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

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.

• Authors: Marie-Christine Simon, Anna Lena Reinbeck, Corinna Wessel, Julia Heindirk, Tomas Jelenik, Kirti Kaul, Juan Arreguin-Cano, Alexander Strom, Michael Blaut, Fredrik Bäckhed, Volker Burkart, Michael Roden
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 295 Issue 4 Pg. 969-980 (01 24 2020) ISSN: 1083-351X [Electronic] United States
• PMID: 31822562 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Simon et al.

Chemical References

• Blood Glucose
• Fatty Acids
• Lipopolysaccharides
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• alpha-2-HS-Glycoprotein

Topics

• Animals
• Blood Glucose (metabolism)
• Body Weight
• Diabetes Mellitus, Experimental (blood, microbiology, pathology)
• Energy Metabolism
• Fatty Acids (metabolism)
• Gastrointestinal Microbiome
• Gastrointestinal Tract (microbiology, pathology)
• Homeostasis
• Lipopolysaccharides (metabolism)
• Liver (pathology)
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Models, Biological
• Oxidation-Reduction
• Toll-Like Receptor 4 (deficiency, metabolism)
• alpha-2-HS-Glycoprotein (metabolism)