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1.
Nature ; 590(7844): 151-156, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33442055

RESUMO

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.


Assuntos
Dor Abdominal/imunologia , Dor Abdominal/patologia , Alérgenos/imunologia , Hipersensibilidade Alimentar/imunologia , Alimentos/efeitos adversos , Intestinos/imunologia , Síndrome do Intestino Irritável/imunologia , Dor Abdominal/etiologia , Dor Abdominal/microbiologia , Adulto , Animais , Citrobacter rodentium/imunologia , Diarreia/imunologia , Diarreia/microbiologia , Diarreia/patologia , Infecções por Enterobacteriaceae/complicações , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/microbiologia , Feminino , Hipersensibilidade Alimentar/complicações , Hipersensibilidade Alimentar/microbiologia , Hipersensibilidade Alimentar/patologia , Glutens/imunologia , Humanos , Imunoglobulina E/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Intestinos/microbiologia , Intestinos/patologia , Síndrome do Intestino Irritável/etiologia , Síndrome do Intestino Irritável/microbiologia , Síndrome do Intestino Irritável/patologia , Masculino , Mastócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Leite/imunologia , Ovalbumina/imunologia , Qualidade de Vida , Receptores Histamínicos H1/metabolismo , Proteínas de Soja/imunologia , Triticum/imunologia
2.
Am J Physiol Gastrointest Liver Physiol ; 312(6): G635-G648, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28385695

RESUMO

Visceral hypersensitivity is an important mechanism underlying increased abdominal pain perception in functional gastrointestinal disorders including functional dyspepsia, irritable bowel syndrome, and inflammatory bowel disease in remission. Although the exact pathophysiological mechanisms are poorly understood, recent studies described upregulation and altered functions of nociceptors and their signaling pathways in aberrant visceral nociception, in particular the transient receptor potential (TRP) channel family. A variety of TRP channels are present in the gastrointestinal tract (TRPV1, TRPV3, TRPV4, TRPA1, TRPM2, TRPM5, and TRPM8), and modulation of their function by increased activation or sensitization (decreased activation threshold) or altered expression in visceral afferents have been reported in visceral hypersensitivity. TRP channels directly detect or transduce osmotic, mechanical, thermal, and chemosensory stimuli. In addition, pro-inflammatory mediators released in tissue damage or inflammation can activate receptors of the G protein-coupled receptor superfamily leading to TRP channel sensitization and activation, which amplify pain and neurogenic inflammation. In this review, we highlight the present knowledge on the functional roles of neuronal TRP channels in visceral hypersensitivity and discuss the signaling pathways that underlie TRP channel modulation. We propose that a better understanding of TRP channels and their modulators may facilitate the development of more selective and effective therapies to treat visceral hypersensitivity.


Assuntos
Hiperalgesia/metabolismo , Mecanotransdução Celular , Nociceptores/metabolismo , Limiar da Dor , Canais de Potencial de Receptor Transitório/metabolismo , Vísceras/inervação , Dor Visceral/metabolismo , Analgésicos/farmacologia , Animais , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Mediadores da Inflamação/metabolismo , Mecanotransdução Celular/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Canais de Potencial de Receptor Transitório/efeitos dos fármacos , Dor Visceral/tratamento farmacológico , Dor Visceral/fisiopatologia
3.
Gastroenterology ; 150(4): 875-87.e9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26752109

RESUMO

BACKGROUND & AIMS: Histamine sensitizes the nociceptor transient reporter potential channel V1 (TRPV1) and has been shown to contribute to visceral hypersensitivity in animals. We investigated the role of TRPV1 in irritable bowel syndrome (IBS) and evaluated if an antagonist of histamine receptor H1 (HRH1) could reduce symptoms of patients in a randomized placebo-controlled trial. METHODS: By using live calcium imaging, we compared activation of submucosal neurons by the TRPV1 agonist capsaicin in rectal biopsy specimens collected from 9 patients with IBS (ROME 3 criteria) and 15 healthy subjects. The sensitization of TRPV1 by histamine, its metabolite imidazole acetaldehyde, and supernatants from biopsy specimens was assessed by calcium imaging of mouse dorsal root ganglion neurons. We then performed a double-blind trial of patients with IBS (mean age, 31 y; range, 18-65 y; 34 female). After a 2-week run-in period, subjects were assigned randomly to groups given either the HRH1 antagonist ebastine (20 mg/day; n = 28) or placebo (n = 27) for 12 weeks. Rectal biopsy specimens were collected, barostat studies were performed, and symptoms were assessed (using the validated gastrointestinal symptom rating scale) before and after the 12-week period. Patients were followed up for an additional 2 weeks. Abdominal pain, symptom relief, and health-related quality of life were assessed on a weekly basis. The primary end point of the study was the effect of ebastine on the symptom score evoked by rectal distension. RESULTS: TRPV1 responses of submucosal neurons from patients with IBS were potentiated compared with those of healthy volunteers. Moreover, TRPV1 responses of submucosal neurons from healthy volunteers could be potentiated by their pre-incubation with histamine; this effect was blocked by the HRH1 antagonist pyrilamine. Supernatants from rectal biopsy specimens from patients with IBS, but not from the healthy volunteers, sensitized TRPV1 in mouse nociceptive dorsal root ganglion neurons via HRH1; this effect could be reproduced by histamine and imidazole acetaldehyde. Compared with subjects given placebo, those given ebastine had reduced visceral hypersensitivity, increased symptom relief (ebastine 46% vs placebo 13%; P = .024), and reduced abdominal pain scores (ebastine 39 ± 23 vs placebo 62 ± 22; P = .0004). CONCLUSIONS: In studies of rectal biopsy specimens from patients, we found that HRH1-mediated sensitization of TRPV1 is involved in IBS. Ebastine, an antagonist of HRH1, reduced visceral hypersensitivity, symptoms, and abdominal pain in patients with IBS. Inhibitors of this pathway might be developed as a new treatment approach for IBS. ClinicalTrials.gov no: NCT01144832.


Assuntos
Analgésicos/uso terapêutico , Butirofenonas/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Síndrome do Intestino Irritável/tratamento farmacológico , Neurônios/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Piperidinas/uso terapêutico , Receptores Histamínicos H1/efeitos dos fármacos , Reto/inervação , Canais de Cátion TRPV/metabolismo , Dor Abdominal/metabolismo , Dor Abdominal/fisiopatologia , Dor Abdominal/prevenção & controle , Adolescente , Adulto , Idoso , Analgésicos/efeitos adversos , Bélgica , Biópsia , Butirofenonas/efeitos adversos , Sinalização do Cálcio/efeitos dos fármacos , Método Duplo-Cego , Feminino , Fármacos Gastrointestinais/efeitos adversos , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Humanos , Síndrome do Intestino Irritável/diagnóstico , Síndrome do Intestino Irritável/metabolismo , Síndrome do Intestino Irritável/fisiopatologia , Masculino , Pessoa de Meia-Idade , Neurônios/metabolismo , Medição da Dor , Piperidinas/efeitos adversos , Qualidade de Vida , Receptor Cross-Talk/efeitos dos fármacos , Receptores Histamínicos H1/metabolismo , Indução de Remissão , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
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