Innate immunity and intestinal microbiota in the development of Type 1 diabetes

Abstract

Type 1 diabetes (T1D) is a debilitating autoimmune disease that results from T cell-mediated destruction of insulin-producing β cells. Its incidence has increased during the past several decades in developed countries 1, 2, suggesting that changes in the environment (including human microbial environment) may influence disease pathogenesis. The incidence of spontaneous T1D in non-obese diabetic (NOD) mice can be affected by the microbial environment in the animal housing facility3 or by exposure to microbial stimuli, such as injection with mycobacteria or various microbial products 4,5. Here we show that specific-pathogen free (SPF) NOD mice lacking MyD88 protein (an adaptor for multiple innate immune receptors that recognize microbial stimuli) do not develop T1D. The effect is dependent on commensal microbes as germ-free (GF) MyD88-negative NOD mice develop robust diabetes, whereas colonization of these GF NOD.MyD88-negative mice with a defined microbial consortium (representing bacterial phyla normally present in human gut) attenuates T1D. We also find that MyD88-deficiency changes the composition of the distal gut microbiota, and that exposure to the microbiota of SPF NOD.MyD88-negative donors attenuates T1D in GF NOD recipients. Together, these findings indicate that interaction of the intestinal microbes with the innate immune system is a critical epigenetic factor modifying T1D predisposition.

Inflammasomes make the case for littermate-controlled experimental design in studying host-microbiota interactions

“…Indeed, although Toll-like receptor (TLR) as well as Nod2 signaling had been implicated in modelling the intestinal ecosystem, 33 , 34 subsequent studies using littermate comparisons showed that these pathways did not exert the previously described effects on the gut microbiota composition. 20 , 35 Hence, these studies confirmed using littermates as the appropriate experimental setup when investigating host genetic effects in intestinal microbiota regulation.…”

Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice

“…Reports have shown that children with type 1 diabetes have increased barrier defects in their small intestines ( [8] and reviewed in [35]) and have a higher incidence of enteroviral infections [36]. Moreover, recent studies have also implicated innate recognition of enteric commensal microbes in the modulation of diabetes suffered by NOD mice [37]. An altered commensal gut flora because of interrupted toll-like receptor (TLR) signalling was shown to prevent diabetes.…”

“…Innate and adaptive immune responses coordinated by epithelial TLR signalling modulate the enteric flora and in turn are affected by gut microbes [37,[39][40][41]. Epithelial TLR signalling is critical in maintaining intestinal epithelial integrity [40].…”

Integrating nutrition and immunology: A new frontier

“…The increased incidence of modern lifestyle diseases such as allergies, diabetes, inflammatory bowel diseases and obesity to epidemic levels strongly links changes in nutrition, gut microbiota and immune function. (Backhed et al, 2004;Ley et al, 2006;Noverr and Huffnagle, 2004;Vijay-Kumar et al, 2010;Wen et al, 2008).…”