1. Knockout of the non-essential gene SUGCT creates diet-linked, age-related microbiome disbalance with a diabetes-like metabolic syndrome phenotype
- Author
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Kia Ngee Low, Igor V. Kurochkin, Christine M. F. Goh, Matias J. Caldez, Vincenzo Coppola, Philipp Kaldis, Frank Eisenhaber, Yoganathan Kanagasundaram, Sebastian Maurer-Stroh, Hyungwon Choi, Lakshmi Gopinathan, Elisabeth Pfeiffenberger, Yang Lay Kien, Oliver S. Jones, Joanna Niska-Blakie, Chee Bing Ong, and Lino Tessarollo
- Subjects
Aging ,Adipose tissue ,Gut flora ,Kidney ,Feces ,Mice ,0302 clinical medicine ,Sugct ,Metabolic Syndrome ,Mice, Knockout ,0303 health sciences ,Tryptophan ,Phenotype ,Lipids ,Anti-Bacterial Agents ,medicine.anatomical_structure ,Liver ,Glutaric aciduria type 3 (GA3) ,Metabolome ,Molecular Medicine ,Original Article ,C7orf10 ,medicine.medical_specialty ,Biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Internal medicine ,Diabetes mellitus ,Carnitine ,medicine ,Animals ,Humans ,Metabolomics ,Microbiome ,Obesity ,Molecular Biology ,030304 developmental biology ,Pharmacology ,Gut microflora ,Bacteria ,Lysine ,Cell Biology ,medicine.disease ,biology.organism_classification ,Lipid Metabolism ,Gastrointestinal Microbiome ,Endocrinology ,Dietary Supplements ,Metabolic syndrome ,Coenzyme A-Transferases ,Dysbiosis ,030217 neurology & neurosurgery - Abstract
SUGCT (C7orf10) is a mitochondrial enzyme that synthesizes glutaryl-CoA from glutarate in tryptophan and lysine catabolism, but it has not been studied in vivo. Although mutations in Sugct lead to Glutaric Aciduria Type 3 disease in humans, patients remain largely asymptomatic despite high levels of glutarate in the urine. To study the disease mechanism, we generated SugctKO mice and uncovered imbalanced lipid and acylcarnitine metabolism in kidney in addition to changes in the gut microbiome. After SugctKO mice were treated with antibiotics, metabolites were comparable to WT, indicating that the microbiome affects metabolism in SugctKO mice. SUGCT loss of function contributes to gut microbiota dysbiosis, leading to age-dependent pathological changes in kidney, liver, and adipose tissue. This is associated with an obesity-related phenotype that is accompanied by lipid accumulation in kidney and liver, as well as “crown-like” structures in adipocytes. Furthermore, we show that the SugctKO kidney pathology is accelerated and exacerbated by a high-lysine diet. Our study highlights the importance of non-essential genes with no readily detectable early phenotype, but with substantial contributions to the development of age-related pathologies, which result from an interplay between genetic background, microbiome, and diet in the health of mammals.
- Published
- 2019