ABSTRACT
Upon parasitic helminth infection, activated intestinal tuft cells secrete interleukin-25 (IL-25), which initiates a type 2 immune response during which lamina propria type 2 innate lymphoid cells (ILC2s) produce IL-13. This causes epithelial remodeling, including tuft cell hyperplasia, the function of which is unknown. We identified a cholinergic effector function of tuft cells, which are the only epithelial cells that expressed choline acetyltransferase (ChAT). During parasite infection, mice with epithelial-specific deletion of ChAT had increased worm burden, fitness, and fecal egg counts, even though type 2 immune responses were comparable. Mechanistically, IL-13-amplified tuft cells release acetylcholine (ACh) into the gut lumen. Finally, we demonstrated a direct effect of ACh on worms, which reduced their fecundity via helminth-expressed muscarinic ACh receptors. Thus, tuft cells are sentinels in naive mice, and their amplification upon helminth infection provides an additional type 2 immune response effector function.
Subject(s)
Acetylcholine , Intestinal Mucosa , Animals , Acetylcholine/metabolism , Mice , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intestinal Mucosa/parasitology , Choline O-Acetyltransferase/metabolism , Interleukin-13/metabolism , Interleukin-13/immunology , Mice, Knockout , Mice, Inbred C57BL , Helminthiasis/immunology , Helminthiasis/parasitology , Epithelial Cells/immunology , Epithelial Cells/metabolism , Immunity, Innate , Nematospiroides dubius/immunology , Tuft CellsABSTRACT
Gut microbiota imbalance (dysbiosis) is increasingly associated with pathological conditions, both within and outside the gastrointestinal tract. Intestinal Paneth cells are considered to be guardians of the gut microbiota, but the events linking Paneth cell dysfunction with dysbiosis remain unclear. We report a three-step mechanism for dysbiosis initiation. Initial alterations in Paneth cells, as frequently observed in obese and inflammatorybowel diseases patients, cause a mild remodeling of microbiota, with amplification of succinate-producing species. SucnR1-dependent activation of epithelial tuft cells triggers a type 2 immune response that, in turn, aggravates the Paneth cell defaults, promoting dysbiosis and chronic inflammation. We thus reveal a function of tuft cells in promoting dysbiosis following Paneth cell deficiency and an unappreciated essential role of Paneth cells in maintaining a balanced microbiota to prevent inappropriate activation of tuft cells and deleterious dysbiosis. This succinate-tuft cell inflammation circuit may also contribute to the chronic dysbiosis observed in patients.
Subject(s)
Dysbiosis , Mucous Membrane , Humans , Inflammation , Paneth Cells , Succinates , Succinic AcidABSTRACT
Colorectal cancer initiation and progression result from the accumulation of genetic and epigenetic alterations. Although aberrant gene expression and DNA methylation profiles are considered hallmarks of colorectal cancer development, the precise timing at which these are produced during tumor establishment remains elusive. Here we investigated the early transcriptional and epigenetic changes induced by adenomatous polyposis coli (Apc) inactivation in intestinal crypts. Hyperactivation of the Wnt pathway via Apc inactivation in crypt base columnar intestinal stem cells (ISC) led to their rapid accumulation driven by an impaired molecular commitment to differentiation, which was associated with discrete alterations in DNA methylation. Importantly, inhibiting the enzymes responsible for de novo DNA methylation restored the responsiveness of Apc-deficient intestinal organoids to stimuli regulating the proliferation-to-differentiation transition in ISC. This work reveals that early DNA methylation changes play critical roles in the establishment of the impaired fate decision program consecutive to Apc loss of function. SIGNIFICANCE: This study demonstrates the functional impact of changes in DNA methylation to determine the colorectal cancer cell phenotype following loss of Apc function.
Subject(s)
Adenomatous Polyposis Coli Protein/genetics , DNA Methylation , Intestine, Small/cytology , Intestine, Small/metabolism , Receptors, G-Protein-Coupled/biosynthesis , Stem Cells/pathology , Adenomatous Polyposis Coli Protein/deficiency , Adenomatous Polyposis Coli Protein/metabolism , Animals , Cell Differentiation/physiology , Cell Division/physiology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , DNA Modification Methylases/genetics , DNA Modification Methylases/metabolism , Gene Silencing , Intestine, Small/pathology , Mice , Mice, Inbred C57BL , Receptors, G-Protein-Coupled/genetics , Stem Cells/metabolism , Wnt Signaling PathwayABSTRACT
Introducción: la ley 18.335 refiere que: ôToda persona tiene derecho a acceder a una atención integral que comprendaà los cuidados paliativosõ. La Organización Mundial de la Salud (OMS) define los cuidados paliativos pediátricos como ôun modelo global de atención tanto al niño con enfermedad que limita y/o amenaza su vida, como a su familiaõ. El Centro Hospitalario Pereira Rossell cuenta con una unidad de cuidados paliativos pediátricos con fines asistenciales y docentes. Objetivo: describir las características principales de los primeros pacientes asistidos por dicha unidad. Material y método: se realizó un estudio descriptivo, retrospectivo, de las características de los niños asistidos entre el 30 de diciembre de 2008 y el 30 de diciembre de 2010, en base a la revisión de las fichas de registro y las historias clínicas de los pacientes. Se incluyeron todos losniños asistidos, hospitalizados en áreas de cuidados moderados del Departamento de Pediatría. Resultados: se asistieron 87 pacientes, 54 niñas. Mediana de edad: 3 años (rango: 28 días a 16 años). Las condiciones de salud por las que requerían cuidados paliativos fueron muy variadas,predominando los niños con afectación neurológica severa no progresiva. La causa más frecuente de hospitalización fueron las infecciones respiratorias, pero además se constataron otros muy variados problemas biológicos, psicológicos y sociales. Fallecieron 25% de los niños, la mayoría en el hospital.Conclusiones: los cuidados paliativos pediátricos son un derecho de la población. Es por tanto necesario que todos los profesionales de la salud que trabajan con niños se familiaricen con losproblemas presentados y se capaciten en su abordaje integral porque es una obligación del sistema de salud garantizar tal derecho.
Introduction: Law 18,335 provides that: ôAll individuals have the right to receive comprehensive health servicesà including palliative careõ. The World Health Organization (WHO) defined pediatric palliative care as ôa globalmodel for health care services both for the child with a disease that limits and/or threatens his life, and his familyõ. Pereira Rossell Hospital Center has created a Pediatric Palliative Care Unit to provide attention and trainprofessionals in these health care services. Objective: to describe the main characteristics of the first patients seen in the above mentioned unit.Method: We conducted a retrospective, descriptive study of the characteristics of the children seen from December30, 2008 through December 30, 2010, based on their files and medical records. All children hospitalized in the intermediate health care in the Department of Pediatrics were included in the study. Results: 87 patients were seen, 54 of them were girls. Median age was three years old (ranging from 28 days until 16 years old). Health conditions requiring palliative care were varied, mainly non-progressive severe neurological disorders. The most frequent cause of hospitalizationwas respiratory infections, although several other biological, psychological and social problems were seen.25% of the children died, most of them in the hospital. Conclusions: pediatric palliative care is a right. Thus,all health professionals working with children must be familiar with the problems presented and receive training for a comprehensive approach of the condition, since it is an obligation of the health system to guarantee this right.
Introdução: a lei 18.335 estabelece que: ôToda pessoa tem direito ao acesso a uma atenção integral que incluaàos cuidados paliativosõ. A Organização Mundial da Saúde (OMS) define os cuidados paliativos pediátricos comoôum modelo global de atenção tanto para a criança com uma doença que limita ou ameaça sua vida, como para sua famíliaõ. O Centro Hospitalar Pereira Rossell conta com uma unidade de cuidados paliativos pediátricos com fins assistenciais e docentes. Objetivo: descrever as principais características dos primeiros pacientes atendidos por essa unidade. Material e método: um estudo descritivo, retrospectivo, das características das crianças atendidas no período 30 de dezembro de 2008 - 30 de dezembro de 2010, foi realizado baseado na revisão das fichas de registro e dos expedientes médicos dos pacientes. Todas as crianças atendidas e internadas nas áreas de cuidados moderados do Departamento de Pediatria, foram incluídas. Resultados: 87 crianças foram atendidas, sendo 54 do sexo feminino, com uma mediana de idade de 3 anos (intervalo: 28 dias a 16 anos). As condições de saúde pelasquais necessitavam cuidados paliativos foram muito variadas, predominando crianças com afecções neurológicasseveras não progressivas. A causa mais freqüente de internação foram as infecções respiratórias, mas tambémforam identificados outros problemas biológicos, psicológicos e sociais. Vinte e cinco por cento (25%) das crianças faleceram, a maioria estando internada.Conclusões: os cuidados paliativos pediátricos são um direito da população. Por tanto é necessário que todos os profissionais da saúde que trabalham com crianças estejam familiarizados com os problemas apresentados eestejam capacitados para uma abordagem integral porque é uma obrigação do sistema de saúde assegurar esse direito.
Subject(s)
Palliative Care , ChildABSTRACT
En todos los escenarios de atención pediátrica es creciente el número de niños* asistidos con enfermedades o condiciones de salud que amenazan y/o limitan su vida y la de sus familias. De acuerdo a las definiciones internacionales actuales todos estos niños son pasibles de Cuidados paliativos (CP) y deberían beneficiarse de esta estrategia integral de atención. La presente revisión, es la visión de la Unidad de Cuidados Paliativos Pediátricos del C.H.P.R., basada en la literatura, la experiencia recogida y la reflexión sobre las prácticas. El objetivo es que sea de utilidad para aquellos profesionales que en forma personal o en equipos tengan también interés en mejorar la calidad de asistencia y de vida de estos niños y sus familias. En la misma se presentan herramientas para el razonamiento y abordaje clínico según los siguientes capítulos: I) Identificación de niños pasibles de CP; II) Identificación de problemas biológicos, psicológicos, sociales y de comunicación; III) Identificación y respeto de las necesidades, preferencias y valores del niño y la familia; IV) Equipo de trabajo; V) Comunicación; VI) Toma de decisiones. Garantizar el derecho a los CP, implica desafíos personales en capacitación y desafíos organizativos para el sistema de salud que debemos asumir.
