Simon 2019 J Biol Chem
|Simon MC, Reinbeck AL, Wessel C, Heindirk J, Jelenik T, Kaul K, Arreguin-Cano J, Strom A, Blaut M, Bäckhed F, Burkart V, Roden M (2019) Distinct alterations of gut morphology and microbiota characterize accelerated diabetes onset in non-obese diabetic mice. J Biol Chem 295:969-80.|
Abstract: The rising prevalence of type 1 diabetes (T1D) over the last decades has been linked to lifestyle changes, but the underlying mechanisms are largely unknown. Recent findings point to gut-associated mechanisms in the control of T1D pathogenesis. In non-obese diabetic (NOD) mice, a model of T1D, diabetes development accelerates after deletion of the Toll-like receptor 4 (TLR4). We hypothesized that altered intestinal functions contribute to metabolic alterations, which favor accelerated diabetes development in TLR4-deficient (TLR4-/-) NOD mice. In 70-90 days old normoglycemic (prediabetic) female NOD TLR4+/+ and NOD TLR4-/- mice, gut morphology and microbiome composition were analyzed. Parameters of lipid metabolism, glucose homeostasis and mitochondrial respiratory activity were measured in vivo and ex vivo. Compared to NOD TLR4+/+ mice, NOD TLR4-/- animals showed lower muscle mass of the small intestine, higher abundance of Bacteroidetes and lower Firmicutes in the large intestine, along with lower levels of circulating short-chain fatty acids (SCFA). These changes associated with higher body weight, hyperlipidemia and severe insulin and glucose intolerance, all occurring before the onset of diabetes. These mice also exhibited insulin resistance-related abnormalities of energy metabolism, such as lower total respiratory exchange rates and higher hepatic oxidative capacity. Distinct alterations of gut morphology and microbiota composition associated with reduction of circulating SCFA may contribute to metabolic disorders promoting the progression of insulin-deficient diabetes/T1D development.
Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
• Keywords: Toll-like receptor 4 (TLR4), Type 1 diabetes, Animal model, Autoimmune disease, Glucose metabolism, Insulin resistance, Islet, Microbiome, Mitochondrial metabolism • Bioblast editor: Plangger M • O2k-Network Lab: DE Duesseldorf Roden M
Labels: MiParea: Respiration, Genetic knockout;overexpression Pathology: Diabetes
Organism: Mouse Tissue;cell: Skeletal muscle, Liver Preparation: Permeabilized tissue
Coupling state: LEAK, OXPHOS, ET Pathway: N, NS, ROX HRR: Oxygraph-2k