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Distinct alterations of gut morphology and microbiota characterize accelerated diabetes onset in nonobese diabetic mice

Journal article
Authors Marie-Christine Simon
A. L. Reinbeck
C. Wessel
J. Heindirk
T. Jelenik
K. Kaul
J. Arreguin-Cano
A. Strom
M. Blaut
Fredrik Bäckhed
V. Burkart
M. Roden
Published in Journal of Biological Chemistry
Volume 295
Issue 4
Pages 969-980
ISSN 0021-9258
Publication year 2020
Published at Wallenberg Laboratory
Center for Cardiovascular and Metabolic Research (CMR)
Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 969-980
Language en
Links dx.doi.org/10.1074/jbc.RA119.010816
Keywords animal model, autoimmune disease, glucose metabolism, insulin, resistance, islet, microbiome, mitochondrial metabolism, type 1, diabetes, Toll-like receptor 4 (TLR4), chain fatty-acids, toll-like receptors, insulin-resistance, intestinal, microbiota, innate immunity, smooth-muscle, risk-factor, fetuin-a, type-1, activation, Biochemistry & Molecular Biology
Subject categories Endocrinology and Diabetes

Abstract

The rising prevalence of type 1 diabetes (T1D) over the past 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 nonobese 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-day-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 with 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 are 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.

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