Enhanced mitochondrial activity reshapes a gut microbiota profile that delays NASH progression

[EN] Background and Aims: Recent studies suggest that mitochondrial dysfunction promotes progression to NASH by aggravating the gut-liver status. However, the underlying mechanism remains unclear. Herein, we hypothesized that enhanced mitochondrial activity might reshape a specific microbiota signat...

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Detalles Bibliográficos
Autores: Juárez Fernández, María, Goikoetxea Usandizaga, Naroa, Porras Sanabria, David, García Mediavilla, María Victoria, Bravo, Miren, Serrano Maciá, Marina, Simón, Jorge, Delgado, Teresa C., Lachiondo Ortega, Sofía, Martínez Flórez, Susana, Lorenzo, Óscar, Rincón, Mercedes, Varela Rey, Marta, Abecia, Leticia, Rodríguez, Héctor, Anguita, Juan, Nistal González, Maria Esther, Martínez Chantar, María Luz, Sánchez Campos, Sonia
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de León
Repositorio:BULERIA. Repositorio Institucional de la Universidad de León
OAI Identifier:oai:buleria.unileon.es:10612/15320
Acceso en línea:http://hdl.handle.net/10612/15320
Access Level:acceso abierto
Palabra clave:Fisiología
Mitochondrial dysfunction
Nonalcoholic Steatohepatitis (NASH)
2411 Fisiología Humana
Descripción
Sumario:[EN] Background and Aims: Recent studies suggest that mitochondrial dysfunction promotes progression to NASH by aggravating the gut-liver status. However, the underlying mechanism remains unclear. Herein, we hypothesized that enhanced mitochondrial activity might reshape a specific microbiota signature that, when transferred to germ-free (GF) mice, could delay NASH progression. Approach and Results: Wild-type and methylation-controlled J protein knockout (MCJ-KO) mice were fed for 6 weeks with either control or a choline-deficient, L-amino acid–defined, high-fat diet (CDA-HFD). One mouse of each group acted as a donor of cecal microbiota to GF mice, who also underwent the CDA-HFD model for 3 weeks. Hepatic injury, intestinal barrier, gut microbiome, and the associated fecal metabolome were then studied. Following 6 weeks of CDA-HFD, the absence of methylation-controlled J protein, an inhibitor of mitochondrial complex I activity, reduced hepatic injury and improved gut-liver axis in an aggressive NASH dietary model. This effect was transferred to GF mice through cecal microbiota transplantation. We suggest that the specific microbiota profile of MCJ-KO, characterized by an increase in the fecal relative abundance of Dorea and Oscillospira genera and a reduction in AF12, Allboaculum, and [Ruminococcus], exerted protective actions through enhancing short-chain fatty acids, nicotinamide adenine dinucleotide (NAD+) metabolism, and sirtuin activity, subsequently increasing fatty acid oxidation in GF mice. Importantly, we identified Dorea genus as one of the main modulators of this microbiota-dependent protective phenotype. Conclusions: Overall, we provide evidence for the relevance of mitochondria–microbiota interplay during NASH and that targeting it could be a valuable therapeutic approach.

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