Using corticosteroids to reshape the gut microbiome: implications for inflammatory bowel diseases

Inflamm Bowel Dis. 2015 May;21(5):963-72. doi: 10.1097/MIB.0000000000000332.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Colon / drug effects
  • Colon / microbiology
  • DNA, Bacterial / genetics
  • Dexamethasone / pharmacology*
  • Enzyme-Linked Immunosorbent Assay
  • Feces / microbiology
  • Gastrointestinal Microbiome / drug effects*
  • Gastrointestinal Tract / drug effects*
  • Gastrointestinal Tract / microbiology
  • Inflammation / drug therapy*
  • Inflammation / etiology
  • Inflammation / pathology
  • Inflammatory Bowel Diseases / drug therapy*
  • Inflammatory Bowel Diseases / etiology
  • Inflammatory Bowel Diseases / pathology
  • Interleukin-10 / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mucin-2 / physiology*
  • Polymerase Chain Reaction
  • Polymorphism, Restriction Fragment Length
  • RNA, Ribosomal, 16S / genetics

Substances

  • Anti-Inflammatory Agents
  • DNA, Bacterial
  • IL10 protein, mouse
  • Muc2 protein, mouse
  • Mucin-2
  • RNA, Ribosomal, 16S
  • Interleukin-10
  • Dexamethasone