed. In the recent years, the great impact of the gut microbiota on its host has been clarified more and more. Since the gut microbiota produces a number of metabolites and molecules that can affect host metabolism, modulating it with dietary restriction can influence the health and the progression of disease of its host on various levels. This review comprises 15 studies investigating the effect of different variants of fasting and caloric restriction on the gastrointestinal microbiome and its metabolites. The data suggest that changing the gut microbiota composition by dietary restriction has the potential to positively influence the progression of several diseases such as obesity, diabetes, neurological diseases or inflammatory bowel disease. Finally, the relevance of the findings for clinical practice is evaluated and approaches for future research are proposed.

Effect of the ketogenic diet in excitable tissues.

In the past decade, ketogenic diet (KD) has gained some popularity as a potential treatment for a wide range of diseases, including neurological and metabolic disorders, thanks to a beneficial role mainly related to its anti-inflammatory properties. The high-fat and carbohydrate-restricted regimen causes changes in the metabolism, leading, through the ß-oxidation of fatty acids, to the hepatic production of ketone bodies (KBs), which are used by many extrahepatic tissues as energy fuels. Once synthetized, KBs are delivered through the systemic circulation to all the tissues of the organism, where they play pleiotropic roles acting directly and indirectly on various targets, and among them ion channels and neurotransmitters. Moreover, they can operate as signaling metabolites and epigenetic modulators. Therefore, it is inappropriate to consider that the KD regimen can improve the patients' clinical condition simply by means of specific and localized effects; rather, it is more correct to think that KBs affect the organism as a whole. In this review, we tried to summarize the recent knowledge of the effects of KBs on various tissues, with a particular attention on the excitable ones, namely the nervous system, heart, and muscles.

Nutritional Therapy to Modulate Tryptophan Metabolism and Aryl Hydrocarbon-Receptor Signaling Activation in Human Diseases.

The aryl hydrocarbon receptor (AhR) is a nuclear protein which, upon association with certain endogenous and exogenous ligands, translocates into the nucleus, binds DNA and regulates gene expression. Tryptophan (Trp) metabolites are one of the most important endogenous AhR ligands. The intestinal microbiota is a critical player in human intestinal homeostasis. Many of its effects are mediated by an assembly of metabolites, including Trp metabolites. In the intestine, Trp is metabolized by three main routes, leading to kynurenine, serotonin, and indole derivative synthesis under the direct or indirect involvement of the microbiota. Disturbance in Trp metabolism and/or AhR activation is strongly associated with multiple gastrointestinal, neurological and metabolic disorders, suggesting Trp metabolites/AhR signaling modulation as an interesting therapeutic perspective. In this review, we describe the most recent advances concerning Trp metabolism and AhR signaling in human health and disease, with a focus on nutrition as a potential therapy to modulate Trp metabolites acting on AhR. A better understanding of the complex balance between these pathways in human health and disease will yield therapeutic opportunities.

Nutrición enteral domiciliaria en el paciente con patología neurológica de un área de salud del sureste español / Home enteral nutrition in patients with neurological disease in an area of the southeast of Spain

Introducción: la desnutrición en el paciente neurológico presenta una alta prevalencia, aumentando las complicaciones y disminuyendo la calidad de vida. La nutrición artificial minimiza el riesgo de malnutrición. En los últimos años, en Murcia, se pone en marcha una vía clínica de adecuación a la Guía Nacional de Nutrición Enteral Domiciliaria (NED) para optimizar este recurso y reducir la variabilidad de prescripción. Objetivo: analizar las características de la NED en el paciente neurológico, de un área de salud de Murcia, antes y después de la adecuación a las directrices nacionales. Método: diseño observacional de corte transversal. Análisis y comparación de las muestras NED de adultos del Área 1 de salud de Murcia, en 2010 y 2014. Resultados: la patología más asociada a las prescripciones de NED fue la neurológica. La vía de administración más utilizada fue la oral, aunque desciende en la muestra de 2014 a favor de la sonda de nutrición y ostomía. El tipo de fórmula más usado en 2010 fue la no específica. Tras la vía clínica se reduce el uso de fórmulas específicas, disminuyendo especialmente las fórmulas hiperproteicas y/o hipercalóricas. Conclusiones: la implementación de una vía clínica de adecuación a la Guía Nacional NED ha provocado un cambio en la realidad de este tipo de nutrición artificial en el Área 1 de salud del Servicio Murciano de Salud, consiguiendo normalizar su uso bajo criterios unificados y profesionales especializados. Finalmente, estos logros se han generalizado a toda la región

Introduction: malnutrition in patients with neurological disease is very prevalent, worsening their complications and diminishing their quality of life. For that reason, nutritional support can provide a reduction in comorbidities. Over the past years, in Murcia (southeast of Spain), a clinical pathway has been stablished in accordance to the National Home Enteral Nutrition guide (HEN) to optimize this resource and reduce the prescription gap. Objective: to analyze the HEN characteristics in neurological patients in an area of Murcia, before and after the adequacy of the national recommendations. Method: observational cross-sectional study. Analysis and comparison of HEN in health area no. 1 in Murcia in 2010 and 2014. Results: the most prevalent cause for HEN was neurological disease. In 2010, oral nutrition was the most used way compared with 2014, when it had changed to enteral nutrition through feeding tube or ostomy. Non-specific formula was the most frequently used in 2010. However, after the establishment of the clinical pathway there was a reduction in specific enteral formula use, specially hypercaloric and hyperproteic. Conclusions: the implementation of a clinical pathway according to the National HEN guide has caused a change in the reality of artificial nutrition in health area no. 1 in Murcia (Spain), which means a standardization of its use under unified criteria made by specialized professionals. Finally, due to these results, this clinical pathway has been generalized to the rest of the region

Ketogenic dietary therapies for epilepsy and beyond.

PURPOSE OF REVIEW: The ketogenic diet, a high-fat, low-carbohydrate therapy, has become an established treatment for pediatric epilepsy since 1921. There has recently been an increase in important studies on the ketogenic diet, and this review will highlight the most recent in order to provide a synthesis of where this field stands today. RECENT FINDINGS: Clinical studies continue to support the use of ketogenic diets in epilepsy, with more recent trials supporting its use in adults. Clinical recommendations published in 2018 based on a decade of practice and research, guide implementation and management of the ketogenic diet in epilepsy. One of the most rapidly growing 'indications' includes the role of ketogenic diets in status epilepticus. An exciting new potential mechanism for how the ketogenic diet exerts its antiseizure effects is through changing the composition of the gut microbiome. Lastly, ketogenic diets are being applied to a range of neurological conditions from autism to Alzheimer's disease. SUMMARY: The ketogenic diet is a versatile therapy, with growing clinical evidence and guidelines, widely used for the treatment of epilepsy. New indications include status epilepticus and neurological conditions other than epilepsy.

Selectivity of Dietary Phenolics for Inhibition of Human Monoamine Oxidases A and B.

Monoamine oxidases (MAOs) regulate local levels of neurotransmitters such as dopamine, norepinephrine, and serotonin and thus have been targeted by drugs for the treatment of certain CNS disorders. However, recent studies have shown that these enzymes are upregulated with age in nervous and cardiac tissues and may be involved in degeneration of these tissues, since their metabolic mechanism releases hydrogen peroxide leading to oxidative stress. Thus, targeting these enzymes may be a potential anti-aging strategy. The purpose of this study was to compare the MAO inhibition and selectivity of selected dietary phenolic compounds, using a previously validated assay that would avoid interference from the compounds. Kynuramine metabolism by human recombinant MAO-A and MAO-B leads to formation of 4-hydroxyquinoline, with Vmax values of 10.2±0.2 and 7.35±0.69 nmol/mg/min, respectively, and Km values of 23.1±0.8 µM and 18.0±2.3 µM, respectively. For oral dosing and interactions with the gastrointestinal tract, curcumin, guaiacol, isoeugenol, pterostilbene, resveratrol, and zingerone were tested at their highest expected luminal concentrations from an oral dose. Each of these significantly inhibited both enzymes except for zingerone, which only inhibited MAO-A. The IC50 values were determined, and selectivity indices (MAO-A/MAO-B IC50 ratios) were calculated. Resveratrol and isoeugenol were selective for MAO-A, with IC50 values of 0.313±0.008 and 3.72±0.20 µM and selectivity indices of 50.5 and 27.4, respectively. Pterostilbene was selective for MAO-B, with IC50 of 0.138±0.013 µM and selectivity index of 0.0103. The inhibition of resveratrol (MAO-A) and pterostilbene (MAO-B) was consistent with competitive time-independent mechanisms. Resveratrol 4'-glucoside was the only compound which inhibited MAO-A, but itself, resveratrol 3-glucoside, and pterostilbene 4'-glucoside failed to inhibit MAO-B. Additional studies are needed to establish the effects of these compounds on MAO-A and/or MAO-B in humans.

Blood phenylalanine reduction corrects CNS dopamine and serotonin deficiencies and partially improves behavioral performance in adult phenylketonuric mice.

Central nervous system (CNS) deficiencies of the monoamine neurotransmitters dopamine and serotonin have been implicated in the pathophysiology of neuropsychiatric dysfunction in human phenylketonuria (PKU). In this study, we confirmed the occurrence of brain dopamine and serotonin deficiencies in association with severe behavioral alterations and cognitive impairments in hyperphenylalaninemic C57BL/6-Pahenu2/enu2 mice, a model of human PKU. Phenylalanine-reducing treatments, including either dietary phenylalanine restriction or liver-directed gene therapy, initiated during adulthood were associated with increased brain monoamine content along with improvements in nesting behavior but without a change in the severe cognitive deficits exhibited by these mice. At euthanasia, there was in Pahenu2/enu2 brain a significant reduction in the protein abundance and maximally stimulated activities of tyrosine hydroxylase (TH) and tryptophan hydroxylase 2 (TPH2), the rate limiting enzymes catalyzing neuronal dopamine and serotonin synthesis respectively, in comparison to levels seen in wild type brain. Phenylalanine-reducing treatments initiated during adulthood did not affect brain TH or TPH2 content or maximal activity. Despite this apparent fixed deficit in striatal TH and TPH2 activities, initiation of phenylalanine-reducing treatments yielded substantial correction of brain monoamine neurotransmitter content, suggesting that phenylalanine-mediated competitive inhibition of already constitutively reduced TH and TPH2 activities is the primary cause of brain monoamine deficiency in Pahenu2 mouse brain. We propose that CNS monoamine deficiency may be the cause of the partially reversible adverse behavioral effects associated with chronic HPA in Pahenu2 mice, but that phenylalanine-reducing treatments initiated during adulthood are unable to correct the neuropathology and attendant cognitive deficits that develop during juvenile life in late-treated Pahenu2/enu2 mice.

Magnesium in the CNS: recent advances and developments.

A potential neuroprotective role for magnesium in neurological disease has been appreciated for almost three decades, yet translation to the clinical arena has proven elusive. Accumulating experimental evidence continues to suggest that magnesium plays a critical role in a number of neurological conditions including headache, stress, alcohol/drug intoxication, acute brain injury, seizures, Parkinson's disease and Alzheimer's disease. Simple administration of a magnesium salt in these conditions has not always been therapeutically successful, with a number of studies showing poor penetration of serum magnesium across the blood brain barrier. Several studies have since demonstrated that using a carrier such as polyethylene glycol can address this, simultaneously reducing the dose of magnesium required to achieve the desired central effects while at the same time attenuating deleterious peripheral effects. Alternatively, administering a more permeable magnesium salt, such as magnesium threonate, is seen as the preferred option in more chronic neurological conditions, with positive results having been achieved in experimental models of Alzheimer's disease. Irrespective of the approach, improved central penetration of a magnesium compound that avoids peripheral side effects of high magnesium dosages is clearly a desirable outcome, and should now be investigated in animal models that accurately mimic the complex human condition.

Omega-3 Fatty Acids and their Role in Central Nervous System - A Review.

Polyunsaturated fatty acids (PUFAs) are crucial for our health and wellbeing; therefore, they have been widely investigated for their roles in maintaining human health and in disease treatment. Most Western diets include significant amount of saturated and omega-6 fatty acids and insufficient quantity of omega-3; however, the balance between omega-6 and omega-3 PUFA, in particular, is essential for the formation of pro- and anti-inflammatory lipids to promote health and prevent disease. As our daily diet affects our health, this paper draws attention to unique representatives of the omega-3 fatty acid group: alpha-linolenic acid and its derivatives. Recently, this has been shown to be effective in treating and preventing various diseases. It has been confirmed that omega-3 PUFAs may act as therapeutic agents as well and their significant role against inflammatory diseases, such as cardiovascular and neurodegenerative diseases, has been described. Some of nutritional factors have been described as a significant modifiers, which can influence brain elasticity and thus, effect on central nervous system functioning. Therefore, appropriate dietary management appears to be a non-invasive and effective approach to counteract neurological and cognitive disorders.

Bioavailability of dietary polyphenols: Factors contributing to their clinical application in CNS diseases.

The anatomical location of the central nervous system (CNS) renders it immunologically and pharmacologically privileged due to the blood brain barrier (BBB). Although this limits the transport of unfavorable molecules to the CNS, the ensuing privilege could be disadvantageous for therapeutic compounds. Hence, the greatest challenge in the pharmacotherapy of CNS diseases is to ensure efficient brain targeting and drug delivery. Research evidences indicate that dietary polyphenols have neuroprotective potential against CNS diseases. However, their selective permeability across BBB, poor absorption, rapid metabolism and systemic elimination limit their bioavailability and therapeutic efficacy. Consequently, the beneficial effects of these orally administered agents in the CNS still remain a subject of debate. This has also limited its clinical application either as independent or adjunctive therapy. Improving the in vivo bioavailability by novel methods could improve the therapeutic feasibility of polyphenols and assist in evolving novel drugs and their derivatives with improved efficacy in vivo. Here we review the mechanistic and pharmacological issues related to the bioavailability of polyphenols with therapeutic implications for CNS diseases. We surmise that improving the bioavailability of polyphenols entails efficient in vivo transport across BBB, biochemical stability, improved half-life and persistent neuroprotection in the CNS.

Relationship between oxidative stress, pathology, and behavioral signs of lead poisoning in mallards.

Some of the adverse effects of lead (Pb) may be associated with oxidative damage of lipids, proteins, or DNA. In a previous study a linkage was observed between the susceptibilities of waterfowl species to Pb poisoning with oxidative stress. To investigate this relationship among the individuals of a single species, for 3 wk 4 groups of 12 mallards were fed diets containing high or low levels of vitamin E (20 or 220 UI/kg) and high or low levels of Pb (0 or 2 g/kg). During the first week of Pb exposure, mallards developed hemolytic anemia, and during the second week, signs of neurological impairment. Histological findings in the Pb-exposed mallards were hemosiderosis, demyelinization of sciatic and brachial nerves, and tumefaction of renal tubular epithelium with the presence of intranuclear inclusion bodies. Lipid peroxidation increased with Pb exposure in blood, liver, bile, and brain, but decreased in nerves. Glutathione (GSH) increased with Pb exposure in liver and bile, and its oxidized/reduced ratio only increased in bile. Pb exposure inhibited GSH peroxidase activity (GPX) in plasma, liver, and brain, and decreased protein thiols (PSH) in blood and liver. Vitamin E resulted in significantly lower lipid peroxidation in nerves of control birds relative to unsupplemented controls, but did not alleviate any sign of lead posioning. Pb-induced pathological changes associated with hepatic and nervous functions were significantly correlated with lower GPX activity and PSH concentrations in these tissues rather than lipid peroxidation. Data suggest that inhibition of antioxidant enzymes and interaction with sulfhydryl groups of proteins may play a more important role in Pb poisoning of waterfowl than lipid peroxidation.

Gastrostomía percutánea endoscópica en lactantes con daño neurológico severo / Percutaneous endoscopic gastrostomy in infants with severe neurological impairment

La gastrostomía percutánea endoscópica (GEP) es una técnica para instalar una gastrostomía de alimentación sin necesidad de laparotomía ni anestesia general. Hemos efectuado dos de estos procedimientos en lactantes con daño neurológico severo, uno congénito y el otro secundario a hipoxia perinatal. Ambos procedimientos realizados en la sala de endoscopía, resultaron simples y rápidos (7 y 8 minutos) provocando mínimas molestias a los pacientes. Los lactantes llevan 7 y 4 meses alimentándose por esta nueva vía. No han presentado infección de la herida en torno a la sonda ni reflujo gastroesofágico de la papilla. Han mejorado notablemente su estado nutritivo y no han vuelto a presentar trastornos respiratorios. Creemos que la GPE es una técnica segura, simple y de bajo costo que permite la alimentación enteral por largos períodos en lactantes con daño neurológico severo

Neurologic disorders of vitamin b12 deficiency.

Neurologic complications associated with vitamin B12 deficiency include spinal cord degeneration, peripheral neuropathy and alteration of mental status. The possibility of vitamin B12 deficiency must be considered in all patients with these nervous system disorders, even in those who do not have anemia. If treatment is started early, most of the neurologic deficits will resolve. Delayed therapy usually halts the progression of the disease, but permanent sequelae may occur.