Papel de los factores ambientales tempranos en la inmunocompetencia y el proceso de colonización intestinal en lactantes con riesgo de enfermedad celíaca. Inmunomodulación de potenciales probióticos

Tesis doctoral inédita, leída en la Universidad Autónoma de Madrid. Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 30 de Enero de 201

Immune Development and Intestinal Microbiota in Celiac Disease

Celiac disease (CD) is an immune-mediated enteropathy, triggered by dietary wheat gluten and similar proteins of barley and rye in genetically susceptible individuals. The etiology of this disorder is complex, involving both environmental and genetic factors. The major genetic risk factor for CD is represented by HLA-DQ genes, which account for approximately 40% of the genetic risk; however, only a small percentage of carriers develop the disease. Gluten is the main environmental factor responsible for the signs and symptoms of the disease, but exposure to gluten does not fully explain the manifestation of CD. Epidemiological and clinical data suggest that environmental factors other than gluten might play a role in disease development, including early feeding practices (e.g., breast milk versus formula and duration of breastfeeding), infections, and alterations in the intestinal microbiota composition. Herein, we review what is known about the influence of dietary factors, exposure to infectious agents, and intestinal microbiota composition, particularly in early life, on the risk of developing CD, as well as the possible dietary strategies to induce or increase gluten tolerance

In silico clinical trial evaluating lisdexamfetamine’s and methylphenidate’s mechanism of action computational models in an attention-deficit/hyperactivity disorder virtual patients’ population

IntroductionAttention-deficit/hyperactivity disorder (ADHD) is an impairing psychiatric condition with the stimulants, lisdexamfetamine (LDX), and methylphenidate (MPH), as the first lines pharmacological treatment.MethodsHerein, we applied a novel in silico method to evaluate virtual LDX (vLDX) and vMPH as treatments for ADHD applying quantitative systems pharmacology (QSP) models. The objectives were to evaluate the model’s output, considering the model characteristics and the information used to build them, to compare both virtual drugs’ efficacy mechanisms, and to assess how demographic (age, body mass index, and sex) and clinical characteristics may affect vLDX’s and vMPH’s relative efficacies.Results and DiscussionWe molecularly characterized the drugs and pathologies based on a bibliographic search, and generated virtual populations of adults and children-adolescents totaling 2,600 individuals. For each virtual patient and virtual drug, we created physiologically based pharmacokinetic and QSP models applying the systems biology-based Therapeutic Performance Mapping System technology. The resulting models’ predicted protein activity indicated that both virtual drugs modulated ADHD through similar mechanisms, albeit with some differences. vMPH induced several general synaptic, neurotransmitter, and nerve impulse-related processes, whereas vLDX seemed to modulate neural processes more specific to ADHD, such as GABAergic inhibitory synapses and regulation of the reward system. While both drugs’ models were linked to an effect over neuroinflammation and altered neural viability, vLDX had a significant impact on neurotransmitter imbalance and vMPH on circadian system deregulation. Among demographic characteristics, age and body mass index affected the efficacy of both virtual treatments, although the effect was more marked for vLDX. Regarding comorbidities, only depression negatively impacted both virtual drugs’ efficacy mechanisms and, while that of vLDX were more affected by the co-treatment of tic disorders, the efficacy mechanisms of vMPH were disturbed by wide-spectrum psychiatric drugs. Our in silico results suggested that both drugs could have similar efficacy mechanisms as ADHD treatment in adult and pediatric populations and allowed raising hypotheses for their differential impact in specific patient groups, although these results require prospective validation for clinical translatability

Clustering patterns of physical activity, sedentary and dietary behavior among European adolescents: The HELENA study.

Evidence suggests possible synergetic effects of multiple lifestyle behaviors on health risks like obesity and other health outcomes. A better insight in the clustering of those behaviors, could help to identify groups who are at risk in developing chronic diseases. This study examines the prevalence and clustering of physical activity, sedentary and dietary patterns among European adolescents and investigates if the identified clusters could be characterized by socio-demographic factors. METHODS: The study comprised a total of 2084 adolescents (45.6% male), from eight European cities participating in the HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) study. Physical activity and sedentary behavior were measured using self-reported questionnaires and diet quality was assessed based on dietary recall. Based on the results of those three indices, cluster analyses were performed. To identify gender differences and associations with socio-demographic variables, chi-square tests were executed. RESULTS: Five stable and meaningful clusters were found. Only 18% of the adolescents showed healthy and 21% unhealthy scores on all three included indices. Males were highly presented in the cluster with high levels of moderate to vigorous physical activity (MVPA) and low quality diets. The clusters with low levels of MVPA and high quality diets comprised more female adolescents. Adolescents with low educated parents had diets of lower quality and spent more time in sedentary activities. In addition, the clusters with high levels of MVPA comprised more adolescents of the younger age category. CONCLUSION: In order to develop effective primary prevention strategies, it would be important to consider multiple health indices when identifying high risk groups.Peer Reviewe

El practicum como espacio de aprendizaje profesional para docentes en formación del Grado de Maestro en Educación Infantil y Educación Primaria

Memoria ID-0189. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2016-2017

Physical activity, immunity and infection.

Peer Reviewe

Dietary strategies of immunomodulation in infants at risk for celiac disease

Celiac disease is an inflammatory disorder of the small intestine, triggered by the ingestion of gluten proteins contained in wheat, barley or rye, in genetically susceptible individuals. This disorder is considered to be mainly mediated by cellular immunity and restricted to the human leucocyte antigen-DQ presentation of gluten-derived toxic peptides to T-cells. Moreover, the involvement of innate immunity has been recently demonstrated to be necessary also for the development of intestinal tissue damage. Genetic susceptibility accounts for an uncertain proportion of the disease risk and gluten introduction works as the precipitating factor. However, currently, the research interest is also focused on environmental factors and gene¿environment interactions, especially during the first months of life, which might help explain the onset of the disease. Infectious and dietary factors that could modulate the immune response orientating it either towards tolerance or intolerance/autoimmunity are the focus of primary attention. A significant number of studies have looked into the protective effect of breast-feeding against the disease. It is generally accepted that breast-feeding during the introduction of dietary gluten and increasing the duration of breast-feeding are associated with reduced risk of developing celiac disease. However, it is still not fully established whether breast-feeding truly protects with permanent tolerance acquisition or only reduces the symptoms and delays the diagnosis. Moreover, the timing and dose of gluten introduction also seem to be relevant and long-term prospective cohort studies are being carried out in order to elucidate its role in celiac disease development.Peer Reviewe

Interplay between human leukocyte antigen genes and the microbial colonization process of the newborn intestine.

Coeliac disease (CD) development involves genetic (HLA-DQ2/DQ8) and environmental factors. Herein, the influence of the HLA-DQ genotype on the gut colonization process of breast-fed children was determined. A cohort of 20 newborns, with at least one first-degree relative with CD, were classified according to their HLA-DQ genotype into high, intermediate and low genetic risk groups, showing 24-28%, 7-8% and less than 1% probability to develop CD, respectively. Faecal microbiota was analysed at 7 days, 1 and 4 months of children's age by fluorescence in situ hybridization. When considering all data, Gram-negative bacteria and Bacteroides-Prevotella group proportions were higher (P<0.05) in the high than in the intermediate and low genetic risk groups. E. coli, Streptococcus-Lactococcus, E. rectale-C. coccoides, sulphate-reducing bacteria, C. lituseburense and C. histolyticum group proportions were also significantly higher (P<0.05) in the high than in the low genetic risk group. Correlations between these bacterial groups and the genetic risk were also detected (P<0.05). In addition, the number and type of CD relative seemed to influence (P<0.050) these bacterial proportions in children at CD risk. At 4 months of age, similar relationships were established between the high genetic risk to develop CD and the proportions of Streptococcus-Lactococcus (P<0.05), E. rectale-C. coccoides (P<0.05), C. lituseburense (P<0.05), C. histolyticum (P<0.05), Bacteroides-Prevotella (P<0.10) groups and total Gram-negative bacteria (P<0.05). The results suggest a relationship between HLA-DQ genes and the gut microbial colonization process that could lead to a change in the way this disorder is investigated.Peer Reviewe

El papel de la actividad física en la función inmune

Peer Reviewe

Immunostimulatory effect of faecal Bifidobacterium species of breast-fed and formula-fed infants in a PBMC/CaCO-2 coculture system

Bifidobacterium spp. typical of the human intestinal microbiota are believed to influence the balance of immune responses in the intestinal mucosa. Aim: To investigate the effect of different bifidobacterial species and mixtures of them in in vitro experiments with PBMCs and CaCo-2 cells. Methods: Bifidobacterium adolescentis; Bifidobacterium angulatum; Bifidobacterium breve; Bifidobacterium catenulatum; Bifidobacterium infantis; Bifidobacterium longum; and two combinations of these bifidobacteria simulating the species composition found in fecal samples from breast fed (BF) and formula fed (FF) infants were used. The levels of several cytokines were measured by direct stimulation of PBMCs and by stimulation of a Caco-2/PBMCs co-culture with bifidobacteria. Results: B. catenulatum and B. breve were the strongest enhancers of IFN-γ, production by direct stimulation of PBMCs. B. longum was the highest inducer of IL-10 and the lowest TNF-α stimulus. In the Caco-2/PBMC system, B. breve was the highest inducer of IL-8 production by Caco-2 cells; significantly different from B. infantis, B. adolescentis and the FF mixture (p<0·05). IFN-γ produced by PBMCs stimulated with the BF mixture (containing 22% B. breve, compared to 7% in FF mixture) was significantly higher compared to B. adolescentis, B. infantis, and B. longum. B. adolescentis also inhibited IFN-γ production compared to FF mixture and B. longum. Conclusions: The proportion of different Bifidobacterium strains seems to be an important determinant of the cytokine balance in the simulated intestinal environment studied. B. breve and the combination of the Bifidobacterium species typically found in the microbiota of breast-fed infants have shown the most significant effects.Peer reviewe