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.

Evaluating the Causal Role of Gut Microbiota in Type 1 Diabetes and Its Possible Pathogenic Mechanisms

“…Importantly, a different microbiota profile was found in TRIF-deficient NOD mice compared to wild-type NOD mice, suggesting that the protective effect of TRIF deficiency is through changing microbial composition (110). In addition, a recent study performed by Simon et al found that NOD TLR4 −/− animals had an increased risk of progression to diabetes along with higher abundance of Bacteroidetes and lower Firmicutes in the large intestine before the onset of T1D when compared to NOD TLR4 +/+ mice, indicating that TLR4 expression status determined early alterations of gut microbial composition (111). NOD-like receptors (NLRs), another important PRR, have also been reported to be involved in T1D development through the recognition of bacterial products.…”

Gut Microbiota-Modulated Metabolomic Profiling Shapes the Etiology and Pathogenesis of Autoimmune Diseases

“…Moreover, antibiotic use is involved in the increased incidence of some diseases, such as obesity, and Clostridium difficile infections [ 59 ]. Increasing evidence indicates that environmental factors that alter the composition of gut microbiota strongly impact the risk of developing T1D [ 60 , 61 , 62 ]. Wild-type neonatal NOD mice treated with vancomycin (a glycopeptide antibiotic that inhibits cell wall synthesis by targeting Gram-positive bacteria) from birth until weaning (4 weeks) showed slower onset and lower incidence of diabetes compared with the untreated group.…”

Significance of the Gut Microbiome for Viral Diarrheal and Extra-Intestinal Diseases

“…A combination of dietary conditions and altered gut microbiomes was found to be associated with T2D [ 52 , 67 , 72 ], obesity [ 73 ], nonalcoholic fatty liver disease [ 74 , 75 ], idiopathic nephrotic syndrome [ 43 ], and cardiovascular diseases such as hypertension [ 76 ] or atherosclerotic disease [ 60 , 61 , 77 ]. In detail, the pathogenic mechanisms are complex and often systemic.…”