Innate immunity and intestinal microbiota in the development of Type 1 diabetes
Open accessAbstract
Type 1 diabetes (T1D) is a debilitating autoimmune disease that results from T-cell-mediated destruction of insulin-producing beta-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.
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Mice deficient in MyD88 display an altered microbiota composition.
“Mice deficient in MyD88 display an altered microbiota composition.56”
From Interaction between microbiota and immunity in health and disease (2020) · cites this paper as [56]
TLR5 is important in shaping the gut microbiota, which might be confined to a critical time window during neonatal life.
“TLR5 is of particular importance in shaping the gut microbiota,53–56 which might be confined to a critical time window during neonatal life.40”
From Interaction between microbiota and immunity in health and disease (2020) · cites this paper as [56]
Germ-free non-obese diabetic mice lacking MyD88 signaling robustly develop type 1 diabetes.
“GF non-obese diabetic mice lacking MyD88 signaling robustly develop T1D”
From Interaction between microbiota and immunity in health and disease (2020) · cites this paper as [56]
Microbial colonization of germ-free non-obese diabetic mice lacking MyD88 signaling attenuates type 1 diabetes.
“while microbial colonization of these mice attenuates the disease.56”
From Interaction between microbiota and immunity in health and disease (2020) · cites this paper as [56]
Changes in the proportions of specific taxa of gut microbiota have been observed in various disease states including obesity, inflammatory bowel disease, type 1 and type 2 diabetes mellitus, biliary disease, and intestinal cancers.
“Changes in the proportions of specific taxa of gut microbiota have been observed in various disease states, including obesity68,69, inflammatory bowel disease70, type 1 and type 2 diabetes mellitus71,72, biliary disease73, and intestinal cancers74,75 among many others.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [71]
Particular population changes in the oral microbiota are associated with pathologies that confer an increased risk of developing PH and other vascular disease, including obesity, diabetes, and insulin resistance.
“there is evidence that particular population changes are associated with pathologies that confer an increased risk of developing PH and other vascular disease, including obesity[273–275], diabetes[276], and insulin resistance[277].”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [276]
Elevations in the Firmicutes:Bacteroidetes ratio have been associated with a high-fat diet and obesity, irritable bowel syndrome, hypertension, type 1 diabetes, and HIV.
“Elevations in the Firmicutes:Bacteroidetes ratio have been associated with a high-fat diet and obesity[274,328,329], irritable bowel syndrome[330], hypertension[331], type 1 diabetes[276], and HIV[332].”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [276]
Muc2-KO mice possess a distinct gut-associated bacterial community influenced by altered genetic and immune states.
“The Muc2-KO mouse possesses a distinct gut-associated bacterial community that is influenced by its altered genetic and immune states, as has been shown in other genetic knockout mouse models.4,53–55”
From Using Corticosteroids to Reshape the Gut Microbiome: Implications for Inflammatory Bowel Diseases (2015) · cites this paper as [55]
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- Authors
- Wen, L., Ley, R. E., Volchkov, P. Y., Stranges, P. B., Avanesyan, L., Stonebraker, A. C., Hu, C., Wong, F. S., Szot, G. L., Bluestone, J. A., Gordon, J. I., & Chervonsky, A. V.
- Affiliations
- Washington University in St. Louis (US)
- University of Chicago (US)
- Jackson Laboratory (US)
- Yale University (US)
- University of Bristol (GB)
- University of California, San Francisco (US)
- Corresponding author
- Chervonsky, Alexander V.
- ORCID
- Venue
- Nature
- Published
- 2008-09-21
- Volume
- 455
- Issue
- 7216
- Pages
- 1109-1113
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2574766
- OpenAlex
- W2148067809
- Cited by
- 1,921
- References
- 39
- Citations by year
- 2026: 23 · 2025: 49 · 2024: 75 · 2023: 69 · 2022: 105 · 2021: 86 · 2020: 112 · 2019: 137 · 2018: 134 · 2017: 128 · 2016: 141 · 2015: 137 · 2014: 138 · 2013: 119 · 2012: 132
- FWCI
- 62.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Explore Bristol Research (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R37AI046643)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK030292, DK-30292, DK 45735, DK063452, R21DK063452, DK 70977, DK42086, R01DK070977, P30DK063720, P30DK042086, P30DK056341, R01DK030292, P30DK045735)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- type 1 diabetes, innate immunity, gut microbiota, MyD88, Toll-like receptors, NOD mice, germ-free mice, commensal bacteria, autoimmune disease susceptibility, microbial products, mycobacteria, disease prevention, beta cell destruction, host-microbe interactions
- MeSH terms
- Animals, Bacteria, Diabetes Mellitus, Type 1, Female, Immunity, Innate, Interferon-gamma, Intestines, Islets of Langerhans, Male, Molecular Sequence Data, Phylogeny, Specific Pathogen-Free Organisms, Time Factors, Mice, SCID, Mice, Inbred NOD, Mice, Knockout, CD8-Positive T-Lymphocytes, Mice, Myeloid Differentiation Factor 88
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