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1.
Nature ; 572(7770): 474-480, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31330533

RESUMO

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder, in which the clinical manifestations may be influenced by genetic and unknown environmental factors. Here we show that ALS-prone Sod1 transgenic (Sod1-Tg) mice have a pre-symptomatic, vivarium-dependent dysbiosis and altered metabolite configuration, coupled with an exacerbated disease under germ-free conditions or after treatment with broad-spectrum antibiotics. We correlate eleven distinct commensal bacteria at our vivarium with the severity of ALS in mice, and by their individual supplementation into antibiotic-treated Sod1-Tg mice we demonstrate that Akkermansia muciniphila (AM) ameliorates whereas Ruminococcus torques and Parabacteroides distasonis exacerbate the symptoms of ALS. Furthermore, Sod1-Tg mice that are administered AM are found to accumulate AM-associated nicotinamide in the central nervous system, and systemic supplementation of nicotinamide improves motor symptoms and gene expression patterns in the spinal cord of Sod1-Tg mice. In humans, we identify distinct microbiome and metabolite configurations-including reduced levels of nicotinamide systemically and in the cerebrospinal fluid-in a small preliminary study that compares patients with ALS with household controls. We suggest that environmentally driven microbiome-brain interactions may modulate ALS in mice, and we call for similar investigations in the human form of the disease.


Assuntos
Esclerose Lateral Amiotrófica/microbiologia , Esclerose Lateral Amiotrófica/fisiopatologia , Microbioma Gastrointestinal/fisiologia , Niacinamida/metabolismo , Akkermansia , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Antibacterianos/farmacologia , Modelos Animais de Doenças , Disbiose , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Vida Livre de Germes , Humanos , Longevidade , Masculino , Camundongos , Camundongos Transgênicos , Niacinamida/biossíntese , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Taxa de Sobrevida , Simbiose/efeitos dos fármacos , Verrucomicrobia/metabolismo , Verrucomicrobia/fisiologia
2.
Cell ; 174(6): 1388-1405.e21, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-30193112

RESUMO

Empiric probiotics are commonly consumed by healthy individuals as means of life quality improvement and disease prevention. However, evidence of probiotic gut mucosal colonization efficacy remains sparse and controversial. We metagenomically characterized the murine and human mucosal-associated gastrointestinal microbiome and found it to only partially correlate with stool microbiome. A sequential invasive multi-omics measurement at baseline and during consumption of an 11-strain probiotic combination or placebo demonstrated that probiotics remain viable upon gastrointestinal passage. In colonized, but not germ-free mice, probiotics encountered a marked mucosal colonization resistance. In contrast, humans featured person-, region- and strain-specific mucosal colonization patterns, hallmarked by predictive baseline host and microbiome features, but indistinguishable by probiotics presence in stool. Consequently, probiotics induced a transient, individualized impact on mucosal community structure and gut transcriptome. Collectively, empiric probiotics supplementation may be limited in universally and persistently impacting the gut mucosa, meriting development of new personalized probiotic approaches.


Assuntos
Microbioma Gastrointestinal , Probióticos/administração & dosagem , Adolescente , Adulto , Idoso , Animais , Bactérias/genética , Bactérias/isolamento & purificação , Fezes/microbiologia , Feminino , Mucosa Gástrica/microbiologia , Humanos , Mucosa Intestinal/microbiologia , Masculino , Metagenômica , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Efeito Placebo , Análise de Componente Principal , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/metabolismo , Transcriptoma , Adulto Jovem
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