Using corticosteroids to reshape the gut microbiome: implications for inflammatory bowel diseases.
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.
*Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, Illinois; †2nd Department of Internal Medicine, Osaka Medical College, Takatsuki, Japan; ‡Department of Surgery, University of Chicago, Chicago, Illinois; §Department of Food Science and Human Nutrition, University of Illinois, Urbana, Illinois; ‖Biosciences Division, Argonne National Laboratory, Argonne, Illinois; ¶Department of Ecology and Evolution, University of Chicago, Chicago, Illinois; **Marine Biological Laboratory, Woods Hole, Massachusetts; and ††College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, China.
Edmond Y
EY
Huang
Takuya
T
Inoue
Vanessa A
VA
Leone
Sushila
S
Dalal
Ketrija
K
Touw
Yunwei
Y
Wang
Mark W
MW
Musch
Betty
B
Theriault
Kazuhide
K
Higuchi
Sharon
S
Donovan
Jack
J
Gilbert
Eugene B
EB
Chang
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000382:microbiology; D004269:DNA, Bacterial / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005243:Feces / Q000382:microbiology; D000069196:Gastrointestinal Microbiome / Q000187:drug effects*; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000382:microbiology; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D016753:Interleukin-10 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055262:Mucin-2 / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012336:RNA, Ribosomal, 16S / Q000235:genetics
D000893:Anti-Inflammatory Agents; D004269:DNA, Bacterial; C556062:IL10 protein, mouse; C524626:Muc2 protein, mouse; D055262:Mucin-2; D012336:RNA, Ribosomal, 16S; D016753:Interleukin-10; D003907:Dexamethasone