RESUMO
Gastrointestinal (GI) disruptions and inflammatory bowel disease (IBD) are commonly associated with Parkinson's disease (PD), but how they may impact risk for PD remains poorly understood. Herein, we provide evidence that prodromal intestinal inflammation expedites and exacerbates PD endophenotypes in rodent carriers of the human PD risk allele LRRK2 G2019S in a sex-dependent manner. Chronic intestinal damage in genetically predisposed male mice promotes α-synuclein aggregation in the substantia nigra, loss of dopaminergic neurons and motor impairment. This male bias is preserved in gonadectomized males, and similarly conferred by sex chromosomal complement in gonadal females expressing human LRRK2 G2019S. The early onset and heightened severity of neuropathological and behavioral outcomes in male LRRK2 G2019S mice is preceded by increases in α-synuclein in the colon, α-synuclein-positive macrophages in the colonic lamina propria, and loads of phosphorylated α-synuclein within microglia in the substantia nigra. Taken together, these data reveal that prodromal intestinal inflammation promotes the pathogenesis of PD endophenotypes in male carriers of LRRK2 G2019S, through mechanisms that depend on genotypic sex and involve early accumulation of α-synuclein in myeloid cells within the gut.
Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson , Animais , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Camundongos , Masculino , Feminino , Endofenótipos , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Sintomas Prodrômicos , Modelos Animais de Doenças , Camundongos Transgênicos , Humanos , Fatores Sexuais , Inflamação/metabolismo , Inflamação/genética , Camundongos Endogâmicos C57BL , Caracteres SexuaisRESUMO
The gut microbiome influences many host physiologies, spanning gastrointestinal function, metabolism, immune homeostasis, neuroactivity, and behavior. Many microbial effects on the host are orchestrated by bidirectional interactions between the microbiome and immune system. Imbalances in this dialogue can lead to immune dysfunction and immune-mediated conditions in distal organs including the brain. Dysbiosis of the gut microbiome and dysregulated neuroimmune responses are common comorbidities of neurodevelopmental, neuropsychiatric, and neurological disorders, highlighting the importance of the gut microbiome-neuroimmune axis as a regulator of central nervous system homeostasis. In this review, we discuss recent evidence supporting a role for the gut microbiome in regulating the neuroimmune landscape in health and disease.
Assuntos
Microbioma Gastrointestinal , Microbiota , Animais , Encéfalo , Disbiose , Humanos , NeuroimunomodulaçãoRESUMO
Many studies highlight direct interactions between immune cells and enteric neurons, but whether immune signals can indirectly modulate enteric function through neurotransmitter regulation is poorly understood. In this issue of Immunity, Chen et al. reveal how IL-33 induces intestinal serotonin to promote gut motility.
