Microbiota-derived short-chain fatty acids as modulators of intestinal serotonin transporter

Serotonin is a key neuromodulator of intestinal physiology. Serotonin transporter (SERT) is responsible for serotonin uptake, modulating its availability and consequently, serotonergic signalling. Recently, microbiota has been described to affect intestinal homeostasis through microbiota recognition receptors (TLRs). In fact,TLRs activation seems to regulate intestinal serotonergic system. However, whether intestinal microbiota can modulate SERT by short-chain fatty acids (SCFA) is unknown. Microbiota-derived short-chain fatty acids such as acetate, propionate and butyrate, are important metabolites from non-digestible dietary fibers bacterial fermentation. These metabolites have been shown to maintain intestinal homeostasis through protecting epithelial barrier integrity, promoting IgA production and regulating T-cell differentiation. In this study human enterocyte-like Caco-2/TC7 cells were used as intestinal epithelial cells model, which expresses serotonin transporter. Caco-2/TC7 cells were treated for 24 h with different concentrations of acetate, propionate and butyrate and then, and 5-HT uptake was measured. SERT molecular expression was analysed by measuring both, mRNA levels by real-time PCR and protein expression by western blotting. Our results show that the treatment with SCFA modulates SERT function and expression, in a different way for each fatty acid. Consequently, a different production of SCFA by microbiota could differently modulate SERT and affect to serotonergic signalling and intestinal physiology. Our study contributes to growing evidence about the key role of microbiota on host physiology regulation, and it opens a cutting-edge opportunity of microbiota modulation to balance serotonergic signalling alterations

Simulación de la contracción del tejido muscular esquelético mediante redes neuronales

Este Trabajo Final de Grado tiene como objetivo el desarrollo de una metodologíacomputacional con la capacidad de poder simular la contracción del tejido muscularesquelético en tiempo real.En primer lugar, se realiza una breve introducción del aprendizaje profundo (DeepLearning) y las redes neuronales. Previamente a la predicción de la contracción deltejido utilizando redes neuronales, se realiza un estudio de la simulación computacionaldel tejido musculo esquelético empleando un software de elementos finitos. Paraello, se describe el comportamiento del tejido durante la contracción, incluyendo elcomportamiento pasivo y el activo, y se simulan distintas geometrías tridimensionalespara estudiar y analizar la respuesta del tejido ante la variación de diferentesparámetros.Posteriormente, se han utilizado estos modelos tridimensionales para generar lasmuestras para el entrenamiento de las redes neuronales, las cuales generarán unapredicción del comportamiento del músculo durante la contracción muscular.Por último, se analizará y discutirá las predicciones obtenidas mediante las redesneuronales con los resultados obtenidos mediante el software de elementos finitos, conel objetivo de comprobar la validez de esta metodología en la simulación del tejidomuscular.<br /

Gut microbiota-derived short-chain fatty acids: novel regulators of intestinal serotonin transporter

Serotonin (5-HT) is a key neurotransmitter synthesized both in the gut and the central nervous system. It exerts its signaling through specific receptors (5-HTR), which regulate numerous behaviors and functions such as mood, cognitive function, platelet aggregation, gastrointestinal motility, and inflammation. Serotonin activity is determined mainly by the extracellular availability of 5-HT, which is controlled by the serotonin transporter (SERT). Recent studies indicate that, by activation of innate immunity receptors, gut microbiota can modulate serotonergic signaling by SERT modulation. As part of its function, gut microbiota metabolize nutrients from diet to produce different by-products, including short-chain fatty acids (SCFAs): propionate, acetate, and butyrate. However, it is not known whether these SCFAs regulate the serotonergic system. The objective of this study was to analyze the effect of SCFAs on the gastrointestinal serotonergic system using the Caco-2/TC7 cell line that expresses SERT and several receptors constitutively. Cells were treated with different SCFAs concentrations, and SERT function and expression were evaluated. In addition, the expression of 5-HT receptors 1A, 2A, 2B, 3A, 4, and 7 was also studied. Our results show that the microbiota-derived SCFAs regulate intestinal serotonergic system, both individually and in combination, modulating the function and expression of SERT and the 5-HT1A, 5-HT2B, and 5-HT7 receptors expression. Our data highlight the role of gut microbiota in the modulation of intestinal homeostasis and suggest microbiome modulation as a potential therapeutic treatment for intestinal pathologies and neuropsychiatric disorders involving serotonin

Opening treatment windows for treatment-resistant schizophrenia: improving emotion regulation strategies using the unified protocol in a case study in spain

Approximately 30%-50% of people with schizophrenia worldwide have treatment-resistant schizophrenia (TRS). Currently available standard psychopharmacological and psychological treatments have proven insufficient to achieve full recovery in these patients. Alternative psychological interventions focused on improving emotion regulation, such as the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP), could potentially improve treatment outcomes in this difficult to treat population. The aim of the present case study is to demonstrate how the UP can be adapted for the treatment of TRS. We decided to use UP to treat this particular patient due to the presence of intense unpleasant emotions, aversive reactions, and emotional avoidance strategies. After completing the full treatment protocol, the patient showed significant decreases in scores on the Difficulties in Emotion Regulation Scale (DERS), including total and emotional rejection, life interference, and emotional lack of control. A significant reduction was also observed in anxiety (OASIS) and depressive symptoms (ODSIS). The intervention had a positive impact on auditory hallucinations, with decreased severity, less intense anxiety, and less interference in life. The treatment led to greater control over voices and the patient reported feeling more confident in her relationship with those voices. These results provide preliminary support for the use of UP for the treatment of TRS

Intestinal serotonergic system is modulated by Toll-like receptor 9

Intestinal serotonergic system is a key modulator of intestinal homeostasis; however, its regulation is still unclear. Toll-like receptor 9 (TLR9), an innate immune receptor, detects different external agents in the intestine, preserving intestinal integrity. Since little is known about TLR9 role in the intestine, our aim was to address the potential regulation between TLR9 and intestinal serotonergic system. Caco-2/TC7 cell line and intestinal tract of Tlr9−/− mice were used in this study. Serotonin uptake studies were performed, and molecular expression of different serotonergic components was analyzed by western blot and real-time PCR. Our results show that TLR9 activation inhibits serotonin transporter activity and expression, involving p38/MAPK and ERK/MAPK intracellular pathways, and reciprocally, serotonin increases TLR9 expression. Supporting this interaction, serotonin transporter, serotonin receptors and serotonin producer enzymes were found altered in intestinal tract of Tlr9−/− mice. We conclude that TLR9 could contribute to intestinal homeostasis by modulation of intestinal serotonergic system

A Method to Compare the Delivery of Psychiatric Care for People with Treatment-Resistant Schizophrenia

Esquizofrènia resistent al tractament; Tecnologies de la informació i la comunicació (TIC); Serveis de salut mentalEsquizofrenia resistente al tratamiento; Tecnologías de la información y la comunicación (TIC); Servicios de salud mentalTreatment-resistant schizophrenia; Information and communication technologies (ICT); Mental health servicesIntroduction: Community services are gaining ground when it comes to attention to patients with psychiatric diseases. Regarding patients with treatment-resistant schizophrenia (TRS), the use of information and communication technology (ICT) could help to shift the focus from hospital-centered attention to community services. This study compares the differences in mental health services provided for patients with TRS in Budapest (Hungary), Tel-Aviv (Israel) and Catalonia (Spain) by means of a method for the quick appraisal of gaps among the three places, for a potential implementation of the same ICT tool in these regions. Methods: An adapted version of the Description and Standardised Evaluation of Services and Directories in Europe for Long Term Care (DESDE-LTC) instrument was made by researchers in Semmelweis University (Budapest, Hungary), Gertner Institute (Tel-Aviv, Israel) and Hospital de la Santa Creu I Sant Pau and Parc Sanitari Sant Joan de Déu (Catalonia, Spain). Results: Two types of outpatient care services were available in the three regions. Only one type of day-care facility was common in the whole study area. Two residential care services, one for acute and the other for non-acute patients were available in every region. Finally, two self-care and volunteer-care facilities were available in the three places. Conclusion: Although the availability of services was different in each region, most of the services provided were sufficiently similar to allow the implementation of the same ICT solution in the three places.This work has been supported by the Horizon 2020 Framework Programme of the European Union (grant number 643552). This research was also funded by ONA CORPORATION

TLR2 and TLR4 interact with sulfide system in the modulation of mouse colonic motility

Background H2S is a neuromodulator that may inhibit intestinal motility. H2S production in colon is yielded by cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE) enzymes and sulfate-reducing bacteria (SRB). Toll-like receptors (TLRs) recognize intestinal microbiota. The aim of this work was to evaluate the influence of TLR2 and TLR4 on the endogenous and SRB-mediated synthesis of H2S and its consequences on the colonic motility of mouse. Methods Muscle contractility studies were performed in colon from WT, Tlr2(-/-), and Tlr4(-/-) mice. The mRNA levels of TLR2, TLR4, CBS, CSE, and SRB were measured by real-time PCR. Free sulfide levels in colon and feces were determined by colorimetric assays. Results NaHS and GYY4137, donors of H2S, reduced the contractility of colon. Aminooxyacetic acid (AOAA), inhibitor of CBS, and D-L propargylglycine (PAG), inhibitor of CSE, increased the contractility of colon. In vivo treatment with NaHS or GYY4137 inhibited the spontaneous contractions and upregulated TLR2 expression. The in vivo activation of TLR4 with lipopolysaccharide increased the contractile response to PAG, mRNA levels of CSE, and the free sulfide levels of H2S in colon. In Tlr2(-/-) and Tlr4(-/-) mice, the contractions induced by AOAA and PAG and mRNA levels of CBS and CSE were lower with respect to WT mice. Deficiency of TLR2 or TLR4 provokes alterations in free sulfide levels and SRB of colon. Conclusions and Inferences Our study demonstrates interaction between TLR2 and TLR4 and the sulfide system in the regulation of colonic motility and contributes to the pathophysiology knowledge of intestinal motility disorders

Comparative effect of bovine buttermilk, whey, and lactoferrin on the innate immunity receptors and oxidative status of intestinal epithelial cells

Milk contains active molecules with important functional properties as the defensive proteins; among them are the whey protein lactoferrin and proteins of the milk fat globule membrane (MFGM) present in buttermilk. The aim of this study has been to investigate the effect of lactoferrin, whey and buttermilk as modulators of intestinal innate immunity and oxidative stress on intestinal epithelial cells, to evaluate its potential use for the development of functional foods. Innate immune Toll-like receptors (TLR2, TLR4, and TLR9) mRNA expression, lipid peroxidation (MDA+4-HDA) and protein carbonyl levels were analyzed in enterocyte-like Caco-2/TC7 cells treated for 24 hours with different concentrations of lactoferrin, whey or buttermilk. None of the substances analyzed caused oxidative damage; however, whey significantly decreased the levels of lipid peroxidation. Furthermore, both lactoferrin and whey were able to reduce the oxidative stress induced by lipopolysaccharide. Respect to TLR receptors, lactoferrin, whey and buttermilk specifically altered the expression of TLR2, TLR4 and TLR9 receptors, with a strong decrease in TLR4 expression. These results suggest that lactoferrin, whey and buttermilk could be interesting potential ingredients for functional foods as they seem to modulate oxidative stress and inflammatory response induced by TLRs activation

m-RESIST, a Mobile Therapeutic Intervention for Treatment-Resistant Schizophrenia: Feasibility, Acceptability, and Usability Study

Mental disorder; Schizophrenia; Treatment-resistantTrastorno mental; Esquizofrenia; Resistentencia al tratamientoMalaltia mental; Esquizofrènia; Resistència al tractamentBackground: In the European Union, around 5 million people are affected by psychotic disorders, and approximately 30%-50% of people with schizophrenia have treatment-resistant schizophrenia (TRS). Mobile health (mHealth) interventions may be effective in preventing relapses, increasing treatment adherence, and managing some of the symptoms of schizophrenia. People with schizophrenia seem willing and able to use smartphones to monitor their symptoms and engage in therapeutic interventions. mHealth studies have been performed with other clinical populations but not in populations with TRS. Objective: The purpose of this study was to present the 3-month prospective results of the m-RESIST intervention. This study aims to assess the feasibility, acceptability, and usability of the m-RESIST intervention and the satisfaction among patients with TRS after using this intervention. Methods: A prospective multicenter feasibility study without a control group was undertaken with patients with TRS. This study was performed at 3 sites: Sant Pau Hospital (Barcelona, Spain), Semmelweis University (Budapest, Hungary), and Sheba Medical Center and Gertner Institute of Epidemiology and Health Policy Research (Ramat-Gan, Israel). The m-RESIST intervention consisted of a smartwatch, a mobile app, a web-based platform, and a tailored therapeutic program. The m-RESIST intervention was delivered to patients with TRS and assisted by mental health care providers (psychiatrists and psychologists). Feasibility, usability, acceptability, and user satisfaction were measured. Results: This study was performed with 39 patients with TRS. The dropout rate was 18% (7/39), the main reasons being as follows: loss to follow-up, clinical worsening, physical discomfort of the smartwatch, and social stigma. Patients' acceptance of m-RESIST ranged from moderate to high. The m-RESIST intervention could provide better control of the illness and appropriate care, together with offering user-friendly and easy-to-use technology. In terms of user experience, patients indicated that m-RESIST enabled easier and quicker communication with clinicians and made them feel more protected and safer. Patients' satisfaction was generally good: 78% (25/32) considered the quality of service as good or excellent, 84% (27/32) reported that they would use it again, and 94% (30/32) reported that they were mostly satisfied. Conclusions: The m-RESIST project has provided the basis for a new modular program based on novel technology: the m-RESIST intervention. This program was well-accepted by patients in terms of acceptability, usability, and satisfaction. Our results offer an encouraging starting point regarding mHealth technologies for patients with TRS.This work has been supported by the Horizon 2020 Framework Programme of the European Union (grant 643552) and partly funded by CERCA (Centres de Recerca de Catalunya) Programme/Generalitat de Catalunya

Mobile Phone and Wearable Sensor-Based mHealth Approach for Psychiatric Disorders and Symptoms : Systematic Review and Link to the m-RESIST Project

Background: Mobile Therapeutic Attention for Patients with Treatment-Resistant Schizophrenia (m-RESIST) is an EU Horizon 2020-funded project aimed at designing and validating an innovative therapeutic program for treatment-resistant schizophrenia. The program exploits information from mobile phones and wearable sensors for behavioral tracking to support intervention administration. Objective: To systematically review original studies on sensor-based mHealth apps aimed at uncovering associations between sensor data and symptoms of psychiatric disorders in order to support the m-RESIST approach to assess effectiveness of behavioral monitoring in therapy. Methods: A systematic review of the English-language literature, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, was performed through Scopus, PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials databases. Studies published between September 1, 2009, and September 30, 2018, were selected. Boolean search operators with an iterative combination of search terms were applied. Results: Studies reporting quantitative information on data collected from mobile use and/or wearable sensors, and where that information was associated with clinical outcomes, were included. A total of 35 studies were identified; most of them investigated bipolar disorders, depression, depression symptoms, stress, and symptoms of stress, while only a few studies addressed persons with schizophrenia. The data from sensors were associated with symptoms of schizophrenia, bipolar disorders, and depression. Conclusions: Although the data from sensors demonstrated an association with the symptoms of schizophrenia, bipolar disorders, and depression, their usability in clinical settings to support therapeutic intervention is not yet fully assessed and needs to be scrutinized more thoroughly.Peer reviewe