RESUMEN
In a patient with severe status asthmaticus, enoximone, a phosphodiesterase-3 inhibitor, caused immediate bronchodilation http://bit.ly/38UYpUn.
RESUMEN
Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis. Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis. Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset. These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function.
Asunto(s)
Artritis Reumatoide/prevención & control , Permeabilidad de la Membrana Celular/efectos de los fármacos , Disbiosis/complicaciones , Haptoglobinas/antagonistas & inhibidores , Mucosa Intestinal/efectos de los fármacos , Oligopéptidos/administración & dosificación , Precursores de Proteínas/antagonistas & inhibidores , Adulto , Animales , Artritis Experimental/sangre , Artritis Experimental/inmunología , Artritis Experimental/microbiología , Artritis Experimental/prevención & control , Artritis Reumatoide/sangre , Artritis Reumatoide/inmunología , Artritis Reumatoide/microbiología , Traslocación Bacteriana/efectos de los fármacos , Traslocación Bacteriana/inmunología , Células CACO-2 , Permeabilidad de la Membrana Celular/inmunología , Estudios de Cohortes , Estudios Transversales , Disbiosis/inmunología , Disbiosis/microbiología , Femenino , Microbioma Gastrointestinal/inmunología , Haptoglobinas/metabolismo , Voluntarios Sanos , Humanos , Íleon/citología , Íleon/efectos de los fármacos , Íleon/microbiología , Íleon/patología , Mucosa Intestinal/citología , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Masculino , Ratones , Persona de Mediana Edad , Precursores de Proteínas/sangre , Precursores de Proteínas/metabolismo , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/metabolismoRESUMEN
Microbial metabolites are known to modulate immune responses of the host. The main metabolites derived from microbial fermentation of dietary fibers in the intestine, short-chain fatty acids (SCFA), affect local and systemic immune functions. Here we show that SCFA are regulators of osteoclast metabolism and bone mass in vivo. Treatment of mice with SCFA as well as feeding with a high-fiber diet significantly increases bone mass and prevents postmenopausal and inflammation-induced bone loss. The protective effects of SCFA on bone mass are associated with inhibition of osteoclast differentiation and bone resorption in vitro and in vivo, while bone formation is not affected. Mechanistically, propionate (C3) and butyrate (C4) induce metabolic reprogramming of osteoclasts resulting in enhanced glycolysis at the expense of oxidative phosphorylation, thereby downregulating essential osteoclast genes such as TRAF6 and NFATc1. In summary, these data identify SCFA as potent regulators of osteoclast metabolism and bone homeostasis.