期刊
INFLAMMATORY BOWEL DISEASES
卷 21, 期 5, 页码 963-972出版社
OXFORD UNIV PRESS INC
DOI: 10.1097/MIB.0000000000000332
关键词
animal models of IBD; inflammation in IBD; microbiology of IBD; steroids in IBD
资金
- NIDDK Digestive Disease Research Center [DK-42086]
- NIH [DK097268, T32 DK07074, DK47722]
- Gastrointestinal Research Foundation
- NIDDK [UH3DK083993]
- Harry and Leone Helmsley Charitable Trust
Background:Commensal gut microbiota play an important role in regulating metabolic and inflammatory conditions. Reshaping intestinal microbiota through pharmacologic means may be a viable treatment option. We sought to delineate the functional characteristics of glucocorticoid-mediated alterations on gut microbiota and their subsequent repercussions on host mucin regulation and colonic inflammation.Methods:Adult male C57Bl/6 mice, germ-free, Muc2-heterozygote (), or Muc2-knockout (-/-) were injected with dexamethasone, a synthetic glucocorticoid, for 4 weeks. Fecal samples were collected for gut microbiota analysis through 16S rRNA terminal restriction fragment length polymorphism and amplicon sequencing. Intestinal mucosa was collected for mucin gene expression studies. Germ-free mice were conventionalized with gut microbes from treated and nontreated groups to determine their functional capacities in recipient hosts.Results:Exposure to dexamethasone in wild-type mice led to substantial shifts in gut microbiota over a 4-week period. Furthermore, a significant downregulation of colonic Muc2 gene expression was observed after treatment. Muc2-knockout mice harbored a proinflammatory environment of gut microbes, characterized by the increase or decrease in prevalence of specific microbiota populations such as Clostridiales and Lactobacillaceae, respectively. This colitogenic phenotype was transmissible to IL10-knockout mice, a genetically susceptible model of colonic inflammatory disorders. Microbiota from donors pretreated with dexamethasone, however, ameliorated symptoms of inflammation.Conclusions:Commensal gut bacteria may be a key mediator of the anti-inflammatory effects observed in the large intestine after glucocorticoid exposure. These findings underscore the notion that intestinal microbes comprise a microbial organ essential for host physiology that can be targeted by therapeutic approaches to restore intestinal homeostasis.
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