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1.
Clin Microbiol Rev ; 37(3): e0004523, 2024 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-38940505

RESUMEN

SUMMARYThe gut microbiota is a major factor contributing to the regulation of energy homeostasis and has been linked to both excessive body weight and accumulation of fat mass (i.e., overweight, obesity) or body weight loss, weakness, muscle atrophy, and fat depletion (i.e., cachexia). These syndromes are characterized by multiple metabolic dysfunctions including abnormal regulation of food reward and intake, energy storage, and low-grade inflammation. Given the increasing worldwide prevalence of obesity, cachexia, and associated metabolic disorders, novel therapeutic strategies are needed. Among the different mechanisms explaining how the gut microbiota is capable of influencing host metabolism and energy balance, numerous studies have investigated the complex interactions existing between nutrition, gut microbes, and their metabolites. In this review, we discuss how gut microbes and different microbiota-derived metabolites regulate host metabolism. We describe the role of the gut barrier function in the onset of inflammation in this context. We explore the importance of the gut-to-brain axis in the regulation of energy homeostasis and glucose metabolism but also the key role played by the liver. Finally, we present specific key examples of how using targeted approaches such as prebiotics and probiotics might affect specific metabolites, their signaling pathways, and their interactions with the host and reflect on the challenges to move from bench to bedside.


Asunto(s)
Microbioma Gastrointestinal , Obesidad , Humanos , Microbioma Gastrointestinal/fisiología , Obesidad/microbiología , Animales , Comorbilidad , Metabolismo Energético/fisiología , Homeostasis , Probióticos/uso terapéutico , Inflamación/microbiología , Caquexia/microbiología , Caquexia/metabolismo
2.
Int J Food Sci Nutr ; 75(1): 58-69, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37921224

RESUMEN

Gut microbiota is implicated in the control of host physiology by releasing bioactive actors that could exert a direct or indirect effect on tissue. A dysfunction of the gut microbiota to tissue axis could participate in the development of pathological states such as obesity and diabetes. The aim of this study was to identify the metabolic effect of Limosilactobacillus reuteri (known as Lactobacillus reuteri) BIO7251 (L. reuteri BIO7251) isolated from Corsican clementine orange. Body weight gain, adiposity, glucose tolerance, glucose absorption and food intake were measured in mice fed a high-fat diet in response to a preventive oral administration of L. reuteri BIO7251. This strain of bacteria exerts a beneficial effect on body weight gain by decreasing the subcutaneous adipose tissue mass. The treatment with L. reuteri BIO7251 decreases glucose absorption and food intake in obese/diabetic mice. L. reuteri BIO7251 could be tested as new probiotic strain that could manage body weight during obesity.


Asunto(s)
Diabetes Mellitus Experimental , Resistencia a la Insulina , Limosilactobacillus reuteri , Probióticos , Ratones , Animales , Dieta Alta en Grasa/efectos adversos , Ratones Obesos , Obesidad/metabolismo , Peso Corporal , Aumento de Peso , Glucosa/metabolismo , Fenotipo , Tejido Adiposo/metabolismo , Sistema Nervioso/metabolismo
3.
Gut ; 70(6): 1078-1087, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33020209

RESUMEN

OBJECTIVE: The enteric nervous system (ENS) plays a key role in controlling the gut-brain axis under normal and pathological conditions, such as type 2 diabetes. The discovery of intestinal actors, such as enterosynes, able to modulate the ENS-induced duodenal contraction is considered an innovative approach. Among all the intestinal factors, the understanding of the role of gut microbes in controlling glycaemia is still developed. We studied whether the modulation of gut microbiota by prebiotics could permit the identification of novel enterosynes. DESIGN: We measured the effects of prebiotics on the production of bioactive lipids in the intestine and tested the identified lipid on ENS-induced contraction and glucose metabolism. Then, we studied the signalling pathways involved and compared the results obtained in mice to human. RESULTS: We found that modulating the gut microbiota with prebiotics modifies the actions of enteric neurons, thereby controlling duodenal contraction and subsequently attenuating hyperglycaemia in diabetic mice. We discovered that the signalling pathway involved in these effects depends on the synthesis of a bioactive lipid 12-hydroxyeicosatetraenoic acid (12-HETE) and the presence of mu-opioid receptors (MOR) on enteric neurons. Using pharmacological approaches, we demonstrated the key role of the MOR receptors and proliferator-activated receptor γ for the effects of 12-HETE. These findings are supported by human data showing a decreased expression of the proenkephalin and MOR messanger RNAs in the duodenum of patients with diabetic. CONCLUSIONS: Using a prebiotic approach, we identified enkephalin and 12-HETE as new enterosynes with potential real beneficial and safety impact in diabetic human.


Asunto(s)
Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/biosíntesis , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Duodeno/fisiología , Sistema Nervioso Entérico/fisiología , Prebióticos , Receptores Opioides mu/metabolismo , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/farmacología , Adulto , Anciano , Animales , Eje Cerebro-Intestino , Diabetes Mellitus Experimental/fisiopatología , Duodeno/inervación , Encefalinas/genética , Encefalinas/metabolismo , Sistema Nervioso Entérico/efectos de los fármacos , Microbioma Gastrointestinal , Prueba de Tolerancia a la Glucosa , Humanos , Contracción Isotónica/efectos de los fármacos , Masculino , Ratones , Persona de Mediana Edad , Músculo Liso/fisiología , Neuronas/fisiología , Óxido Nítrico Sintasa de Tipo I/genética , Óxido Nítrico Sintasa de Tipo I/metabolismo , Oligosacáridos/farmacología , PPAR gamma/metabolismo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , ARN Mensajero/metabolismo , Receptores Opioides mu/genética , Transducción de Señal
4.
Neuroendocrinology ; 110(1-2): 139-146, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31280267

RESUMEN

The gut-brain axis is of crucial importance for controlling glucose homeostasis. Alteration of this axis promotes the type 2 diabetes (T2D) phenotype (hyperglycaemia, insulin resistance). Recently, a new concept has emerged to demonstrate the crucial role of the enteric nervous system in the control of glycaemia via the hypothalamus. In diabetic patients and mice, modification of enteric neurons activity in the proximal part of the intestine generates a duodenal hyper-contractility that generates an aberrant message from the gut to the brain. In turn, the hypothalamus sends an aberrant efferent message that provokes a state of insulin resistance, which is characteristic of a T2D state. Targeting the enteric nervous system of the duodenum is now recognized as an innovative strategy for treatment of diabetes. By acting in the intestine, bioactive gut molecules that we called "enterosynes" can modulate the function of a specific type of neurons of the enteric nervous system to decrease the contraction of intestinal smooth muscle cells. Here, we focus on the origins of enterosynes (hormones, neurotransmitters, nutrients, microbiota, and immune factors), which could be considered therapeutic factors, and we describe their modes of action on enteric neurons. This unsuspected action of enterosynes is proposed for the treatment of T2D, but it could be applied for other therapeutic solutions that implicate communication between the gut and brain.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Sistema Nervioso Entérico/efectos de los fármacos , Sistema Nervioso Entérico/fisiología , Obesidad/tratamiento farmacológico , Animales , Humanos
5.
J Lipid Res ; 60(3): 636-647, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30626624

RESUMEN

Inside the human host, Leishmania infection starts with phagocytosis of infective promastigotes by macrophages. In order to survive, Leishmania has developed several strategies to manipulate macrophage functions. Among these strategies, Leishmania as a source of bioactive lipids has been poorly explored. Herein, we assessed the biosynthesis of polyunsaturated fatty acid metabolites by infective and noninfective stages of Leishmania and further explored the role of these metabolites in macrophage polarization. The concentration of docosahexaenoic acid metabolites, precursors of proresolving lipid mediators, was increased in the infective stage of the parasite compared with the noninfective stage, and cytochrome P450-like proteins were shown to be implicated in the biosynthesis of these metabolites. The treatment of macrophages with lipids extracted from the infective forms of the parasite led to M2 macrophage polarization and blocked the differentiation into the M1 phenotype induced by IFN-γ. In conclusion, Leishmania polyunsaturated fatty acid metabolites, produced by cytochrome P450-like protein activity, are implicated in parasite/host interactions by promoting the polarization of macrophages into a proresolving M2 phenotype.


Asunto(s)
Ácidos Grasos Insaturados/metabolismo , Interacciones Huésped-Parásitos , Leishmania/fisiología , Animales , Células CHO , Cricetulus , Leishmania/metabolismo , Macrófagos/citología , Macrófagos/metabolismo , Macrófagos/parasitología , Masculino , Ratones , Ratones Endogámicos C57BL , Fenotipo
6.
Ecotoxicol Environ Saf ; 161: 459-466, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-29909315

RESUMEN

Since 2010, Bisphenol A (BPA), an endocrine disruptor has been restricted and replaced by analogues like Bisphenol S (BPS). However, little is known about BPS effects and growing concern have suspected the "BPA-free" Label. Several recent studies suggest that BPS is associated with increased risk of diabetes and obesity. However, the underlying mechanisms remain unidentified. The current study investigates investigate BPS effects on hypothalamic neuropeptides regulating feeding behavior, either orexigenic or anorexigenic in Swiss Albino mice. We also studied the effect of BPS on the apelinergic system (apelin/apelin receptor (APJ)) as an original physiological system with pleiotropic actions. Bisphenol S at 25, 50, 100 µg/kg was administered to mice in water drink for 10 weeks started after weaning. Our results showed that BPS exposure alters orexigenic hypothalamic neuropeptide (AgRP) regulating feeding behavior but not anorexigenic neuropeptides (POMC, CART). Such orexigenic alterations may underlay appetite disorders leading to a concomitant food intake and body weight gain increase. In addition, data show that BPS affects the hypothalamic apelinergic system. We found a significant decrease in APJ mRNA but not in apelin expression. Based on hypothalamic APJ distribution, we suggested a potent specific physiological alteration of this receptor in mediating neuroendocrine responses in hypothalamus. Thus, our findings provide that BPS exposure could contribute to the development of obesity and metabolic disorders.


Asunto(s)
Apelina/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Neuropéptidos/metabolismo , Fenoles/toxicidad , Sulfonas/toxicidad , Animales , Receptores de Apelina/metabolismo , Compuestos de Bencidrilo , Peso Corporal , Conducta Alimentaria/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Ratones , Proteínas del Tejido Nervioso/metabolismo , Neuropéptidos/genética , Obesidad/inducido químicamente , Proopiomelanocortina/metabolismo , ARN Mensajero/metabolismo , Aumento de Peso
7.
Proc Natl Acad Sci U S A ; 111(2): E283-90, 2014 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-24371309

RESUMEN

Estrogen receptor alpha (ERα) activation functions AF-1 and AF-2 classically mediate gene transcription in response to estradiol (E2). A fraction of ERα is targeted to plasma membrane and elicits membrane-initiated steroid signaling (MISS), but the physiological roles of MISS in vivo are poorly understood. We therefore generated a mouse with a point mutation of the palmitoylation site of ERα (C451A-ERα) to obtain membrane-specific loss of function of ERα. The abrogation of membrane localization of ERα in vivo was confirmed in primary hepatocytes, and it resulted in female infertility with abnormal ovaries lacking corpora lutea and increase in luteinizing hormone levels. In contrast, E2 action in the uterus was preserved in C451A-ERα mice and endometrial epithelial proliferation was similar to wild type. However, E2 vascular actions such as rapid dilatation, acceleration of endothelial repair, and endothelial NO synthase phosphorylation were abrogated in C451A-ERα mice. A complementary mutant mouse lacking the transactivation function AF-2 of ERα (ERα-AF2(0)) provided selective loss of function of nuclear ERα actions. In ERα-AF2(0), the acceleration of endothelial repair in response to estrogen-dendrimer conjugate, which is a membrane-selective ER ligand, was unaltered, demonstrating integrity of MISS actions. In genome-wide analysis of uterine gene expression, the vast majority of E2-dependent gene regulation was abrogated in ERα-AF2(0), whereas in C451A-ERα it was nearly fully preserved, indicating that membrane-to-nuclear receptor cross-talk in vivo is modest in the uterus. Thus, this work genetically segregated membrane versus nuclear actions of a steroid hormone receptor and demonstrated their in vivo tissue-specific roles.


Asunto(s)
Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Receptor alfa de Estrógeno/genética , Ovario/fisiología , Útero/metabolismo , Análisis de Varianza , Animales , Western Blotting , Movimiento Celular , Biología Computacional , Células Endoteliales , Receptor alfa de Estrógeno/metabolismo , Femenino , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Lipoilación/genética , Ratones , Ratones Transgénicos , Análisis por Micromatrices , Ovario/metabolismo , Mutación Puntual/genética , Receptor Cross-Talk/fisiología
8.
BMC Genomics ; 17: 671, 2016 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-27552843

RESUMEN

BACKGROUND: Microorganisms constitute a reservoir of enzymes involved in environmental carbon cycling and degradation of plant polysaccharides through their production of a vast variety of Glycoside Hydrolases (GH). The CAZyChip was developed to allow a rapid characterization at transcriptomic level of these GHs and to identify enzymes acting on hydrolysis of polysaccharides or glycans. RESULTS: This DNA biochip contains the signature of 55,220 bacterial GHs available in the CAZy database. Probes were designed using two softwares, and microarrays were directly synthesized using the in situ ink-jet technology. CAZyChip specificity and reproducibility was validated by hybridization of known GHs RNA extracted from recombinant E. coli strains, which were previously identified by a functional metagenomic approach. The GHs arsenal was also studied in bioprocess conditions using rumen derived microbiota. CONCLUSIONS: The CAZyChip appears to be a user friendly tool for profiling the expression of a large variety of GHs. It can be used to study temporal variations of functional diversity, thereby facilitating the identification of new efficient candidates for enzymatic conversions from various ecosystems.


Asunto(s)
Glicósido Hidrolasas/genética , Metagenoma , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Análisis de Secuencia de ARN/métodos , Proteínas Bacterianas/genética , Pared Celular/metabolismo , Bases de Datos Genéticas , Escherichia coli/genética , Regulación Bacteriana de la Expresión Génica , Plantas/metabolismo , Polisacáridos/metabolismo
9.
Am J Physiol Gastrointest Liver Physiol ; 310(9): G645-58, 2016 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-26939867

RESUMEN

The gastrointestinal tract is an important interface of exchange between ingested food and the body. Glucose is one of the major dietary sources of energy. All along the gastrointestinal tube, e.g., the oral cavity, small intestine, pancreas, and portal vein, specialized cells referred to as glucosensors detect variations in glucose levels. In response to this glucose detection, these cells send hormonal and neuronal messages to tissues involved in glucose metabolism to regulate glycemia. The gastrointestinal tract continuously communicates with the brain, especially with the hypothalamus, via the gut-brain axis. It is now well established that the cross talk between the gut and the brain is of crucial importance in the control of glucose homeostasis. In addition to receiving glucosensing information from the gut, the hypothalamus may also directly sense glucose. Indeed, the hypothalamus contains glucose-sensitive cells that regulate glucose homeostasis by sending signals to peripheral tissues via the autonomous nervous system. This review summarizes the mechanisms by which glucosensors along the gastrointestinal tract detect glucose, as well as the results of such detection in the whole body, including the hypothalamus. We also highlight how disturbances in the glucosensing process may lead to metabolic disorders such as type 2 diabetes. A better understanding of the pathways regulating glucose homeostasis will further facilitate the development of novel therapeutic strategies for the treatment of metabolic diseases.


Asunto(s)
Tracto Gastrointestinal/metabolismo , Glucosa/metabolismo , Homeostasis , Hiperglucemia/metabolismo , Animales , Tracto Gastrointestinal/fisiología , Humanos , Hipotálamo/metabolismo , Hipotálamo/fisiología
10.
Appl Environ Microbiol ; 81(1): 31-9, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25304507

RESUMEN

Biocatalysts are essential for the development of bioprocesses efficient for plant biomass degradation. Previously, a metagenomic clone containing DNA from termite gut microbiota was pinpointed in a functional screening that revealed the presence of arabinofuranosidase activity. Subsequent genetic and bioinformatic analysis revealed that the DNA fragment belonged to a member of the genus Bacteroides and encoded 19 open reading frames (ORFs), and annotation suggested the presence of hypothetical transporter and regulator proteins and others involved in the catabolism of pentose sugar. In this respect and considering the phenotype of the metagenomic clone, it was noted that among the ORFs, there are four putative arabinose-specific glycoside hydrolases, two from family GH43 and two from GH51. In this study, a thorough bioinformatics analysis of the metagenomic clone gene cluster has been performed and the four aforementioned glycoside hydrolases have been characterized. Together, the results provide evidence that the gene cluster is a polysaccharide utilization locus dedicated to the breakdown of the arabinan component in pectin and related substrates. Characterization of the two GH43 and the two GH51 glycoside hydrolases has revealed that each of these enzymes displays specific catalytic capabilities and that when these are combined the enzymes act synergistically, increasing the efficiency of arabinan degradation.


Asunto(s)
Bacteroides/genética , Bacteroides/metabolismo , Isópteros/microbiología , Redes y Vías Metabólicas/genética , Polisacáridos/metabolismo , Animales , Biología Computacional , Tracto Gastrointestinal/microbiología , Glicósido Hidrolasas/genética , Metagenómica , Familia de Multigenes
11.
Am J Pathol ; 183(1): 304-12, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23669343

RESUMEN

Based on both experimental and clinical data, tamoxifen has been proposed to have cardiovascular benefits, although the mechanism(s) contributing to that protective effect are still poorly understood. In vitro experiments demonstrated that tamoxifen elicits its transcriptional effect through estrogen receptor (ER) α, but other targets can participate in its actions. However, although tamoxifen selectively activates the activating function (AF)-1 of ERα, we recently showed that this ERα subfunction is dispensable for the atheroprotective action of 17ß-estradiol (E2), the main ligand of ERs. The goal of the present work is to determine to which extent ERα and its AF-1 mediate the vasculoprotective action of tamoxifen. Our data confirm that tamoxifen exerts an atheroprotective action on low density lipoprotein receptor (LDL-r(-/-)) female mice, but, in contrast to E2, it fails to accelerate reendothelialization after carotid electric injury. Tamoxifen and E2 elicit differences in gene expression profiles in the mouse aorta. Finally, the atheroprotective action of tamoxifen is abrogated in ERα(-/-)LDL-r(-/-) mice and in LDL-r(-/-) mice selectively deficient in ERαAF-1 (ERαAF-1(0/0)LDL-r(-/-)). Our results demonstrate, for the first time to our knowledge, that tamoxifen mediates its actions in vivo through the selective activation of ERαAF-1, which is sufficient to prevent atheroma, but not to accelerate endothelial healing.


Asunto(s)
Aorta/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Receptor alfa de Estrógeno/metabolismo , Coactivadores de Receptor Nuclear/metabolismo , Placa Aterosclerótica/prevención & control , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Tamoxifeno/farmacología , Animales , Biomarcadores/metabolismo , Arterias Carótidas/efectos de los fármacos , Traumatismos de las Arterias Carótidas , Endotelio Vascular/lesiones , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Placa Aterosclerótica/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Tamoxifeno/uso terapéutico
12.
Nucleic Acids Res ; 40(7): e51, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22228834

RESUMEN

Genomic DNA (gDNA) contamination is an inherent problem during RNA purification that can lead to non-specific amplification and aberrant results in reverse transcription quantitative PCR (RT-qPCR). Currently, there is no alternative to RT(-) controls to evaluate the impact of the gDNA background on RT-PCR data. We propose a novel method (ValidPrime) that is more accurate than traditional RT(-) controls to test qPCR assays with respect to their sensitivity toward gDNA. ValidPrime measures the gDNA contribution using an optimized gDNA-specific ValidPrime assay (VPA) and gDNA reference sample(s). The VPA, targeting a non-transcribed locus, is used to measure the gDNA contents in RT(+) samples and the gDNA reference is used to normalize for GOI-specific differences in gDNA sensitivity. We demonstrate that the RNA-derived component of the signal can be accurately estimated and deduced from the total signal. ValidPrime corrects with high precision for both exogenous (spiked) and endogenous gDNA, contributing ∼60% of the total signal, whereas substantially reducing the number of required qPCR control reactions. In conclusion, ValidPrime offers a cost-efficient alternative to RT(-) controls and accurately corrects for signals derived from gDNA in RT-qPCR.


Asunto(s)
Contaminación de ADN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Animales , ADN/análisis , Cartilla de ADN , Genómica , Ratones , Ratones Endogámicos C57BL
13.
Proc Natl Acad Sci U S A ; 108(32): 13311-6, 2011 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-21788522

RESUMEN

17ß-Estradiol (E2) regulates estrogen receptor-α (ERα) target gene transcription through the two independent activation functions (AFs), AF1 and AF2, located in the N-terminal and ligand binding domain of ERα, respectively. We previously reported that ERα is required for the E2 atheroprotective action as well as for its accelerative action on endothelial healing, but its AF1 function is dispensable. Here, we investigated the role of ERαAF2 in these two major beneficial actions of E2 by electively targeting ERαAF2 (named ERαAF2(0)). Our results prove four points. (i) Compared with WT ERα, the ability of ERαAF2(0) to stimulate the C3 complement or the estrogen response element-thymidine kinase promoter in two cell lines was dramatically decreased, confirming the importance of AF2 in the E2-induced transcriptional activity of ERα. (ii) The uterotrophic action of E2 was totally absent in ERαAF2(0) mice, showing the crucial role of ERαAF2 in E2-induced uterus hyperplasia. (iii) ERαAF2 was dispensable for the accelerative action of E2 on endothelial healing, underlining the functionality of ERαAF2(0) in vivo. (iv) Finally, the atheroprotective effect of E2 was abrogated in ERαAF2(0) LDL-r(-/-) mice. Thus, whereas ERαAF1 and ERαAF2 are both required for the uterotrophic action of E2, we show that only ERαAF2 is necessary for its atheroprotective effect.


Asunto(s)
Aterosclerosis/prevención & control , Endotelio Vascular/patología , Estradiol/farmacología , Receptor alfa de Estrógeno/metabolismo , Sustancias Protectoras/farmacología , Activación Transcripcional/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Aorta/patología , Aterosclerosis/patología , Peso Corporal/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Células HeLa , Células Hep G2 , Humanos , Ratones , Ratones Noqueados , Tamaño de los Órganos/efectos de los fármacos , Reproducibilidad de los Resultados , Útero/efectos de los fármacos , Útero/metabolismo , Útero/patología
14.
Heliyon ; 10(7): e28320, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38586362

RESUMEN

Background and objective: The leaky gut syndrome is characterized by an intestinal hyperpermeability observed in multiple chronic disorders. Alterations of the gut barrier are associated with translocation of bacterial components increasing inflammation, oxidative stress and eventually dysfunctions of cellular interactions at the origin pathologies. Therapeutic and/or preventive approaches have to focus on the identification of novel targets to improve gut homeostasis. In this context, this study aims to identify the role of PERMEAPROTECT + TOLERANE©, known as PERMEA, a food complement composed of a combination of factors (including l-Glutamine) known to improve gut physiology. Methods: We tested the effects of PERMEA or l-Glutamine alone (as reference) on gut permeability (FITC dextran method, expression of tight junctions) and its inflammatory/oxidative consequences (cytokines and redox assays, RT-qPCR) in a co-culture of human cells (peripheral blood mononuclear cells and intestinal epithelial cells) challenged with TNFα. Results: PERMEA prevented intestinal hyperpermeability induced by inflammation. This was linked with its antioxidant and immunomodulatory properties showing a better efficacity than l-Glutamine alone on several parameters including permeability, global antioxidant charge and production of cytokines. Conclusion: PERMEA is more efficient to restore intestinal physiology, reinforcing the concept that combination of food constituents could be used to prevent the development of numerous diseases.

15.
Heliyon ; 9(7): e18196, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37501991

RESUMEN

Background and objective: Pasteurized Akkermansia muciniphila cells have shown anti-diabetic effects in rodents and human. Although, its primary site of action consists in maintaining the gut barrier function, there are no study exploring if A. muciniphila controls glycemia via a gut to brain axis. Targeting the gut motility represents an alternative pathway to treat hyperglycemia. Here, we tested the impact of pasteurized A. muciniphila on gut motility, gut-brain axis and glucose metabolism. Methods: We used mice fed a 45% high-fat (HFD) treated or not with pasteurized A. muciniphila MucT during 12 weeks. We measured the effects of the treatment on body weight gain, glucose metabolism (insulin, glycemia, glucose tolerance), gut contraction and enteric neurotransmitter release, and hypothalamic nitric oxide (NO) release. Results: We show that pasteurized A. muciniphila exerts positive effects on different metabolic parameters such as body weight, fat mass, insulin, glycemia and glucose tolerance. This could be explained by the ability of pasteurized A. muciniphila supplementation to decrease duodenal contraction and to increase hypothalamic NO release in HFD mice. Conclusion: We demonstrate a novel mode of action of pasteurized A. muciniphila explaining its beneficial impact on the control of glycemia in a preclinical model of type 2 diabetes via gut-brain axis signaling.

16.
Commun Biol ; 6(1): 1168, 2023 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-37968381

RESUMEN

Opioid-dependent immune-mediated analgesic effects have been broadly reported upon inflammation. In preclinical mouse models of intestinal inflammatory diseases, the local release of enkephalins (endogenous opioids) by colitogenic T lymphocytes alleviate inflammation-induced pain by down-modulating gut-innervating nociceptor activation in periphery. In this study, we wondered whether this immune cell-derived enkephalin-mediated regulation of the nociceptor activity also operates under steady state conditions. Here, we show that chimeric mice engrafted with enkephalin-deficient bone marrow cells exhibit not only visceral hypersensitivity but also an increase in both epithelial paracellular and transcellular permeability, an alteration of the microbial topography resulting in increased bacteria-epithelium interactions and a higher frequency of IgA-producing plasma cells in Peyer's patches. All these alterations of the intestinal homeostasis are associated with an anxiety-like behavior despite the absence of an overt inflammation as observed in patients with irritable bowel syndrome. Thus, our results show that immune cell-derived enkephalins play a pivotal role in maintaining gut homeostasis and normal behavior in mice. Because a defect in the mucosal opioid system remarkably mimics some major clinical symptoms of the irritable bowel syndrome, its identification might help to stratify subgroups of patients.


Asunto(s)
Síndrome del Colon Irritable , Humanos , Animales , Ratones , Analgésicos Opioides , Encefalinas/genética , Inflamación , Dolor
17.
Nat Metab ; 5(3): 495-515, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36941451

RESUMEN

Muscle degeneration is the most prevalent cause for frailty and dependency in inherited diseases and ageing. Elucidation of pathophysiological mechanisms, as well as effective treatments for muscle diseases, represents an important goal in improving human health. Here, we show that the lipid synthesis enzyme phosphatidylethanolamine cytidyltransferase (PCYT2/ECT) is critical to muscle health. Human deficiency in PCYT2 causes a severe disease with failure to thrive and progressive weakness. pcyt2-mutant zebrafish and muscle-specific Pcyt2-knockout mice recapitulate the participant phenotypes, with failure to thrive, progressive muscle weakness and accelerated ageing. Mechanistically, muscle Pcyt2 deficiency affects cellular bioenergetics and membrane lipid bilayer structure and stability. PCYT2 activity declines in ageing muscles of mice and humans, and adeno-associated virus-based delivery of PCYT2 ameliorates muscle weakness in Pcyt2-knockout and old mice, offering a therapy for individuals with a rare disease and muscle ageing. Thus, PCYT2 plays a fundamental and conserved role in vertebrate muscle health, linking PCYT2 and PCYT2-synthesized lipids to severe muscle dystrophy and ageing.


Asunto(s)
Insuficiencia de Crecimiento , ARN Nucleotidiltransferasas , Animales , Humanos , Ratones , Ratones Noqueados , Debilidad Muscular/genética , Músculos , ARN Nucleotidiltransferasas/química , ARN Nucleotidiltransferasas/genética , Pez Cebra
18.
Antioxid Redox Signal ; 37(4-6): 394-415, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-34714099

RESUMEN

Significance: The role of reactive oxygen/nitrogen species as "friend" or "foe" messengers in the whole body is well characterized. Depending on the concentration in the tissue considered, these molecular actors exert beneficial or deleterious impacts leading to a pathological state, as observed in metabolic disorders such as type 2 diabetes and obesity. Recent Advances: Among the tissues impacted by oxidation and inflammation in this pathological state, the intestine is a site of dysfunction that can establish diabetic symptoms, such as alterations in the intestinal barrier, gut motility, microbiota composition, and gut/brain axis communication. In the intestine, reactive oxygen/nitrogen species (from the host and/or microbiota) are key factors that modulate the transition from physiological to pathological signaling. Critical Issues: Controlling the levels of intestinal reactive oxygen/nitrogen species is a complicated balance between positive and negative impacts that is in constant equilibrium. Here, we describe the synthesis and degradation of intestinal reactive oxygen/nitrogen species and their interactions with the host. The development of novel redox-based therapeutics that alter these processes could restore intestinal health in patients with metabolic disorders. Future Directions: Deciphering the mode of action of reactive oxygen/nitrogen species in the gut of obese/diabetic patients could result in a future therapeutic strategy that combines nutritional and pharmacological approaches. Consequently, preventive and curative treatments must take into account one of the first sites of oxidative and inflammatory dysfunctions in the body, that is, the intestine. Antioxid. Redox Signal. 37, 394-415.


Asunto(s)
Diabetes Mellitus Tipo 2 , Humanos , Nitrógeno , Obesidad/metabolismo , Oxígeno/metabolismo , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo
19.
Nutrients ; 14(10)2022 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-35631317

RESUMEN

(1) Background: Type 2 diabetes (T2D) is associated with a duodenal hypermotility in postprandial conditions that favors hyperglycemia and insulin resistance via the gut-brain axis. Enterosynes, molecules produced within the gut with effects on the enteric nervous system, have been recently discovered and pointed to as potential key modulators of the glycemia. Indeed, targeting the enteric nervous system that controls gut motility is now considered as an innovative therapeutic way in T2D to limit intestinal glucose absorption and restore the gut-brain axis to improve insulin sensitivity. So far, little is known about the role of glucose on duodenal contraction in fasted and fed states in normal and diabetic conditions. The aim of the present study was thus to investigate these effects in adult mice. (2) Methods: Gene-expression level of glucose transporters (SGLT-1 and GLUT2) were quantified in the duodenum and jejunum of normal and diabetic mice fed with an HFD. The effect of glucose at different concentrations on duodenal and jejunal motility was studied ex vivo using an isotonic sensor in fasted and fed conditions in both normal chow and HFD mice. (3) Results: Both SGLT1 and GLUT2 expressions were increased in the duodenum (47 and 300%, respectively) and jejunum (75% for GLUT2) of T2D mice. We observed that glucose stimulates intestinal motility in fasted (200%) and fed (400%) control mice via GLUT2 by decreasing enteric nitric oxide release (by 600%), a neurotransmitter that inhibits gut contractions. This effect was not observed in diabetic mice, suggesting that glucose sensing and mechanosensing are altered during T2D. (4) Conclusions: Glucose acts as an enterosyne to control intestinal motility and glucose absorption through the enteric nervous system. Our data demonstrate that GLUT2 and a reduction of NO production could both be involved in this stimulatory contracting effect.


Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Animales , Glucemia/metabolismo , Glucosa/metabolismo , Ratones , Óxido Nítrico/metabolismo
20.
Mol Cell Endocrinol ; 557: 111752, 2022 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-35973528

RESUMEN

Hypothalamic control of reproduction relies on GnRH and kisspeptin (KP) secretions. KP neurons are sensitive to sex steroids and metabolic status and their distribution overlaps with neurons producing apelin, a metabolic hormone known to decrease LH secretion in rats. Here, we observed neuroanatomical contacts between apelin fibers and both KP and GnRH neurons in the hypothalamus of male rodents. Intracerebroventricular apelin infusion for 2 weeks in male mice did not decrease LH levels nor did it affect gene expression for KP, neurokinin B and dynorphin. Finally, increasing apelin concentrations did not modulate Ca2+ levels of cultured GnRH neurons, while 10 µM apelin infusion on forskolin pretreated GnRH neurons revoked a rhythmic activity in 18% of GnRH neurons. These results suggest that acute apelin effect on LH secretion does not involve modulation of gene expression in KP neurons but may affect the secretory activity of GnRH neurons.


Asunto(s)
Hormona Liberadora de Gonadotropina , Neuroquinina B , Animales , Apelina , Receptores de Apelina , Núcleo Arqueado del Hipotálamo/metabolismo , Colforsina/farmacología , Dinorfinas/genética , Hormona Liberadora de Gonadotropina/metabolismo , Kisspeptinas/metabolismo , Hormona Luteinizante/metabolismo , Hormona Luteinizante/farmacología , Masculino , Ratones , Neuroquinina B/genética , Neuronas/metabolismo , Ratas , Esteroides/metabolismo
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