PMID- 26216961
OWN - NLM
STAT- MEDLINE
DCOM- 20151110
LR  - 20181113
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 112
IP  - 32
DP  - 2015 Aug 11
TI  - Microbiota regulates type 1 diabetes through Toll-like receptors.
PG  - 9973-7
LID - 10.1073/pnas.1508740112 [doi]
AB  - Deletion of the innate immune adaptor myeloid differentiation primary response 
      gene 88 (MyD88) in the nonobese diabetic (NOD) mouse model of type 1 diabetes 
      (T1D) results in microbiota-dependent protection from the disease: MyD88-negative 
      mice in germ-free (GF), but not in specific pathogen-free conditions develop the 
      disease. These results could be explained by expansion of particular protective 
      bacteria ("specific lineage hypothesis") or by dominance of negative (tolerizing) 
      signaling over proinflammatory signaling ("balanced signal hypothesis") in mutant 
      mice. Here we found that colonization of GF mice with a variety of intestinal 
      bacteria was capable of reducing T1D in MyD88-negative (but not wild-type NOD 
      mice), favoring the balanced signal hypothesis. However, the receptors and 
      signaling pathways involved in prevention or facilitation of the disease remained 
      unknown. The protective signals triggered by the microbiota were revealed by 
      testing NOD mice lacking MyD88 in combination with knockouts of several critical 
      components of innate immune sensing for development of T1D. Only MyD88- and 
      TIR-domain containing adapter inducing IFN beta (TRIF) double deficient NOD mice 
      developed the disease. Thus, TRIF signaling (likely downstream of Toll-like 
      receptor 4, TLR4) serves as one of the microbiota-induced tolerizing pathways. At 
      the same time another TLR (TLR2) provided prodiabetic signaling by controlling 
      the microbiota, as reduction in T1D incidence caused by TLR2 deletion was 
      reversed in GF TLR2-negative mice. Our results support the balanced signal 
      hypothesis, in which microbes provide signals that both promote and inhibit 
      autoimmunity by signaling through different receptors, including receptors of the 
      TLR family.
FAU - Burrows, Michael P
AU  - Burrows MP
AD  - Department of Pathology and Committee on Immunology, University of Chicago, 
      Chicago, IL 60637;
FAU - Volchkov, Pavel
AU  - Volchkov P
AD  - Department of Pathology and Committee on Immunology, University of Chicago, 
      Chicago, IL 60637;
FAU - Kobayashi, Koichi S
AU  - Kobayashi KS
AD  - Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science 
      Center, College Station, TX 77843.
FAU - Chervonsky, Alexander V
AU  - Chervonsky AV
AD  - Department of Pathology and Committee on Immunology, University of Chicago, 
      Chicago, IL 60637; achervon@bsd.uchicago.edu.
LA  - eng
GR  - UL1 TR000430/TR/NCATS NIH HHS/United States
GR  - P30 DK042086/DK/NIDDK NIH HHS/United States
GR  - TL1 TR000432/TR/NCATS NIH HHS/United States
GR  - DK42086/DK/NIDDK NIH HHS/United States
GR  - R01 AI082418/AI/NIAID NIH HHS/United States
GR  - AI082418/AI/NIAID NIH HHS/United States
GR  - TL1TR000432/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150727
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Adaptor Proteins, Vesicular Transport)
RN  - 0 (Anti-Infective Agents)
RN  - 0 (Myeloid Differentiation Factor 88)
RN  - 0 (TICAM-1 protein, mouse)
RN  - 0 (Toll-Like Receptors)
SB  - IM
MH  - Adaptor Proteins, Vesicular Transport/metabolism
MH  - Animals
MH  - Anti-Infective Agents/metabolism
MH  - Bacteria/metabolism
MH  - Diabetes Mellitus, Type 1/*immunology/*microbiology
MH  - Germ-Free Life
MH  - Islets of Langerhans/pathology
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred NOD
MH  - *Microbiota
MH  - Myeloid Differentiation Factor 88/metabolism
MH  - Phylogeny
MH  - Toll-Like Receptors/*metabolism
PMC - PMC4538618
OTO - NOTNLM
OT  - Toll-like receptors
OT  - commensal microbiota
OT  - type 1 diabetes
COIS- The authors declare no conflict of interest.
EDAT- 2015/07/29 06:00
MHDA- 2015/11/11 06:00
PMCR- 2016/02/11
CRDT- 2015/07/29 06:00
PHST- 2015/07/29 06:00 [entrez]
PHST- 2015/07/29 06:00 [pubmed]
PHST- 2015/11/11 06:00 [medline]
PHST- 2016/02/11 00:00 [pmc-release]
AID - 1508740112 [pii]
AID - 201508740 [pii]
AID - 10.1073/pnas.1508740112 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2015 Aug 11;112(32):9973-7. doi: 
      10.1073/pnas.1508740112. Epub 2015 Jul 27.