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

By L. Wen, Ruth E. Ley, Pavel Volchkov, P. Stranges, Lia Avanesyan, Austin C. Stonebraker, Changyun Hu, F. Wong, G. Szot, J. Bluestone and 2 more. Nature, 2008

1,947 citations recorded by the source corpus.

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, suggesting that changes in the environment (including the 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 facility or by exposure to microbial stimuli, such as injection with mycobacteria or various microbial products. Here we show that specific pathogen-free 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 because germ-free MyD88-negative NOD mice develop robust diabetes, whereas colonization of these germ-free MyD88-negative NOD 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 specific pathogen-free MyD88-negative NOD donors attenuates T1D in germ-free 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.

Subfields: Genetics, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4ddaa8047aecad476296c038582c926cb9b20f23

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Citations in the corpus

InnateDB: systems biology of innate immunity and beyond—recent updates and continuing curation (2012, background): “Therefore complex molecular networks are required to regulate innate immunity and maintain appropriate and speciﬁc responses to different pathogens, while limiting potential harm from dysregulated inﬂammation (1–5).”
The role of gut microbiota in immune homeostasis and autoimmunity (2012, result): “Consistent with the above results, another study indicated that the gut microbiota might have a protective role, as MyD88 NOD mice have been shown to be protected from diabetes onset in an SPF environment.(90) Interestingly, the protective effect of MyD88 deficiency required the presence of gut micr”
The composition and stability of the vaginal microbiota of normal pregnant women is different from that of non-pregnant women (2014, background): “Therefore, studies of the microbiota in several body sites are characterizing stability and resilience, as well as how they relate to health and disease [221-233].”
The Dynamics of the Human Infant Gut Microbiome in Development and in Progression towards Type 1 Diabetes (2015, positive): “Further, heterozygous MyD88 NOD mice, which normally develop robust disease, are protected from diabetes when exposed from birth to the gut microbiota of a MyD88-KO NOD donor (Wen et al., 2008).”
Genetics and pathogenesis of inflammatory bowel disease (2011, background): “Impaired TLR signalling due to Myd88 deficiency in non-obese diabetic (NOD) mice induces changes in microbiota community structure that protect against diabete”
Role of the Microbiota in Immunity and inflammation (2014, background): “Moreover, MyD88 knockout mice bred to the pro-diabetic background are also protected from disease due to the possession of a ‘protective’ microbiota that can be transmitted from mother to child (Wen et al., 2008).”
Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis (2010, background): “Although infections have been speculated for many years to play a role in human diseases (as posited by the hygiene hypothesis), increasing evidence now suggests that nonpathogenic microbes may profoundly affect several autoimmune diseases such as T1D, RA, and EAE.”
Intestinal barrier and gut microbiota: Shaping our immune responses throughout life (2017, background): “adaptor of multiple innate immune receptors, in the nonobese (NOD) diabetic mouse, a model of spontaneous type 1 diabetes, resulted in less severe diabetes and an altered microbial composition, while depletion of microbiota led to development of robust diabetes.(37)”
Current understanding of dysbiosis in disease in human and animal models (2016, background): “IDDM-associated dysbiosis is characterized by a decrease in mucin degrading bacteria, Bifidobacteria, Lactobacillus, and Prevotella, with an increase in Bacteroidetes and Clostridium.(29,30) In contrast, NIDDM-associated dysbiosis is characterized by a decrease in Clostridium, an increase in Lactoba”
Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans. (2016, positive): “The impact of the microbiome on T1D onset and development in NOD mice is dependent on TLR4 and MyD88, critical components of the LPS/TLR4 signal transduction pathway (Gülden et al., 2013; Wen et al., 2008).”