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.
Highlights
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
This indicates hepatic mitochondrial adaptation to greater glucose and lipid availabil-. These data show that profound alterations of gut morphology and microbiota and tissue-specific abnormalities of energy metabolism associate with altered availability of short-chain fatty acids (SCFA) and precede accelerated diabetes progression in a model of T1D
This study suggests a complex relationship between Toll-like receptor 4 (TLR4)-dependent intestinal abnormalities and altered inter-organ communication by an imbalance between SCFA and free fatty acids (FFA) resulting in disease-promoting conditions in the prediabetic state
Summary
Body weight development, and body composition were monitored during the prediabetic period in 70 –90day-old female normoglycemic NOD TLR4ϩ/ϩ and NOD TLR4Ϫ/Ϫ mice. We measured circulating levels of fetuin A in serum, an abundant liver-derived glycoprotein, acting as an adaptor to enable the interaction of FFA with TLR4 [29] Both NOD TLR4ϩ/ϩ and NOD TLR4Ϫ/Ϫ mice showed high but comparable fetuin A concentrations (Fig. 3D). Livers from NOD TLR4Ϫ/Ϫ mice showed 60 – 86% higher rates of oxygen flux in complex I and complexes I and II as well as maximal respiratory capacity compared with those obtained from NOD TLR4ϩ/ϩ mice (Fig. 7B). This indicates hepatic mitochondrial adaptation to greater glucose and lipid availabil-
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