Thesis (Ph. D.)--Case Western Reserve University, 2008. / [School of Medicine] Department of Neurosciences. Includes bibliographical references.

The mucosa of the small intestine is clearly able to discriminate specific chemical components of ingested meals to stimulate gastrointestinal feedback pathways and reduce further food intake. Luminal carbohydrates delay gastric emptying and initiate satiation, which are mediated by reflexes via the vagus nerve upon activation of vagal afferent endings in the mucosa. Nutrients activate these nerve fibres through intermediary epithelial cells, which release neuromediators upon transduction of luminal signals through the apical membrane. 5-hydroxytryptamine (5-HT) and glucagon-like peptide-1 (GLP-1) are released from enteroendocrine cells in response to luminal carbohydrates and both slow gastric emptying and inhibit food intake via vagal afferent pathways. The molecular mechanisms for carbohydrate detection and transduction leading to 5-HT and GLP-1 release are unknown. However molecules key to transduction of taste by receptor cells in the lingual epithelium are expressed in the gastrointestinal mucosa. The studies in this thesis aimed to investigate 1) the possibility that taste molecules expressed in the intestine form part of the carbohydrate sensing pathway that leads to 5-HT and GLP-1 release, which in turn activate mucosal vagal afferents and 2) to gauge any alterations in taste molecule expression that may relate to adaptation of carbohydrate-induced gastric motility reflexes that occurs in dietary and disease states. Firstly these studies show key taste molecules, including sweet taste receptors T1R2 and T1R3, the Gprotein gustducin (alpha-subunit Gαgust), and the taste transduction channel TRPM5, are expressed in the mouse gastrointestinal mucosa shown by RT-PCR and were further localised to individual epithelial ‘taste’ cells using immunohistochemistry. Quantification of transcript levels by real time RT-PCR revealed the proximal small intestine as the preferential site of sweet taste receptor expression along the gastrointestinal tract. This finding was also confirmed in humans using gastric and intestinal mucosal biopsies obtained at enteroscopy with significantly higher transcript expression levels in the small intestine compared to stomach. In the mouse, double label immunohistochemistry with Gα[subscript]gust antibody, as a marker of intestinal taste cells, was performed using lectin UEA-1, a marker of intestinal brush cells, and 5-HT or GLP-1 to link intestinal taste transduction to 5-HT and GLP-1 release. Results show Gα[subscript]gust is expressed within a subset of all three cell types in the small intestine but predominantly within UEA-1-expressing cells. Although Gα[subscript]gust, 5-HT and GLP-1 are largely expressed in mutually exclusive cells, within the jejunum a portion Gαgust positive cells coexpressed 5-HT or GLP-1. This Indicates a subpopulation of intestinal taste cells may be dedicated to carbohydrate-evoked gastrointestinal reflexes through 5-HT and GLP-1 mediated pathways, however, taste transduction within the small intestine appears to predominantly link to alternate mediators. After nutrient detection at the luminal surface, activation of mucosal afferents by 5-HT released from enterochromaffin cells is well documented, however although vagal afferents express GLP-1 receptors direct activation has not been demonstrated. For this purpose the effects of GLP-1 on gastrointestinal vagal afferents were investigated through single fibre recordings in in vitro tissue preparations. GLP-1 had no effect on the activity of mouse gastroesophageal vagal afferents but a rat duodenal preparation proved too problematic to be able to test GLP-1 specifically on duodenal vagal afferents. Altered gastric motility in response to carbohydrate meals due to prior dietary patterns and diabetes mellitus suggest adaptation in feedback mechanisms. Towards the second aim of this thesis taste molecule expression was quantified in fed and fasted mice by real time RT-PCR and revealed taste gene transcription is altered with the changing luminal environment, specifically transcription of taste genes was significantly decreased after feeding compared to the fasted state. Studies comparing expression in the duodenum of type 2 diabetics and non-diabetic controls show no significant difference in taste transcript levels between the two groups. However taste molecule expression was correlated to blood glucose levels in diabetics suggesting transcription of these signal molecules is adapted to both luminal and systemic carbohydrate levels. Findings in both the mouse and human gastrointestinal tract in terms of intestinal chemosensing are discussed. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1363582 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Sciences, 2009

The mucosa of the small intestine is clearly able to discriminate specific chemical components of ingested meals to stimulate gastrointestinal feedback pathways and reduce further food intake. Luminal carbohydrates delay gastric emptying and initiate satiation, which are mediated by reflexes via the vagus nerve upon activation of vagal afferent endings in the mucosa. Nutrients activate these nerve fibres through intermediary epithelial cells, which release neuromediators upon transduction of luminal signals through the apical membrane. 5-hydroxytryptamine (5-HT) and glucagon-like peptide-1 (GLP-1) are released from enteroendocrine cells in response to luminal carbohydrates and both slow gastric emptying and inhibit food intake via vagal afferent pathways. The molecular mechanisms for carbohydrate detection and transduction leading to 5-HT and GLP-1 release are unknown. However molecules key to transduction of taste by receptor cells in the lingual epithelium are expressed in the gastrointestinal mucosa. The studies in this thesis aimed to investigate 1) the possibility that taste molecules expressed in the intestine form part of the carbohydrate sensing pathway that leads to 5-HT and GLP-1 release, which in turn activate mucosal vagal afferents and 2) to gauge any alterations in taste molecule expression that may relate to adaptation of carbohydrate-induced gastric motility reflexes that occurs in dietary and disease states. Firstly these studies show key taste molecules, including sweet taste receptors T1R2 and T1R3, the Gprotein gustducin (alpha-subunit Gαgust), and the taste transduction channel TRPM5, are expressed in the mouse gastrointestinal mucosa shown by RT-PCR and were further localised to individual epithelial ‘taste’ cells using immunohistochemistry. Quantification of transcript levels by real time RT-PCR revealed the proximal small intestine as the preferential site of sweet taste receptor expression along the gastrointestinal tract. This finding was also confirmed in humans using gastric and intestinal mucosal biopsies obtained at enteroscopy with significantly higher transcript expression levels in the small intestine compared to stomach. In the mouse, double label immunohistochemistry with Gα[subscript]gust antibody, as a marker of intestinal taste cells, was performed using lectin UEA-1, a marker of intestinal brush cells, and 5-HT or GLP-1 to link intestinal taste transduction to 5-HT and GLP-1 release. Results show Gα[subscript]gust is expressed within a subset of all three cell types in the small intestine but predominantly within UEA-1-expressing cells. Although Gα[subscript]gust, 5-HT and GLP-1 are largely expressed in mutually exclusive cells, within the jejunum a portion Gαgust positive cells coexpressed 5-HT or GLP-1. This Indicates a subpopulation of intestinal taste cells may be dedicated to carbohydrate-evoked gastrointestinal reflexes through 5-HT and GLP-1 mediated pathways, however, taste transduction within the small intestine appears to predominantly link to alternate mediators. After nutrient detection at the luminal surface, activation of mucosal afferents by 5-HT released from enterochromaffin cells is well documented, however although vagal afferents express GLP-1 receptors direct activation has not been demonstrated. For this purpose the effects of GLP-1 on gastrointestinal vagal afferents were investigated through single fibre recordings in in vitro tissue preparations. GLP-1 had no effect on the activity of mouse gastroesophageal vagal afferents but a rat duodenal preparation proved too problematic to be able to test GLP-1 specifically on duodenal vagal afferents. Altered gastric motility in response to carbohydrate meals due to prior dietary patterns and diabetes mellitus suggest adaptation in feedback mechanisms. Towards the second aim of this thesis taste molecule expression was quantified in fed and fasted mice by real time RT-PCR and revealed taste gene transcription is altered with the changing luminal environment, specifically transcription of taste genes was significantly decreased after feeding compared to the fasted state. Studies comparing expression in the duodenum of type 2 diabetics and non-diabetic controls show no significant difference in taste transcript levels between the two groups. However taste molecule expression was correlated to blood glucose levels in diabetics suggesting transcription of these signal molecules is adapted to both luminal and systemic carbohydrate levels. Findings in both the mouse and human gastrointestinal tract in terms of intestinal chemosensing are discussed. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1363582 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Sciences, 2009

Lic.-avh. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 2 uppsatser.

The current epidemic of obesity has been linked to an increase in fat intake associated with the Western diet. Nutrient-induced stimulation of enteroendocrine cells in the small intestine leads to the release of hormones that contribute to satiety and the control of food intake. In particular, ingested fat, specifically in the form of free fatty acids, is potent activator of enteroendocrine cells in the proximal small intestine. However, the underlying signaling cascade that free fatty acids initiate in these enteroendocrine cells, which leads to secretion of satiety hormones, is not known. In general, my research is focused on identifying nutrient-responsive pathways in enteroendocrine cells involved with the release of satiety signals and using this information to begin to develop novel drug delivery strategies to reduce food intake. In general, my results revealed that activation of the fatty acid receptor GPR120 was ecessary for the linoleic acid-induced intracellular calcium rise, a necessary precursor for hormone release. Using patch clamp recording, I discovered that linoleic acid activated enteroendocrine cells by inducing membrane depolarization, a process requiring the calcium-activated, monovalent cation permeable channel TRPM5, which is activated downstream of GPR120. To validate the unexpected finding that TRPM5 was involved in fattyacid signaling, I performed experiments using bitter compounds, whose transduction pathway is known to involve TRPM5. Enteroendocrine cells express the bitter taste receptors and release cholecystokinin in response to bitter stimuli, suggesting the probable role of gut in initiation of protective behavior against ingestion of potentially harmful substances. Armed with the data on the specifics of the fatty acid transduction, I performed experiments using nanoparticles to determine their utility for delivering pharmaceuticals specifically to the enteroendocrine cells. I fabricated and characterized PLGA nanoparticles and performed intracellular uptake studies in order to optimally delivery payloads inside cells. Finally, I validated their use by using cell-based assays to determine the effects of internalized PLGA nanoparticles on ion channels and signaling pathways involved in CCK release. Taken together, this dissertation research has identified the signaling pathways (pharmacological targets) involved in fatty acid-mediated satiety hormone release and validated the potential therapeutic use of nanoparticle-mediated drug delivery for the eventual control of food intake.

No description available.

L’intestin est un organe majeur de l’organisme de par ses fonctions et sa localisation, établissant une barrière active avec un environnement complexe composé du microbiote intestinal, des aliments digérés et d’éléments sécrétés par l’hôte. Outre ses fonctions digestives, absorptives et immuno-modulatrices, l’intestin est également un important organe endocrinien, sécrétant une vingtaine d’hormones régulant des fonctions physiologiques telles que la prise alimentaire, le métabolisme énergétique ou la digestion et le transit intestinal. Ces hormones sont produites par une famille de cellules épithéliales, les cellules entéroendocrines, et sécrétées en réponse à l’activation de récepteurs reconnaissant des éléments du contenu intestinal. En particulier, les cellules entéroendocrines de type L sécrètent GLP-1 et Peptide YY (PYY), impliqués respectivement dans le contrôle de la sécrétion d’insuline et dans la régulation de la prise alimentaire ainsi que le contôle du transit intestinal. Elles sont majoritairement localisées dans l’iléon et le côlon, là où le microbiote intestinal est le plus dense. Le microbiote intestinal permet notamment la fermentation des fibres en acides gras à chaîne courte (AGCC), la production de vitamines, la maturation du système immunitaire de l’hôte et joue lui-même un rôle de barrière contre les pathogènes. Un dialogue entre le microbiote intestinal et l’hôte est nécessaire dans le maintien de l’homéostasie intestinale, nécessitant la reconnaissance par l’hôte de produits bactériens. En particulier, les récepteurs Toll-Like (TLR) permettent la reconnaissance de motifs moléculaires microbiens conservés et sont impliqués dans l’immunité innée de l’hôte. Certains produits bactériens ont également un rôle physiologique tels que les AGCC qui sont une source d’énergie importante pour les colonocytes, en plus d’activer des voies de signalisation. Il a été montré que des régimes riches en fibres, et donc permettant une production accrue d’AGCC, ou plus directement l’administration d’AGCC dans le colon, induit chez l’Homme ou la souris une augmentation des concentrations plasmatiques de PYY, par des mécanismes encore peu compris. En utilisant des lignées cellulaires humaines modèles de cellules entéroendocrines, nous avons caractérisé les effets des AGCC et des motifs bactériens reconnus par les TLR sur l’expression et la sécrétion de PYY et les réponses calciques dans ces cellules. Nous avons pu démontrer que les TLR sont exprimés de manière fonctionnelle, à l’exception de TLR4 et TLR8 dans ces cellules, et que le butyrate augmente leur expression et leur activité. De plus, la stimulation des TLR augmente l’expression de Pyy d’un rapport de 2, mais a peu d’effet sur la sécrétion dans ces cellules. Les AGCC ont des effets divers sur l’expression et la sécrétion de PYY. Alors que le butyrate et le propionate augmentent très fortement l’expression de Pyy, par des rapports respectivement de 120 et 40, par un mécanisme d’inhibition des déacétylases d’histone et de lysine, l’acétate augmente l’expression de Pyy plus modestement par l’activation des récepteurs aux AGCC FFAR2 et FFAR3. L’activation de FFAR2 par les AGCC induit une forte réponse calcique oscillatoire induisant la sécrétion de PYY alors que l’activation de FFAR3 et de GPR109a par le butyrate diminue la concentration calcique cellulaire et réduit les réponses sécrétoires. Ainsi, les AGCC augmentent la production de PYY et régulent sa sécrétion, mais avec et par des effets différents. Ces travaux ont permis de montrer le rôle des cellules entéroendocrines humaines de type L dans la reconnaissance de produits bactériens par l’expression de TLR et par leurs réponses aux AGCCs modulant l’expression et de la sécrétion de PYY. De plus, ces résultats ont déterminés en partie les mécanismes impliqués dans la réponse bénéfique de l’hôte à la consommation de fibres et l’augmentation de la production d’AGCC. / The human gut exerts major functions, mainly due to its localization and by forming an active barrier between a complex environment made of the gut microbiota, digested food products and secreted elements by the host. The main functions of the gut are digestion and absorption of nutrients and it is the first pool of immune cells and a barrier against pathogens, but the gut is also a main endocrine organ secreting more than twenty different hormones. These hormones regulate a wide range physiological functions including food intake, energy metabolism or digestion. Enteroendocrine cells, a sparse family of intestinal epithelial cells, produce and secrete these hormones in response to the activation of a variety of receptors that sense luminal content. Among them, L-cells secrete GLP-1 and Peptide YY (PYY) that are implicated in the regulation of insulin secretion, food intake and intestinal motility. They are mainly found in the distal ileum and in the colon where the microbiota is the densest. Gut microbiota ferments fibers into short chain fatty acids (SCFAs), produces vitamins, participates in regulation of host immune system and is a barrier against pathogens. The cross talk between microbiota and intestinal epithelium is important to maintain the local homeostasis, and is mediated by host receptors recognizing microbial products. Among them, Toll-like receptors (TLRs) recognize conserved microbial associate molecular patterns (MAMPs) and participate to the host innate immunity. Some microbial products also have important functions for the host such has SCFAs that are an important energy substrate for colonocytes and can also activate different signaling pathways. It was shown that fiber-rich diets, increasing production of SCFAs, as well as direct administration of SCFAs in the colon in humans or mice increased PYY plasma levels through mechanisms still undeciphered. Taking advantage of human cell lines as L-cell models, we assessed the different effects of SCFAs and TLR stimulation on PYY expression and secretion and calcium signaling in these cells. We showed that TLRs are functionally expressed in these cells at the exception of TLR4 and TLR8, and that butyrate, one of the three main SCFAs produced by the microbiota increases cell sensitivity to TLR stimulation by increasing their expression. Moreover, TLR stimulation increases Pyy expression by a fold of two but has little effect on secretion. SCFAs differently regulate Pyy expression. Propionate and butyrate highly increase Pyy expression by a fold of 40 and 120 respectively, and their effects are mainly mediated by inhibition of lysine/histone deacetylases whereas acetate increases expression of Pyy by a fold of 1.8 through stimulation of FFAR2 and FFAR3. SCFAs also induce a strong FFAR2-dependent oscillatory response monitoring PYY secretion whereas butyrate via FFAR3 and GPR109a decreases cytosolic calcium concentration and consequently reduces secretory responses. Thus, SCFAs differently increase PYY production and secretion depending of their chain length. Altogether, these results highlight the role human L-cells in microbiota-host crosstalk by sensing microbial products through expression of TLRs and their responses to SCFAs modulating PYY production and secretion. Furthermore, we deciphered some of the mechanisms implicated in beneficial host response to enriched fiber diets and increased production of SCFAs.

Tesis por compendio / [ES] La obesidad es un gran reto de salud pública que ha alcanzado proporciones epidémicas. El entorno "occidentalizado" en el que vivimos, caracterizado por la accesibilidad a alimentos hipercalóricos, contribuye al desequilibrio crónico entre energía ingerida y gasto energético que causan la obesidad. Las intervenciones conductuales diseñadas para la pérdida de peso tienen limitada efectividad a largo plazo, por lo que existe una urgente necesidad de desarrollar estrategias más eficaces y seguras para prevenir y tratar la obesidad y sus comorbilidades. El desarrollo de estrategias terapéuticas dirigidas al intestino para mejorar la salud metabólica requiere un conocimiento en profundidad de las vías de señalización neuroendocrina intestinal que regulan el la ingesta y el equilibrio energético. El objetivo de esta tesis ha sido profundizar en las interacciones intestino-cerebro implicadas en el control de la homeostasis energética, incluyendo los componentes endocrinos, neurales y la microbiota intestinal, en el contexto del desarrollo de la obesidad inducida por una dieta hipercalórica. En los Capítulos 1 y 2 hemos explorado nuevas funciones de las neuronas sensoriales aferentes que expresan el canal de sodio Nav1.8 en el control de la homeostasis energética, considerando las diferencias entre sexos. Hemos generado un modelo de ratón carente de las neuronas Nav1.8+ mediante ablación con toxina diftérica. En el Capítulo 1 hemos demostrado que las neuronas Nav1.8+ son indispensables para regular específicamente según el sexo las vías neurales y endocrinas implicadas en la homeostasis energética. En hembras, la ablación de estas neuronas mejora la regulación de la glucosa postprandial potenciando la señalización enteroendocrina de GLP-1 y acelera el tránsito intestinal, mientras que en machos induce resistencia al aumento de peso inducido por una dieta obesogénica. En el Capítulo 2 hemos demostrado que, en machos, la ablación de las neuronas Nav1.8+ altera el control coordinado de la ingesta i las variaciones de peso diarias, además de alterar la señalización enteroendocrina y las oscilaciones diarias de la microbiota intestinal en respuesta al estado nutricional (ayuno/ingesta), y perturbar la homeostasis del sistema inmune intestinal. En el capítulo 3, hemos usado un modelo de ratón con obesidad inducida por dieta para explorar los mecanismos por los cuales Phascolarctobacterium faecium DSM 32890, una cepa bacteriana intestinal aislada de humanos metabólicamente sanos, previene la obesidad modulando la ingesta. La administración de P. faecium reduce la ingesta calórica gracias a la hipersecreción de la hormona gastrointestinal saciante el PYY. Independientemente de sus efectos anorexigénicos, la bacteria ejerce sus beneficios metabólicos estimulando el tránsito intestinal y reduciendo la absorción intestinal de lípidos, evitando la acumulación de grasa corporal. En conclusión, esta tesis doctoral proporciona evidencia preclínica que contribuye a una comprensión más precisa de las vías neuroendocrinas que comunican el intestino y el cerebro, y del papel que tiene la microbiota intestinal en la regulación de la ingesta y el gasto energético. Destacamos la importancia de las neuronas sensoriales aferentes Nav1.8+ en la detección de estímulos intestinales por quimiorreceptores para regular el balance energético en ambos sexos, lo cual abre una nueva línea de investigación para diseñar herramientas de neuromodulación de las neuronas Nav1.8+ con el fin de prevenir y tratar los trastornos metabólicos inducidos por la dieta, de forma específica para cada sexo. También destacamos que P. faecium es una bacteria candidata como probiótico de nueva generación, ya que modula el sistema enteroendocrino del hospedador y previene la obesidad en un modelo preclínico. En conjunto, estos hallazgos proporcionan una base para el desarrollo de estrategias terapéuticas basadas en el intestino dirigidas a combatir la obesidad y comorbilidades asociadas. / [CA] L'obesitat és un gran repte de salut pública que ha assolit proporcions epidèmiques. L'entorn "occidentalitzat" en el que vivim, caracteritzat per l'accessibilitat a aliments hipercalòrics, contribueix al desequilibri crònic entre energia ingerida i despesa energètica que causen l'obesitat. Les intervencions conductuals dissenyades per a la pèrdua de pes tenen una eficàcia limitada a llarg termini, per la qual cosa hi ha una necessitat urgent de desenvolupar estratègies més eficaces i segures per a prevenir i tractar l'obesitat i les seues comorbiditats. El desenvolupament d'estratègies terapèutiques dirigides a l'intestí per a millorar la salut metabòlica requereix un coneixement en profunditat de les vies de senyalització neuroendocrina intestinal que regulen la ingesta i l'equilibri energètic. L'objectiu d'aquesta tesi ha sigut aprofundir en les interaccions intestí-cervell implicades en el control de l'homeòstasi energètica, incloent els components endocrins, neurals i la microbiota intestinal, en el context del desenvolupament de l'obesitat induïda per una dieta hipercalòrica. En els Capítols 1 i 2 hem explorat noves funcions de les neurones sensorials aferents que expressen el canal de sodi Nav1.8 en el control de l'homeòstasi energètica, considerant les diferències entre sexes. Hem generat un model de ratolí mancat de les neurones Nav1.8+ mitjançant ablació amb toxina diftèrica. En el Capítol 1 hem demostrat que les neurones Nav1.8+ són indispensables per a regular, específicament segons el sexe, les vies neurals i endocrines implicades en l'homeòstasi energètica. En femelles, l'ablació d'aquestes neurones millora la regulació de la glucosa postprandial potenciant la senyalització enteroendocrina de GLP-1 i accelera el trànsit intestinal, mentre que en mascles indueix resistència a l'augment de pes induït per una dieta obesogènica. En el Capítol 2 hem demostrat que, en mascles, l'ablació de les neurones Nav1.8+ altera el control coordinat de la ingesta i les variacions de pes diàries, a més d'alterar la senyalització enteroendocrina i les oscil·lacions diàries de la microbiota intestinal en resposta a l'estat nutricional (dejuni/ingesta), i pertorbar l'homeòstasi del sistema immunitari intestinal. En el capítol 3, hem utilitzat un model de ratolí amb obesitat induïda per dieta per explorar els mecanismes pels quals Phascolarctobacterium faecium DSM 32890, una soca bacteriana intestinal aïllada d'humans metabòlicament sans, prevé l'obesitat modulant la ingesta. L'administració de P. faecium redueix la ingesta calòrica gràcies a la hipersecreció de l'hormona gastrointestinal saciant PYY. Independentment dels seus efectes anorexigènics, el bacteri exerceix els seus beneficis metabòlics estimulant el trànsit intestinal i reduint l'absorció intestinal de lípids, evitant l'acumulació de greix corporal. En conclusió, aquesta tesi doctoral proporciona evidència preclínica que contribueix a una comprensió més precisa de les vies neuroendocrines que comuniquen l'intestí i el cervell, i del paper que té la microbiota intestinal en la regulació de la ingesta i la despesa energètica. Destaquem la importància de les neurones sensorials aferents Nav1.8+ en la detecció d'estímuls intestinals per quimioreceptors per a regular l'equilibri energètic en ambdós sexes, que obri una nova línia d'investigació per a dissenyar ferramentes de neuromodulació de les neurones Nav1.8+ amb la finalitat de prevenir i tractar els trastorns metabòlics induïts per la dieta, de forma específica per a cada sexe. També destaquem que P. faecium és un bacteri candidat com a probiòtic de nova generació, ja que modula el sistema enteroendocrí de l'hoste i prevé l'obesitat en un model preclínic. En conjunt, aquests troballes proporcionen una base per al desenvolupament d'estratègies terapèutiques basades en l'intestí dirigides a combatre l'obesitat i comorbiditats associades. / [EN] Obesity is a major global public health challenge that has reached epidemic proportions. Besides its profound impact on health and well-being, this metabolic disorder represents a significant economic burden to society. Our westernized environment where high-calorie foods are readily available, represents a major driver of the chronic imbalance between energy intake and energy expenditure that cause obesity. The limited effectiveness of behavioral interventions to manage long-term weight loss highlights the urgent need to develop more effective and minimally invasive approaches to prevent and treat obesity and its comorbidities. The development of gut-targeted therapeutic strategies to improve metabolic health requires a comprehensive understanding of the gut neuroendocrine signaling pathways that, in interaction with the gut microbiota, control feeding behavior to ultimately maintain energy balance. The aim of this thesis has been to gain insight into gut-brain interactions, including those mediated by endocrine, neural and gut microbial components, involved in the control of energy homeostasis, with a focus on obesogenic diet-related dysfunctions that increase susceptibility to develop obesity. In Chapters 1 and 2, we have investigated novel functions of sensory afferent neurons expressing the sodium channel Nav1.8 in the control of energy homeostasis, considering sex-specificities, by generating a mouse model lacking Nav1.8+ neurons through a diphtheria toxin ablation strategy. In Chapter 1, we show that Nav1.8+ neurons are required to control neural and endocrine pathways involved in energy homeostasis in a sex-specific manner. Specifically, ablation of Nav1.8+ neurons in females improves postprandial glucose regulation by enhancing glucagon-like peptide-1 enteroendocrine signaling and accelerating intestinal transit, whereas in males it induces resistance to weight gain in response to an obesogenic diet. To further explore the role of Nav1.8+ neurons in controlling food intake and pre- and post-prandial daily rhythms that influence metabolic phenotype, in Chapter 2 we show in males that ablation of Nav1.8+ sensory neurons impairs the coordinated control of food intake and body weight fluctuations throughout the day. The loss of these neurons also alters the physiological enteroendocrine signaling and daily gut microbiota oscillations in response to the nutritional status (fasting/refeeding cycles) and disrupts intestinal immune homeostasis. In Chapter 3, we used a diet-induced obese mouse model to investigate the mechanisms by which Phascolarctobacterium faecium DSM 32890, a gut bacterial strain isolated from metabolically healthy humans, prevents obesity by modulating food intake. We show that administration of P. faecium reduces caloric intake by promoting hypersecretion of a satiating gastrointestinal hormone, the peptide YY (PYY). Independently of its anorexigenic effects, the bacterium exerts its metabolic benefits via complementary mechanisms, specifically by stimulating intestinal transit and reducing intestinal lipid absorption, thereby preventing body fat accumulation. In conclusion, this doctoral thesis provides preclinical evidence for a better understanding of gut-to-brain neuroendocrine pathways and the role of gut microbiota in the regulation of food intake and energy expenditure. We highlight the importance of Nav1.8+ sensory afferent neurons in gut chemosensing for maintaining energy balance in both sexes, which prompts novel research lines and opportunities to design of sex-specific neuromodulation tools targeting Nav1.8+ neurons for prevention and treatment of diet-induced metabolic disorders. We also highlight that P. faecium is a promising next-generation probiotic candidate, as it modulates the host enteroendocrine system and prevents obesity in a preclinical model. Overall, our findings contribute to the development of gut-based therapeutic strategies to combat obesity and associated comorbidities. / This study has been funded by the European Union 7th Framework Program through the MyNewGut project (Grant agreement No. 613979) and Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 797297 (MRP), the Spanish Ministry of Science and Innovation (Grant PID2020-119536RB-I00), the European Commission – NextGenerationEU, through the CSIC Interdisciplinary Thematic Platform (PTI+) NEURO- AGING+ (PTI-NEURO-AGING+)”. The grant of the Spanish Ministry of Science and Innovation (MCIN/AEI) to IATA-CSIC as Accredited Center of Excellence (CEX2021-001189-S/ MCIN/AEI / 10.13039/501100011033) is acknowledged. / Bullich Vilarrubias, C. (2024). Influence of gut-to-brain neuroendocrine pathways and intestinal microbiota on energy homeostasis [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/207342 / Compendio