RESUMEN
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
The gastrointestinal tract has the important task of absorbing nutrients, a complex process that requires an intact barrier allowing the passage of nutrients but that simultaneously protects the host against invading microorganisms. To maintain and regulate intestinal homeostasis, the gut is equipped with one of the largest populations of macrophages in the body. Here, we will discuss our current understanding of intestinal macrophage heterogeneity and describe their main functions in the different anatomical niches of the gut during steady state. In addition, their role in inflammatory conditions such as infection, inflammatory bowel disease, and postoperative ileus are discussed, highlighting the roles of macrophages in immune defense. To conclude, we describe the interaction between macrophages and the enteric nervous system during development and adulthood and highlight their contribution to neurodegeneration in the context of aging and diabetes.
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Sistema Nervioso Entérico , Enfermedades Inflamatorias del Intestino , Adulto , Homeostasis , Humanos , MacrófagosRESUMEN
In this issue of Immunity, Schiller et al. report that local sympathetic nerve activation decreases endothelial expression of the adhesion molecule MAdCAM-1, reducing immune cell infiltration and colitis-induced inflammation. These findings suggest that local sympathetic stimulation provides a key gateway for regulating organ homeostasis.
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Colitis , Mucoproteínas , Moléculas de Adhesión Celular , Endotelio , Humanos , NeuroinmunomodulaciónRESUMEN
Correct development and maturation of the enteric nervous system (ENS) is critical for survival1. At birth, the ENS is immature and requires considerable refinement to exert its functions in adulthood2. Here we demonstrate that resident macrophages of the muscularis externa (MMÏ) refine the ENS early in life by pruning synapses and phagocytosing enteric neurons. Depletion of MMÏ before weaning disrupts this process and results in abnormal intestinal transit. After weaning, MMÏ continue to interact closely with the ENS and acquire a neurosupportive phenotype. The latter is instructed by transforming growth factor-ß produced by the ENS; depletion of the ENS and disruption of transforming growth factor-ß signalling result in a decrease in neuron-associated MMÏ associated with loss of enteric neurons and altered intestinal transit. These findings introduce a new reciprocal cell-cell communication responsible for maintenance of the ENS and indicate that the ENS, similarly to the brain, is shaped and maintained by a dedicated population of resident macrophages that adapts its phenotype and transcriptome to the timely needs of the ENS niche.
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Sistema Nervioso Entérico , Intestinos , Macrófagos , Sistema Nervioso Entérico/citología , Sistema Nervioso Entérico/crecimiento & desarrollo , Sistema Nervioso Entérico/fisiología , Intestinos/inervación , Linfotoxina-alfa/metabolismo , Macrófagos/metabolismo , Macrófagos/fisiología , Neuronas/fisiología , Destete , Comunicación Celular , Transcriptoma , Fenotipo , Fagocitosis , Sinapsis , Plasticidad Neuronal , Tránsito GastrointestinalRESUMEN
The physiological functions of mast cells remain largely an enigma. In the context of barrier damage, mast cells are integrated in type 2 immunity and, together with immunoglobulin E (IgE), promote allergic diseases. Allergic symptoms may, however, facilitate expulsion of allergens, toxins and parasites and trigger future antigen avoidance1-3. Here, we show that antigen-specific avoidance behaviour in inbred mice4,5 is critically dependent on mast cells; hence, we identify the immunological sensor cell linking antigen recognition to avoidance behaviour. Avoidance prevented antigen-driven adaptive, innate and mucosal immune activation and inflammation in the stomach and small intestine. Avoidance was IgE dependent, promoted by Th2 cytokines in the immunization phase and by IgE in the execution phase. Mucosal mast cells lining the stomach and small intestine rapidly sensed antigen ingestion. We interrogated potential signalling routes between mast cells and the brain using mutant mice, pharmacological inhibition, neural activity recordings and vagotomy. Inhibition of leukotriene synthesis impaired avoidance, but overall no single pathway interruption completely abrogated avoidance, indicating complex regulation. Collectively, the stage for antigen avoidance is set when adaptive immunity equips mast cells with IgE as a telltale of past immune responses. On subsequent antigen ingestion, mast cells signal termination of antigen intake. Prevention of immunopathology-causing, continuous and futile responses against per se innocuous antigens or of repeated ingestion of toxins through mast-cell-mediated antigen-avoidance behaviour may be an important arm of immunity.
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Alérgenos , Reacción de Prevención , Hipersensibilidad , Mastocitos , Animales , Ratones , Alérgenos/inmunología , Reacción de Prevención/fisiología , Hipersensibilidad/inmunología , Inmunoglobulina E/inmunología , Mastocitos/inmunología , Estómago/inmunología , Vagotomía , Inmunidad Innata/inmunología , Inmunidad Mucosa/inmunología , Células Th2/inmunología , Citocinas/inmunología , Leucotrienos/biosíntesis , Leucotrienos/inmunología , Intestino Delgado/inmunologíaRESUMEN
Detailed population-level description of the human immune system has recently become achievable. We used a 'systems-level' approach to establish a resource of cellular immune profiles of 670 healthy individuals. We report a high level of interindividual variation, with low longitudinal variation, at the level of cellular subset composition of the immune system. Despite the profound effects of antigen exposure on individual antigen-specific clones, the cellular subset structure proved highly elastic, with transient vaccination-induced changes followed by a return to the individual's unique baseline. Notably, the largest influence on immunological variation identified was cohabitation, with 50% less immunological variation between individuals who share an environment (as parents) than between people in the wider population. These results identify local environmental conditions as a key factor in shaping the human immune system.
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Envejecimiento/inmunología , Antígenos/inmunología , Exposición a Riesgos Ambientales , Homeostasis/inmunología , Sistema Inmunológico/citología , Leucocitos/inmunología , Características de la Residencia , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Ambiente , Femenino , Humanos , Vacunas contra la Influenza/inmunología , Masculino , Persona de Mediana Edad , Análisis de Sistemas , Adulto JovenRESUMEN
Irritable bowel syndrome (IBS) is a chronic gastrointestinal condition associated with altered bowel habits and recurrent abdominal pain, often triggered by food intake. Current treatments focus on improving stool pattern, but effective treatments for pain in IBS are still lacking due to our limited understanding of pathophysiological mechanisms. Visceral hypersensitivity (VHS), or abnormal visceral pain perception, underlies abdominal pain development in IBS, and mast cell activation has been shown to play an important role in the development of VHS. Our work recently revealed that abdominal pain in response to food intake is induced by the sensitization of colonic pain-sensing neurons by histamine produced by activated mast cells following a local IgE response to food. In this review, we summarize the current knowledge on abdominal pain and VHS pathophysiology in IBS, we outline the work leading to the discovery of the role of histamine in abdominal pain, and we introduce antihistamines as a novel treatment option to manage chronic abdominal pain in patients with IBS.
RESUMEN
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: As achalasia is a chronic disorder, long-term follow-up data comparing different treatments are essential to select optimal clinical management. Here, we report on the 10-year follow-up of the European Achalasia Trial comparing endoscopic pneumodilation (PD) with laparoscopic Heller myotomy (LHM). DESIGN: A total of 201 newly diagnosed patients with achalasia were randomised to either a series of PDs (n=96) or LHM (n=105). Patients completed symptom (Eckardt score) and quality-of-life questionnaires, underwent functional tests and upper endoscopy. Primary outcome was therapeutic success defined as Eckardt score <3 at yearly follow-up. Secondary outcomes were the need for retreatment, lower oesophageal sphincter pressure, oesophageal emptying, gastro-oesophageal reflux and the rate of complications. RESULTS: After 10 years of follow-up, LHM (n=40) and PD (n=36) were equally effective in both the full analysis set (74% vs 74%, p=0.84) and the per protocol set (74% vs 86%, respectively, p=0.07). Subgroup analysis revealed that PD was superior to LHM for type 2 achalasia (p=0.03) while there was a trend, although not significant (p=0.05), that LHM performed better for type 3 achalasia. Barium column height after 5 min at timed barium oesophagram was significantly higher for patients treated with PD compared with LHM, while other parameters, including gastro-oesophageal reflux, were not different. CONCLUSIONS: PD and LHM are equally effective even after 10 years of follow-up with limited risk to develop gastro-oesophageal reflux. Based on these data, we conclude that PD and LHM can both be proposed as initial treatment of achalasia.
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Acalasia del Esófago , Esofagitis Péptica , Reflujo Gastroesofágico , Miotomía de Heller , Laparoscopía , Humanos , Acalasia del Esófago/cirugía , Esfínter Esofágico Inferior/cirugía , Miotomía de Heller/efectos adversos , Estudios de Seguimiento , Dilatación/efectos adversos , Bario , Resultado del Tratamiento , Laparoscopía/métodosRESUMEN
OBJECTIVE: We evaluated the histamine 1 receptor antagonist ebastine as a potential treatment for patients with non-constipated irritable bowel syndrome (IBS) in a randomised, placebo-controlled phase 2 study. METHODS: Non-constipated patients with IBS fulfilling the Rome III criteria were randomly assigned to 20 mg ebastine or placebo for 12 weeks. Subjects scored global relief of symptoms (GRS) and abdominal pain intensity (API). A subject was considered a weekly responder for GRS if total or obvious relief was reported and a responder for API if the weekly average pain score was reduced by at least 30% vs baseline. The primary endpoints were the proportion of subjects who were weekly responders for at least 6 out of the 12 treatment weeks for both GRS and API ('GRS+API', composite endpoint) and for GRS and API separately. RESULTS: 202 participants (32±11 years, 68% female) were randomly allocated to receive ebastine (n=101) or placebo (n=101). Treatment with ebastine resulted in significantly more responders (12%, 12/92) for GRS+API compared with placebo (4%, 4/87, p=0.047) while the proportion of responders for GRS and API separately was higher for ebastine compared with placebo, although not statistically significant (placebo vs ebastine, GRS: 7% (6/87) vs 15% (14/91), p=0.072; API: 25% (20/85) vs 37% (34/92), p=0.081). CONCLUSIONS: Our study shows that ebastine is superior to placebo and should be further evaluated as novel treatment for patients with non-constipated IBS. TRIAL REGISTRATION NUMBER: The study protocol was approved by the local ethics committee of each study site (EudraCT number: 2013-001199-39; ClinicalTrials.gov identifier: NCT01908465).
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Síndrome del Colon Irritable , Piperidinas , Humanos , Femenino , Masculino , Síndrome del Colon Irritable/terapia , Histamina/uso terapéutico , Resultado del Tratamiento , Butirofenonas/efectos adversos , Método Doble Ciego , Dolor Abdominal/tratamiento farmacológicoRESUMEN
BACKGROUND & AIMS: For patients with achalasia experiencing persistent or recurrent symptoms after laparoscopic Heller myotomy (LHM), pneumatic dilation (PD) is the most frequently used treatment. Per-oral endoscopic myotomy (POEM) is increasingly being investigated as rescue therapy. This study aimed to determine the efficacy of POEM vs PD for patients with persistent or recurrent symptoms after LHM. METHODS: This randomized multicenter controlled trial included patients after LHM with an Eckardt score >3 and substantial stasis (≥2 cm) on timed barium esophagogram and randomized to POEM or PD. The primary outcome was treatment success, defined as an Eckardt score of ≤3 and without unscheduled re-treatment. Secondary outcomes included the presence of reflux esophagitis, high-resolution manometry, and timed barium esophagogram findings. Follow-up duration was 1 year after initial treatment. RESULTS: Ninety patients were included. POEM had a higher success rate (28 of 45 patients [62.2%]) than PD (12 of 45 patients [26.7%]; absolute difference, 35.6%; 95% CI, 16.4%-54.7%; P = .001; odds ratio, 0.22; 95% CI, 0.09-0.54; relative risk for success, 2.33; 95% CI, 1.37-3.99). Reflux esophagitis was not significantly different between POEM (12 of 35 [34.3%]) and PD (6 of 40 [15%]). Basal lower esophageal sphincter pressure and integrated relaxation pressure (IRP-4) were significantly lower in the POEM group (P = .034; P = .002). Barium column height after 2 and 5 minutes was significantly less in patients treated with POEM (P = .005; P = .015). CONCLUSIONS: Among patients with achalasia experiencing persistent or recurrent symptoms after LHM, POEM resulted in a significantly higher success rate than PD, with a numerically higher incidence of grade A-B reflux esophagitis. NETHERLANDS TRIAL REGISTRY: NL4361 (NTR4501), https://trialsearch.who.int/Trial2.aspx?TrialID = NTR4501.
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Acalasia del Esófago , Esofagitis Péptica , Miotomía de Heller , Cirugía Endoscópica por Orificios Naturales , Humanos , Acalasia del Esófago/diagnóstico , Acalasia del Esófago/cirugía , Miotomía de Heller/efectos adversos , Miotomía de Heller/métodos , Esfínter Esofágico Inferior/cirugía , Dilatación/efectos adversos , Dilatación/métodos , Bario , Resultado del Tratamiento , Esofagitis Péptica/diagnóstico , Esofagitis Péptica/etiología , Esofagitis Péptica/terapia , Cirugía Endoscópica por Orificios Naturales/efectos adversos , Cirugía Endoscópica por Orificios Naturales/métodosRESUMEN
OBJECTIVE: To appraise the evidence that pathophysiological mechanisms and individualised treatment directed at those mechanisms provide an alternative approach to the treatment of patients with irritable bowel syndrome (IBS). DESIGN: A PubMED-based literature review of mechanisms and treatment of IBS was conducted independently by the two authors, and any differences of perspective or interpretation of the literature were resolved following discussion. RESULTS: The availability of several noninvasive clinical tests can appraise the mechanisms responsible for symptom generation in IBS, including rectal evacuation disorders, abnormal transit, visceral hypersensitivity or hypervigilance, bile acid diarrhoea, sugar intolerances, barrier dysfunction, the microbiome, immune activation and chemicals released by the latter mechanism. The basic molecular mechanisms contributing to these pathophysiologies are increasingly recognised, offering opportunities to intervene with medications directed specifically to food components, receptors and potentially the microbiome. Although the evidence supporting interventions for each mechanism is not at the same level of proof, the current state-of-the-art provides the opportunity to advance the practice from treatment based on symptoms to individualisation of treatment guided by pathophysiology and clinically identified biomarkers. CONCLUSION: These advances augur well for the implementation of evidence-based individualised treatment for patients with IBS based on actionable biomarkers or psychological disturbances.
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Síndrome del Colon Irritable , Humanos , Diarrea , BiomarcadoresRESUMEN
Functional gastrointestinal disorders-recently renamed into disorders of gut-brain interaction-such as irritable bowel syndrome and functional dyspepsia are highly prevalent conditions with bothersome abdominal symptoms in the absence of structural abnormalities. While traditionally considered as motility disorders or even psychosomatic conditions, our understanding of the pathophysiology has evolved significantly over the last two decades. Initial observations of subtle mucosal infiltration with immune cells, especially mast cells and eosinophils, are since recently being backed up by mechanistic evidence demonstrating increased release of nociceptive mediators by immune cells and the intestinal epithelium. These mediators can activate sensitised neurons leading to visceral hypersensitivity with bothersome symptoms. The interaction between immune activation and an impaired barrier function of the gut is most likely a bidirectional one with alterations in the microbiota, psychological stress and food components as upstream players in the pathophysiology. Only few immune-targeting treatments are currently available, but an improved understanding through a multidisciplinary scientific approach will hopefully identify novel, more precise treatment targets with ultimately better outcomes.
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Dispepsia , Enfermedades Gastrointestinales , Síndrome del Colon Irritable , Humanos , Neuroinmunomodulación , Enfermedades Gastrointestinales/etiología , Síndrome del Colon Irritable/etiología , EncéfaloRESUMEN
OBJECTIVES: Clinical studies revealed that early-life adverse events contribute to the development of IBS in adulthood. The aim of our study was to investigate the relationship between prenatal stress (PS), gut microbiota and visceral hypersensitivity with a focus on bacterial lipopeptides containing γ-aminobutyric acid (GABA). DESIGN: We developed a model of PS in mice and evaluated, in adult offspring, visceral hypersensitivity to colorectal distension (CRD), colon inflammation, barrier function and gut microbiota taxonomy. We quantified the production of lipopeptides containing GABA by mass spectrometry in a specific strain of bacteria decreased in PS, in PS mouse colons, and in faeces of patients with IBS and healthy volunteers (HVs). Finally, we assessed their effect on PS-induced visceral hypersensitivity. RESULTS: Prenatally stressed mice of both sexes presented visceral hypersensitivity, no overt colon inflammation or barrier dysfunction but a gut microbiota dysbiosis. The dysbiosis was distinguished by a decreased abundance of Ligilactobacillus murinus, in both sexes, inversely correlated with visceral hypersensitivity to CRD in mice. An isolate from this bacterial species produced several lipopeptides containing GABA including C14AsnGABA. Interestingly, intracolonic treatment with C14AsnGABA decreased the visceral sensitivity of PS mice to CRD. The concentration of C16LeuGABA, a lipopeptide which inhibited sensory neurons activation, was decreased in faeces of patients with IBS compared with HVs. CONCLUSION: PS impacts the gut microbiota composition and metabolic function in adulthood. The reduced capacity of the gut microbiota to produce GABA lipopeptides could be one of the mechanisms linking PS and visceral hypersensitivity in adulthood.
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Microbioma Gastrointestinal , Síndrome del Colon Irritable , Masculino , Femenino , Ratones , Animales , Síndrome del Colon Irritable/microbiología , Disbiosis , Heces/microbiología , InflamaciónRESUMEN
BACKGROUND: Pneumatic dilation and laparoscopic Heller's myotomy (LHM) are established treatments for idiopathic achalasia. Peroral endoscopic myotomy (POEM) is a less invasive therapy with promising early study results. METHODS: In a multicenter, randomized trial, we compared POEM with LHM plus Dor's fundoplication in patients with symptomatic achalasia. The primary end point was clinical success, defined as an Eckardt symptom score of 3 or less (range, 0 to 12, with higher scores indicating more severe symptoms of achalasia) without the use of additional treatments, at the 2-year follow-up; a noninferiority margin of -12.5 percentage points was used in the primary analysis. Secondary end points included adverse events, esophageal function, Gastrointestinal Quality of Life Index score (range, 0 to 144, with higher scores indicating better function), and gastroesophageal reflux. RESULTS: A total of 221 patients were randomly assigned to undergo either POEM (112 patients) or LHM plus Dor's fundoplication (109 patients). Clinical success at the 2-year follow-up was observed in 83.0% of patients in the POEM group and 81.7% of patients in the LHM group (difference, 1.4 percentage points; 95% confidence interval [CI], -8.7 to 11.4; P = 0.007 for noninferiority). Serious adverse events occurred in 2.7% of patients in the POEM group and 7.3% of patients in the LHM group. Improvement in esophageal function from baseline to 24 months, as assessed by measurement of the integrated relaxation pressure of the lower esophageal sphincter, did not differ significantly between the treatment groups (difference, -0.75 mm Hg; 95% CI, -2.26 to 0.76), nor did improvement in the score on the Gastrointestinal Quality of Life Index (difference, 0.14 points; 95% CI, -4.01 to 4.28). At 3 months, 57% of patients in the POEM group and 20% of patients in the LHM group had reflux esophagitis, as assessed by endoscopy; at 24 months, the corresponding percentages were 44% and 29%. CONCLUSIONS: In this randomized trial, POEM was noninferior to LHM plus Dor's fundoplication in controlling symptoms of achalasia at 2 years. Gastroesophageal reflux was more common among patients who underwent POEM than among those who underwent LHM. (Funded by the European Clinical Research Infrastructure Network and others; ClinicalTrials.gov number, NCT01601678.).
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Acalasia del Esófago/cirugía , Miotomía de Heller/métodos , Miotomía/métodos , Cirugía Endoscópica por Orificios Naturales , Adulto , Dilatación , Esofagitis Péptica/etiología , Femenino , Fundoplicación , Miotomía de Heller/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Miotomía/efectos adversos , Cirugía Endoscópica por Orificios Naturales/efectos adversos , Complicaciones PosoperatoriasRESUMEN
Accumulating evidence shows that intestinal homeostasis is mediated by cross-talk between the nervous system, enteric neurons and immune cells, together forming specialized neuroimmune units at distinct anatomical locations within the gut. In this review, we will particularly discuss how the intrinsic and extrinsic neuronal circuitry regulates macrophage function and phenotype in the gut during homeostasis and aberrant inflammation, such as observed in inflammatory bowel disease (IBD). Furthermore, we will provide an overview of basic and translational IBD research using these neuronal circuits as a novel therapeutic tool. Finally, we will highlight the different challenges ahead to make bioelectronic neuromodulation a standard treatment for intestinal immune-mediated diseases.
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Eje Cerebro-Intestino/inmunología , Inflamación/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Animales , Homeostasis/inmunología , Humanos , Neuronas/inmunologíaRESUMEN
Intestinal resident macrophages are at the front line of host defence at the mucosal barrier within the gastrointestinal tract and have long been known to play a crucial role in the response to food antigens and bacteria that are able to penetrate the mucosal barrier. However, recent advances in single-cell RNA sequencing technology have revealed that resident macrophages throughout the gut are functionally specialised to carry out specific roles in the niche they occupy, leading to an unprecedented understanding of the heterogeneity and potential biological functions of these cells. This review aims to integrate these novel findings with long-standing knowledge, to provide an updated overview on our understanding of macrophage function in the gastrointestinal tract and to speculate on the role of specialised subsets in the context of homoeostasis and disease.
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Microambiente Celular , Intestinos/citología , Intestinos/fisiología , Macrófagos/citología , Macrófagos/fisiología , Vasos Sanguíneos/citología , Humanos , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Intestinos/irrigación sanguínea , Músculo Liso/citología , Neuronas , Ganglios Linfáticos Agregados/citología , Fagocitosis , Plexo Submucoso/citologíaRESUMEN
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.