RESUMEN
The intestinal barrier plays a crucial role in homeostasis by both facilitating the absorption of nutrients and fluids and providing a tight shield to prevent the invasion by either pathogen or commensal microorganisms. Intestinal barrier malfunction is associated with systemic inflammation, oxidative stress, and decreased insulin sensitivity, which may lead to the dysregulation of other tissues. Therefore, a deeper understanding of physiological aspects related to an enhanced barrier function is of significant scientific and clinical relevance. The naked mole-rat has many unusual biological features, including attenuated colonic neuron sensitivity to acid and bradykinin and resistance to chemical-induced intestinal damage. However, insight into their intestinal barrier physiology is scarce. Here, we observed notable macroscopic and microscopic differences in intestinal tissue structure between naked mole-rats and mice. Moreover, naked mole-rats showed increased number of larger goblet cells and elevated mucus content. In measuring gut permeability, naked mole-rats showed reduced permeability compared with mice, measured as transepithelial electrical resistance, especially in ileum. Furthermore, intestinal ion secretion induced by serotonin, bradykinin, histamine, and capsaicin was significantly reduced in naked mole-rats compared with mice, despite the expression of receptors for all these agonists. In addition, naked mole-rats exhibited reduced prosecretory responses to the nonselective adenylate cyclase activator forskolin. Collectively, these findings indicate that naked mole-rats possess a robust and hard-to-penetrate gastrointestinal barrier that is resistant to environmental and endogenous irritants. Naked mole-rats may therefore provide valuable insights into the physiology of the intestinal barrier and set the stage for the development of innovative and effective therapies.NEW & NOTEWORTHY This is the first study to characterize the intestinal function of naked mole-rats. We found that these animals show a robust gut tissue structure, displaying thicker intestinal layers, longer villi, and larger crypts. Naked mole-rats showed more and larger goblet cells, with increased mucus content. Intestinal permeability, especially in the ileum, was substantially lower than that of mice. Finally, naked mole-rats showed reduced intestinal anion secretion in response to serotonin, bradykinin, histamine, capsaicin, and forskolin.
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Mucosa Intestinal , Ratas Topo , Permeabilidad , Animales , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Ratones , Masculino , Células Caliciformes/metabolismo , Células Caliciformes/efectos de los fármacos , Capsaicina/farmacología , Bradiquinina/farmacología , Bradiquinina/metabolismo , Serotonina/metabolismo , Ratones Endogámicos C57BL , Funcion de la Barrera IntestinalRESUMEN
Abdominal pain, which is a form of visceral pain, is a highly prevalent symptom worldwide frequently occurring following food ingestion. Its pathophysiology is complex, and many factors, including intestinal environmental cues, the immune system, or the molecular composition of foods, can influence the development of postprandial abdominal pain. Because of the poor efficacy of drug treatments, current strategies are often limited to the exclusion of culprit food(s) from the diet. However, there are two important limitations to this approach. First, patients suffering from food-induced abdominal pain usually recognize several food items as the cause of their gastrointestinal symptoms. Second, not all offending foods can always be identified by these patients. Newly identified mechanisms involving neuroimmune interactions and their communication with the intestinal microbiota shed light on the development of new therapeutic strategies. In this Mini-Review, these novel mechanisms and relevance of such findings are highlighted.
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Enfermedades Gastrointestinales , Microbioma Gastrointestinal , Dolor Visceral , Humanos , Dolor Abdominal/etiología , Enfermedades Gastrointestinales/etiología , Ingestión de AlimentosRESUMEN
Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder that is characterized by abdominal pain and an altered defecation pattern. It affects between 5 and 20% of the general population and can seriously impact quality of life. The pathophysiology of IBS is rather complex and multifactorial including, for example, altered signalling by the gut-brain axis, dysbiosis, abnormal visceral pain signalling and intestinal immune activation. The latter has gained particular interest in recent years, with growing insight into the bidirectional communication between the nervous system and the immune system. In this Review, we detail the current evidence suggesting that immune activation contributes to the pathology seen in patients with IBS and discuss the potential mechanisms involved. Moreover, we describe how immune mediators, particularly those released by mast cells, can directly activate or sensitize pain-transmitting nerves, leading to increased pain signalling and abdominal pain. Finally, we discuss the potential of interventions targeting immune activation as a new therapeutic strategy for patients suffering from IBS.
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Síndrome del Colon Irritable , Humanos , Síndrome del Colon Irritable/tratamiento farmacológico , Calidad de Vida , Dolor Abdominal/etiología , Disbiosis , MastocitosRESUMEN
Background: We previously showed increased susceptibility to dextran sulfate sodium (DSS)-induced colitis in vagotomized mice. Here, we evaluated whether vagus nerve stimulation (VNS) is able to reduce the severity of DSS colitis and aimed to unravel the mechanism involved. Methods: Colitis was induced in wild type mice by 2.5% DSS administration in drinking water for 5 days. VNS (5 Hz, 1 ms, 1 mA) was applied 1 day prior to and after 4 days of DSS administration to evaluate changes in epithelial integrity and inflammatory response, respectively. Epithelial integrity was assessed using TUNEL and Ki67 staining. Monocytes, immature and mature macrophages were sorted from colonic samples and gene expression levels of pro-inflammatory cytokines were studied. Results: VNS applied prior to DSS administration (i.e., prophylactic VNS) reduced disease activity index (VNS 0.8 ± 0.6 vs. sham 2.8 ± 0.7, p < 0.001, n = 5) and tended to improve histology score. Prophylactic VNS significantly increased epithelial cell proliferation and diminished apoptosis compared to sham stimulation. VNS applied at day 4 during DSS administration (i.e., therapeutic VNS) decreased the influx of monocytes, monocyte-derived macrophages and neutrophils, and significantly reduced pro-inflammatory cytokine expression (i.e., Tnfα and Cxcl1) in immature macrophages compared to sham stimulation. Conclusions: A single period of VNS applied prior to DSS exposure reduced DSS-induced colitis by an improvement in epithelial integrity. On the other hand, VNS applied during the inflammatory phase of DSS colitis reduced cytokine expression in immature macrophages. Our data further underscores the potential of VNS as novel therapeutic approach for inflammatory bowel diseases.
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Up to 20% of people worldwide develop gastrointestinal symptoms following a meal1, leading to decreased quality of life, substantial morbidity and high medical costs. Although the interest of both the scientific and lay communities in this issue has increased markedly in recent years, with the worldwide introduction of gluten-free and other diets, the underlying mechanisms of food-induced abdominal complaints remain largely unknown. Here we show that a bacterial infection and bacterial toxins can trigger an immune response that leads to the production of dietary-antigen-specific IgE antibodies in mice, which are limited to the intestine. Following subsequent oral ingestion of the respective dietary antigen, an IgE- and mast-cell-dependent mechanism induced increased visceral pain. This aberrant pain signalling resulted from histamine receptor H1-mediated sensitization of visceral afferents. Moreover, injection of food antigens (gluten, wheat, soy and milk) into the rectosigmoid mucosa of patients with irritable bowel syndrome induced local oedema and mast cell activation. Our results identify and characterize a peripheral mechanism that underlies food-induced abdominal pain, thereby creating new possibilities for the treatment of irritable bowel syndrome and related abdominal pain disorders.
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Dolor Abdominal/inmunología , Dolor Abdominal/patología , Alérgenos/inmunología , Hipersensibilidad a los Alimentos/inmunología , Alimentos/efectos adversos , Intestinos/inmunología , Síndrome del Colon Irritable/inmunología , Dolor Abdominal/etiología , Dolor Abdominal/microbiología , Adulto , Animales , Citrobacter rodentium/inmunología , Diarrea/inmunología , Diarrea/microbiología , Diarrea/patología , Infecciones por Enterobacteriaceae/complicaciones , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Enterobacteriaceae/microbiología , Femenino , Hipersensibilidad a los Alimentos/complicaciones , Hipersensibilidad a los Alimentos/microbiología , Hipersensibilidad a los Alimentos/patología , Glútenes/inmunología , Humanos , Inmunoglobulina E/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Intestinos/microbiología , Intestinos/patología , Síndrome del Colon Irritable/etiología , Síndrome del Colon Irritable/microbiología , Síndrome del Colon Irritable/patología , Masculino , Mastocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Leche/inmunología , Ovalbúmina/inmunología , Calidad de Vida , Receptores Histamínicos H1/metabolismo , Proteínas de Soja/inmunología , Triticum/inmunologíaRESUMEN
OBJECTIVE: Resolvins (RvD1, RvD2 and RvE1) are endogenous anti-inflammatory lipid mediators that display potent analgesic properties in somatic pain by modulating transient receptor potential vanilloid 1 (TRPV1) activation. To what extent these molecules could also have a beneficial effect on TRPV1 sensitisation and visceral hypersensitivity (VHS), mechanisms involved in IBS, remains unknown. DESIGN: The effect of RvD1, RvD2 and RvE1 on TRPV1 activation and sensitisation by histamine or IBS supernatants was assessed on murine dorsal root ganglion (DRG) neurons using live Ca2+ imaging. Based on the results obtained in vitro, we further studied the effect of RvD2 in vivo using a murine model of post-infectious IBS and a rat model of post-inflammatory VHS. Finally, we also tested the effect of RvD2 on submucosal neurons in rectal biopsies of patients with IBS. RESULTS: RvD1, RvD2 and RvE1 prevented histamine-induced TRPV1 sensitisation in DRG neurons at doses devoid of an analgesic effect. Of note, RvD2 also reversed TRPV1 sensitisation by histamine and IBS supernatant. This effect was blocked by the G protein receptor 18 (GPR18) antagonist O-1918 (3-30 µM) and by pertussis toxin. In addition, RvD2 reduced the capsaicin-induced Ca2+ response of rectal submucosal neurons of patients with IBS. Finally, treatment with RvD2 normalised pain responses to colorectal distention in both preclinical models of VHS. CONCLUSIONS: Our data suggest that RvD2 and GPR18 agonists may represent interesting novel compounds to be further evaluated as treatment for IBS.
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Hipersensibilidad/tratamiento farmacológico , Síndrome del Colon Irritable/metabolismo , Receptores de Cannabinoides/metabolismo , Canales Catiónicos TRPV/metabolismo , Adulto , Animales , Capsaicina/farmacología , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/farmacología , Infecciones por Enterobacteriaceae/complicaciones , Femenino , Ganglios Espinales , Histamina , Humanos , Hipersensibilidad/etiología , Hipersensibilidad/metabolismo , Inflamación/inducido químicamente , Inflamación/complicaciones , Síndrome del Colon Irritable/tratamiento farmacológico , Masculino , Ratones , Persona de Mediana Edad , Neuronas/metabolismo , RatasRESUMEN
BACKGROUND: Postprandial stationary pH monitoring studies have identified the acid pocket. To what extent a similar pool of acid is present in the fasting state or at night remains however unclear. METHODS: The study was performed in 9 HV without a hiatal hernia. A pH-impedance-pressure catheter was positioned at the Z-line. First, the presence of the acid pocket was monitored under stationary conditions during 2 hours after ingestion of a standardized meal. Thereafter, the equipment was connected to an ambulatory monitoring device for 24-hour recording. RESULTS: Under stationary conditions, a postprandial acid pocket was present in 7 of the 9 HV, from 9 ± 7 minutes after meal onwards during 47 ± 8 minutes. During ambulatory 24-hour monitoring, postprandial acid pockets emerged significantly later, but no differences in duration or position were detected. During nighttime, an acid pool was detected with its proximal border at the level of the cardia, which at later, time points gradually moved to a more distal position. This led to a gradual decrease in nocturnal acid exposure from proximal to distal, a phenomenon that was preceded by a bust of gastric contractions. Nocturnal reflux originated from the cardiac region, and was more acidic in the early compared with late nocturnal period. CONCLUSION: The acid pocket is present in the postprandial period under both stationary and ambulatory conditions. Of interest, at night, a pool of acid can be demonstrated which is periodically shifted more distally. This pool of acid represents the reservoir from which nocturnal reflux originates.
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Unión Esofagogástrica/química , Determinación de la Acidez Gástrica , Reflujo Gastroesofágico/fisiopatología , Periodo Posprandial/fisiología , Monitorización del pH Esofágico/métodos , Ácido Gástrico/química , Voluntarios Sanos , Humanos , Concentración de Iones de HidrógenoRESUMEN
BACKGROUND: The vagus nerve has emerged as an important modulator of the intestinal immune system. Its anti-inflammatory properties have been previously shown in innate and Th1/Th17 predominant inflammatory models. To what extent the vagus nerve is of importance in Th2 inflammatory responses like food allergy is still unclear. In this study, we therefore aimed to investigate the effect of vagotomy (VGX) and vagus nerve stimulation (VNS), on the development and severity of experimental food allergy. METHODS: Balb/C mice were first sensitized with ovalbumin (OVA) in the presence of alum. Prior to oral challenges with OVA, mice were subjected to VGX or VNS. Disease severity was determined by assessing severity and onset of diarrhoea, OVA-specific antibody production, mast cell number and activity, inflammatory gene expression in duodenal tissue and lamina propria immune cells by flow cytometry analysis. RESULTS: When compared to control mice, VGX did not significantly affect the development and severity of the disease in our model of food allergy. VNS, on the other hand, resulted in a significant amelioration of the different inflammatory parameters assessed. This effect was independent of α7nAChR and is possibly mediated through the dampening of mast cells and increased phagocytosis of OVA by CX3CR1hi macrophages. CONCLUSIONS: These results underscore the anti-inflammatory properties of the vagus nerve and the potential of neuro-immune interactions in the intestine. Further insight into the underlying mechanisms could ultimately lead to novel therapeutic approaches in the treatment of not only food allergy but also other immune-mediated diseases.
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Hipersensibilidad a los Alimentos/etiología , Hipersensibilidad a los Alimentos/metabolismo , Gastroenteritis/etiología , Gastroenteritis/metabolismo , Estimulación del Nervio Vago , Alérgenos , Animales , Biomarcadores , Permeabilidad de la Membrana Celular , Modelos Animales de Enfermedad , Hipersensibilidad a los Alimentos/diagnóstico , Gastroenteritis/patología , Inmunofenotipificación , Macrófagos/inmunología , Macrófagos/metabolismo , Mastocitos/inmunología , Mastocitos/metabolismo , Mastocitosis , Ratones , Ratones Noqueados , Infiltración Neutrófila/inmunología , Ovalbúmina/inmunología , Índice de Severidad de la Enfermedad , Vagotomía , Receptor Nicotínico de Acetilcolina alfa 7/genética , Receptor Nicotínico de Acetilcolina alfa 7/metabolismoRESUMEN
BACKGROUND: Mucosal immune activation has been postulated to play an important role in the pathogenesis of irritable bowel syndrome (IBS). However, data are conflicting and often based on small patient cohorts. Here, we aimed to evaluate the gene expression of a large set of immune-related genes in mucosal biopsies from IBS patients and healthy volunteers (HV). METHODS: A total of 171 IBS patients and 127 HV were included in the study. Rectum biopsies were collected from a cohort of 70 HV and 77 IBS patients (Rome III) and colon descendens biopsies from another cohort of 57 HV and 94 IBS patients (Rome II). Gene expression was assessed using OpenArray technology, and validated questionnaires were used to evaluate clinical characteristics (GI symptoms, somatization, anxiety, and depression). KEY RESULTS: A subset of IBS patients (33%) with increased immune activation in the colon descendens was identified using multivariate analysis and displayed increased gene expression of IL1B (3-fold change), prostaglandin synthase PTGS2 (2.1-fold change), and the G-protein-coupled receptor MRGPRX2 (10.7-fold change). Clinical characteristics in this subgroup were however similar to the rest of the patient cohort. Analysis of rectal biopsies failed to identify such subgroup of "immuno-active" IBS patients in the other patient cohort. CONCLUSION: A subset of IBS patients reveals evidence of immune activation in the colon descendens, but not in the rectum; however, gene expression is unrelated to clinical symptoms. To what extent this subgroup might however respond to anti-inflammatory therapy remains to be investigated.
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Inmunidad Mucosa/inmunología , Mucosa Intestinal/inmunología , Síndrome del Colon Irritable/inmunología , Transcriptoma/inmunología , Adulto , Anciano , Colon Sigmoide/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recto/inmunologíaRESUMEN
BACKGROUND: The role of persistent immune activation in postinfectious irritable bowel syndrome (PI-IBS) remains controversial. Here, we prospectively studied healthy subjects traveling to destinations with a high-risk to develop infectious gastroenteritis (IGE) in order to identify immune-mediated mechanisms and risk factors of PI-IBS. METHODS: One hundred and one travelers were asked to complete questionnaires on psychological profile and gastrointestinal (GI) symptoms before travel, 2 weeks, 6 months and 1 year after travel. At each visit, blood was collected for PBMC isolation and rectal biopsies were taken. PI-IBS was diagnosed using the Rome III criteria and subjects with persistent postinfectious abdominal complaints (PI-AC) were identified using 3 GSRS symptoms (ie, loose stools, urgency and abdominal pain). RESULTS: Forty-seven of the 101 subjects reported IGE during travel. After 1 year, two subjects were diagnosed with PI-IBS and eight subjects were presented with PI-AC versus two subjects with IBS and two with abdominal complaints in the non-infected group. PBMC analysis showed no differences in T and B cell populations in subjects with PI-AC vs healthy. Additionally, no differences in gene expression were observed in the early postinfectious phase or after 1 year. Regression analysis identified looser stools, higher anxiety and somatization before infection and several postinfectious GI symptoms as risk factors for PI-AC. CONCLUSIONS: The incidence of PI-IBS is low following travelers' diarrhea and there is need for larger studies investigating the role of immune activation in PI-IBS. Psychological factors before infection and the severity of symptoms shortly after infection are risk factors for the persistence of PI-AC.
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Dolor Abdominal/complicaciones , Diarrea/complicaciones , Gastroenteritis/complicaciones , Síndrome del Colon Irritable/etiología , Adulto , Ansiedad/complicaciones , Femenino , Humanos , Síndrome del Colon Irritable/diagnóstico , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Encuestas y Cuestionarios , ViajeRESUMEN
Macrophages are highly heterogeneous tissue-resident immune cells that perform a variety of tissue-supportive functions. The current paradigm dictates that intestinal macrophages are continuously replaced by incoming monocytes that acquire a pro-inflammatory or tissue-protective signature. Here, we identify a self-maintaining population of macrophages that arise from both embryonic precursors and adult bone marrow-derived monocytes and persists throughout adulthood. Gene expression and imaging studies of self-maintaining macrophages revealed distinct transcriptional profiles that reflect their unique localization (i.e., closely positioned to blood vessels, submucosal and myenteric plexus, Paneth cells, and Peyer's patches). Depletion of self-maintaining macrophages resulted in morphological abnormalities in the submucosal vasculature and loss of enteric neurons, leading to vascular leakage, impaired secretion, and reduced intestinal motility. These results provide critical insights in intestinal macrophage heterogeneity and demonstrate the strategic role of self-maintaining macrophages in gut homeostasis and intestinal physiology.
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Intestinos/inmunología , Macrófagos/inmunología , Animales , Tipificación del Cuerpo/fisiología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Motilidad Gastrointestinal/inmunología , Motilidad Gastrointestinal/fisiología , Homeostasis , Inflamación/inmunología , Mucosa Intestinal/inmunología , Intestino Delgado/metabolismo , Ratones , Monocitos/metabolismo , Neuronas/metabolismo , Fagocitos/inmunología , TranscriptomaRESUMEN
OBJECTIVE: Psychological factors increase the risk to develop postinfectious IBS (PI-IBS), but the mechanisms involved are unclear. As stress affects the immune system, we investigated the potential interaction between psychological factors, the immune response against infectious gastroenteritis (IGE) and the development of IGE and PI-IBS in a large cohort exposed to contaminated drinking water. DESIGN: 18â 620 people exposed to contaminated drinking water (norovirus, Giardia lamblia, Campylobacter jejuni) were invited to participate in a prospective controlled cohort study. They were asked to complete questionnaires assessing demographic, psychological and clinical data during the outbreak and 1â year later. At both time points, in-depth immune function (peripheral blood and rectal biopsies) was studied in a subgroup of subjects. RESULTS: 1379 subjects completed the questionnaires during the outbreak, of which 271 developed IGE. Risk factors for IGE included younger age, pre-existing dyspepsia-like symptoms, anxiety and drinking contaminated tap water. Anxiety scores before the outbreak inversely correlated with interleukin-2-expressing CD4+ T cells (r=0.6, p=0.01, n=23). At follow-up, 34 of 172 (20%) IGE subjects developed IBS compared with 24/366 exposed participants (7%, p<0.0001, χ(2) test). A Th2 cytokine phenotype at time of infection was associated with increased risk for PI-IBS 1â year later. Except for increased B cell numbers, no evidence for systemic or rectal mucosal immune activation in PI-IBS was demonstrated at follow-up. CONCLUSIONS: Our study shows that the increased risk of patients with psychological comorbidity to develop PI-IBS may partly result from an increased susceptibility to develop IGE, possibly resulting from a Th2-immune bias. TRIAL REGISTRATION NUMBER: (ClinicalTrials.gov NCT01497847).
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Infecciones por Campylobacter , Agua Potable , Gastroenteritis , Giardiasis , Síndrome del Colon Irritable , Estrés Psicológico , Adulto , Bélgica/epidemiología , Biopsia/métodos , Infecciones por Campylobacter/complicaciones , Infecciones por Campylobacter/epidemiología , Infecciones por Campylobacter/inmunología , Campylobacter jejuni/aislamiento & purificación , Comorbilidad , Citocinas/análisis , Brotes de Enfermedades , Susceptibilidad a Enfermedades/psicología , Agua Potable/análisis , Agua Potable/microbiología , Femenino , Gastroenteritis/complicaciones , Gastroenteritis/epidemiología , Gastroenteritis/inmunología , Gastroenteritis/microbiología , Giardia lamblia/aislamiento & purificación , Giardiasis/complicaciones , Giardiasis/epidemiología , Giardiasis/inmunología , Humanos , Síndrome del Colon Irritable/diagnóstico , Síndrome del Colon Irritable/etiología , Síndrome del Colon Irritable/psicología , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Escalas de Valoración Psiquiátrica , Recto/microbiología , Recto/patología , Factores de Riesgo , Estrés Psicológico/diagnóstico , Estrés Psicológico/epidemiología , Estrés Psicológico/inmunología , Estrés Psicológico/fisiopatología , Encuestas y CuestionariosRESUMEN
INTRODUCTION: The proportion of HIV-infected patients with overweight/obesity has increased in recent years. These patients have an increased metabolic/cardiovascular risk compared with non-obese patients. Modulation of gut microbiota composition arises as a promising tool to prevent the development of obesity and associated disorders. The aim of this study was to investigate the impacts of maraviroc (MVC), a CCR5 antagonist approved for clinical use in HIV-infected patients, on gut microbiota composition in a mouse model of obesity. METHODS: Thirty two male C57BL/6 mice were assigned to:a) Control (chow diet), b) MVC (chow diet plus 300 mg/L MVC), c) High-fat diet (HFD) or d) HFD/MVC (HFD plus 300 mg/L MVC) groups. Body weight and food intake was recorded every 2-3 days. Mice were euthanized after 16 weeks of treatment and cecal contents were removed to analyse by real-time PCR four bacterial orders from the most dominant phyla in gut. RESULTS: Mice fed with a HFD showed a significant increase in Enterobacteriales (p<0.001 vs. control). MVC treatment induced a significant decrease in control (p<0.05) and HFD fed mice (p<0.001). Interestingly, this order was positively associated with body weight gain, insulin resistance and fatty liver. HFD induced a significant decrease in Bacteroidales and Clostridiales levels (p<0.05 and p<0.01, respectively). MVC decreased the presence of Bacteroidales (p<0.05 vs. control) while an increase was observed in HFD/MVC mice (p=0.01 vs. HFD). No direct effects of MVC were observed on Clostridiales and Lactobacillales. CONCLUSIONS: MVC may constitute a new therapeutic option to prevent obesity and related disorders in HIV-infected patients.
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Antagonistas de los Receptores CCR5/farmacología , Ciego/microbiología , Ciclohexanos/farmacología , Inhibidores de Fusión de VIH/farmacología , Enfermedades Metabólicas/prevención & control , Microbiota/efectos de los fármacos , Triazoles/farmacología , Animales , Traslocación Bacteriana/efectos de los fármacos , Bacteroidetes/efectos de los fármacos , Bacteroidetes/aislamiento & purificación , Antagonistas de los Receptores CCR5/uso terapéutico , Ciclohexanos/uso terapéutico , Dieta Alta en Grasa , Evaluación Preclínica de Medicamentos , Firmicutes/efectos de los fármacos , Firmicutes/aislamiento & purificación , Inhibidores de Fusión de VIH/uso terapéutico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/metabolismo , Humanos , Resistencia a la Insulina , Masculino , Maraviroc , Enfermedades Metabólicas/etiología , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/microbiología , Obesidad/complicaciones , Obesidad/prevención & control , Proteobacteria/efectos de los fármacos , Proteobacteria/aislamiento & purificación , Distribución Aleatoria , Especificidad de la Especie , Triazoles/uso terapéutico , Aumento de PesoRESUMEN
OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the general population. The NAFLD spectrum ranges from simple steatosis to cirrhosis. The chemokine CCL5/RANTES plays an important role in the progression of hepatic inflammation and fibrosis. The objective of this study was to examine the effects of maraviroc, a CCR5 antagonist, on liver pathology in a NAFLD mouse model. METHODS: A total of 32 male C57BL/6 mice were randomly assigned to one of four groups: (i) control group (chow diet plus tap water); (ii) maraviroc group (chow diet plus maraviroc in drinking water); (iii) high-fat diet (HFD) group (HFD plus tap water); and (iv) maraviroc/HFD group (HFD plus maraviroc). All mice were sacrificed 16 weeks after the beginning of the experiment. Biochemical analyses and liver examinations were performed. RESULTS: Mice in the HFD group showed a tendency towards increased body mass gain and liver damage compared with the maraviroc/HFD group. Moreover, liver weight in the HFD group was significantly higher than in the maraviroc/HFD group. Hepatic triglyceride concentration in the maraviroc/HFD group was significantly lower than in the HFD group. Interestingly, the maraviroc/HFD group exhibited a lower degree of steatosis. Furthermore, hepatic CCL5/RANTES expression was significantly lower in the maraviroc/HFD group than in the HFD group. Overall, no differences were observed between the control group and the maraviroc group. CONCLUSIONS: Maraviroc ameliorates hepatic steatosis in an experimental model of NAFLD.