Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice.
Accumulating evidence supports that the intestinal microbiome is involved in Type 1 diabetes (T1D) pathogenesis through the gut-pancreas nexus. Our aim was to determine whether the intestinal microbiota in the non-obese diabetic (NOD) mouse model played a role in T1D through the gut. To examine the effect of the intestinal microbiota on T1D onset, we manipulated gut microbes by: (1) the fecal transplantation between non-obese diabetic (NOD) and resistant (NOR) mice and (2) the oral antibiotic and probiotic treatment of NOD mice. We monitored diabetes onset, quantified CD4+T cells in the Peyer's patches, profiled the microbiome and measured fecal short-chain fatty acids (SCFA). The gut microbiota from NOD mice harbored more pathobionts and fewer beneficial microbes in comparison with NOR mice. Fecal transplantation of NOD microbes induced insulitis in NOR hosts suggesting that the NOD microbiome is diabetogenic. Moreover, antibiotic exposure accelerated diabetes onset in NOD mice accompanied by increased T-helper type 1 (Th1) and reduced Th17 cells in the intestinal lymphoid tissues. The diabetogenic microbiome was characterized by a metagenome altered in several metabolic gene clusters. Furthermore, diabetes susceptibility correlated with reduced fecal SCFAs. In an attempt to correct the diabetogenic microbiome, we administered VLS#3 probiotics to NOD mice but found that VSL#3 colonized the intestine poorly and did not delay diabetes. We conclude that NOD mice harbor gut microbes that induce diabetes and that their diabetogenic microbiome can be amplified early in life through antibiotic exposure. Protective microbes like VSL#3 are insufficient to overcome the effects of a diabetogenic microbiome.
Department of Biology, University of British Columbia Okanagan, Kelowna, British Columbia, Canada.
Kirsty
K
Brown
Department of Biology, University of British Columbia Okanagan, Kelowna, British Columbia, Canada.
Artem
A
Godovannyi
Department of Paediatrics, Division of Gastroenterology, Vancouver, British Columbia, Canada.
Caixia
C
Ma
Departments of Medicine & Dermatology and Skin Science, Child and Family Research Institute and University of British Columbia, Vancouver, British Columbia, Canada.
YiQun
Y
Zhang
Department of Biology, University of British Columbia Okanagan, Kelowna, British Columbia, Canada.
Zahra
Z
Ahmadi-Vand
Department of Biology, University of British Columbia Okanagan, Kelowna, British Columbia, Canada.
Chaunbin
C
Dai
Department of Biology, University of British Columbia Okanagan, Kelowna, British Columbia, Canada.
Monika A
MA
Gorzelak
Department of Biology, University of British Columbia Okanagan, Kelowna, British Columbia, Canada.
YeeKwan
Y
Chan
Department of Paediatrics, Division of Gastroenterology, Vancouver, British Columbia, Canada.
Justin M
JM
Chan
Department of Paediatrics, Division of Gastroenterology, Vancouver, British Columbia, Canada.
Arion
A
Lochner
Departments of Medicine & Dermatology and Skin Science, Child and Family Research Institute and University of British Columbia, Vancouver, British Columbia, Canada.
Jan P
JP
Dutz
Department of Paediatrics, Division of Gastroenterology, Vancouver, British Columbia, Canada.
Bruce A
BA
Vallance
Department of Biology, University of British Columbia Okanagan, Kelowna, British Columbia, Canada.
Deanna L
DL
Gibson
D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology*; D018450:Disease Progression; D000069196:Gastrointestinal Microbiome / Q000187:drug effects*; D006801:Humans; D007422:Intestines / Q000187:drug effects / Q000276:immunology / Q000382:microbiology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology
D000900:Anti-Bacterial Agents