ACOD1 deficiency offers protection in a mouse model of diet-induced obesity by maintaining a healthy gut microbiota.

Autor: Eberhart T; Cancer Metabolism Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy., Stanley FU; Cancer Metabolism Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy., Ricci L; Cancer Metabolism Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy., Chirico T; Cancer Metabolism Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy., Ferrarese R; Laboratory of Medical Microbiology and Virology, Vita-Salute San Raffaele University, Milan, 20100, Italy.; IRCCS San Raffaele Hospital, Milan, 20100, Italy.; Synlab Italia, Castenedolo, BS, Italy., Sisti S; Laboratory of Medical Microbiology and Virology, Vita-Salute San Raffaele University, Milan, 20100, Italy.; IRCCS San Raffaele Hospital, Milan, 20100, Italy., Scagliola A; Cancer Metabolism Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy.; Istituto Nazionale di Genetica Molecolare, INGM, 'Romeo ed Enrica Invernizzi', Milan, Italy., Baj A; Department of Medicine and Technological Innovation, University of Insubria, Varese, Italy., Badurek S; Preclinical Phenotyping Facility, Vienna BioCenter Core Facilities (VBCF), member of the Vienna BioCenter (VBC), Vienna, Austria., Sommer A; Next Generation Sequencing Facility, Vienna BioCenter Core Facilities (VBCF), member of the Vienna BioCenter (VBC), Vienna, Austria., Culp-Hill R; Department of Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, CO, 80045, USA., Dzieciatkowska M; Department of Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, CO, 80045, USA., Shokry E; CRUK Beatson Institute, Glasgow, UK., Sumpton D; CRUK Beatson Institute, Glasgow, UK., D'Alessandro A; Department of Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, CO, 80045, USA., Clementi N; Laboratory of Medical Microbiology and Virology, Vita-Salute San Raffaele University, Milan, 20100, Italy.; IRCCS San Raffaele Hospital, Milan, 20100, Italy., Mancini N; Laboratory of Medical Microbiology and Virology, Vita-Salute San Raffaele University, Milan, 20100, Italy.; IRCCS San Raffaele Hospital, Milan, 20100, Italy.; Laboratory of Medical Microbiology and Virology, Department of Medicine and Technological Innovation, University of Insubria, Varese, Italy.; Laboratory of Medical Microbiology and Virology, Fondazione Macchi University Hospital, Varese, Italy., Cardaci S; Cancer Metabolism Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. cardaci.simone@hsr.it.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2024 Feb 01; Vol. 15 (2), pp. 105. Date of Electronic Publication: 2024 Feb 01.
DOI: 10.1038/s41419-024-06483-2
Abstrakt: Aconitate decarboxylase 1 (ACOD1) is the enzyme synthesizing itaconate, an immuno-regulatory metabolite tuning host-pathogen interactions. Such functions are achieved by affecting metabolic pathways regulating inflammation and microbe survival. However, at the whole-body level, metabolic roles of itaconate remain largely unresolved. By using multiomics-integrated approaches, here we show that ACOD1 responds to high-fat diet consumption in mice by promoting gut microbiota alterations supporting metabolic disease. Genetic disruption of itaconate biosynthesis protects mice against obesity, alterations in glucose homeostasis and liver metabolic dysfunctions by decreasing meta-inflammatory responses to dietary lipid overload. Mechanistically, fecal metagenomics and microbiota transplantation experiments demonstrate such effects are dependent on an amelioration of the intestinal ecosystem composition, skewed by high-fat diet feeding towards obesogenic phenotype. In particular, unbiased fecal microbiota profiling and axenic culture experiments point towards a primary role for itaconate in inhibiting growth of Bacteroidaceae and Bacteroides, family and genus of Bacteroidetes phylum, the major gut microbial taxon associated with metabolic health. Specularly to the effects imposed by Acod1 deficiency on fecal microbiota, oral itaconate consumption enhances diet-induced gut dysbiosis and associated obesogenic responses in mice. Unveiling an unrecognized role of itaconate, either endogenously produced or exogenously administered, in supporting microbiota alterations underlying diet-induced obesity in mice, our study points ACOD1 as a target against inflammatory consequences of overnutrition.
(© 2024. The Author(s).)
Databáze: MEDLINE
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