RESUMEN
BACKGROUND: Mediterranean diet rich in polyphenolic compounds holds great promise to prevent and alleviate multiple sclerosis (MS), a central nervous system autoimmune disease associated with gut microbiome dysbiosis. Health-promoting effects of natural polyphenols with low bioavailability could be attributed to gut microbiota reconstruction. However, its underlying mechanism of action remains elusive, resulting in rare therapies have proposed for polyphenol-targeted modulation of gut microbiota for the treatment of MS. RESULTS: We found that oral ellagic acid (EA), a natural polyphenol rich in the Mediterranean diet, effectively halted the progression of experimental autoimmune encephalomyelitis (EAE), the animal model of MS, via regulating a microbiota-metabolites-immunity axis. EA remodeled the gut microbiome composition and particularly increased the relative abundances of short-chain fatty acids -producing bacteria like Alloprevotella. Propionate (C3) was most significantly up-regulated by EA, and integrative modeling revealed a strong negative correlation between Alloprevotella or C3 and the pathological symptoms of EAE. Gut microbiota depletion negated the alleviating effects of EA on EAE, whereas oral administration of Alloprevotella rava mimicked the beneficial effects of EA on EAE. Moreover, EA directly promoted Alloprevotella rava (DSM 22548) growth and C3 production in vitro. The cell-free supernatants of Alloprevotella rava co-culture with EA suppressed Th17 differentiation by modulating acetylation in cell models. C3 can alleviate EAE development, and the mechanism may be through inhibiting HDAC activity and up-regulating acetylation thereby reducing inflammatory cytokines secreted by pathogenic Th17 cells. CONCLUSIONS: Our study identifies EA as a novel and potentially effective prebiotic for improving MS and other autoimmune diseases via the microbiota-metabolites-immunity axis. Video Abstract.
Asunto(s)
Ácido Elágico , Encefalomielitis Autoinmune Experimental , Microbioma Gastrointestinal , Esclerosis Múltiple , Propionatos , Ácido Elágico/farmacología , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/microbiología , Propionatos/metabolismo , Ratones , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/microbiología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Femenino , Autoinmunidad/efectos de los fármacos , Disbiosis/microbiología , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/inmunología , Humanos , Administración OralRESUMEN
Facing the complicated life phenomemon, both metabonomics and pharmaco-metabonomics take an organic conception of the human body, which conforms to the way of thinking of traditional Chinese medicine (TCM). The application of metabonomics and pharmaco-metabonomics in the modernization of TCM will deepen the evaluation of the therapeutic effects of TCM, the study of intrinsic quality of TCM syndrome and the treatment by differentiation of syndrome, facilitate the integration of TCM with modern biological science and technology, promote the modernization of TCM, and provide a new space for the development of TCM.