1. Interleukin-15 promotes intestinal dysbiosis with butyrate deficiency associated with increased susceptibility to colitis.
- Author
-
Meisel M, Mayassi T, Fehlner-Peach H, Koval JC, O'Brien SL, Hinterleitner R, Lesko K, Kim S, Bouziat R, Chen L, Weber CR, Mazmanian SK, Jabri B, and Antonopoulos DA
- Subjects
- Animals, Bacteria classification, Bacteria genetics, Bacteria isolation & purification, Colitis genetics, Colitis microbiology, Colitis therapy, Disease Susceptibility, Dysbiosis genetics, Dysbiosis metabolism, Fecal Microbiota Transplantation, Feces microbiology, Female, Germ-Free Life, Humans, Interleukin-15 genetics, Intestinal Mucosa metabolism, Intestinal Mucosa microbiology, Male, Mice, Mice, Inbred C57BL, Bacteria metabolism, Butyrates metabolism, Colitis metabolism, Dysbiosis microbiology, Gastrointestinal Microbiome, Interleukin-15 metabolism, Intestines microbiology
- Abstract
Dysbiosis resulting in gut-microbiome alterations with reduced butyrate production are thought to disrupt intestinal immune homeostasis and promote complex immune disorders. However, whether and how dysbiosis develops before the onset of overt pathology remains poorly defined. Interleukin-15 (IL-15) is upregulated in distressed tissue and its overexpression is thought to predispose susceptible individuals to and have a role in the pathogenesis of celiac disease and inflammatory bowel disease (IBD). Although the immunological roles of IL-15 have been largely studied, its potential impact on the microbiota remains unexplored. Analysis of 16S ribosomal RNA-based inventories of bacterial communities in mice overexpressing IL-15 in the intestinal epithelium (villin-IL-15 transgenic (v-IL-15tg) mice) shows distinct changes in the composition of the intestinal bacteria. Although some alterations are specific to individual intestinal compartments, others are found across the ileum, cecum and feces. In particular, IL-15 overexpression restructures the composition of the microbiota with a decrease in butyrate-producing bacteria that is associated with a reduction in luminal butyrate levels across all intestinal compartments. Fecal microbiota transplant experiments of wild-type and v-IL-15tg microbiota into germ-free mice further indicate that diminishing butyrate concentration observed in the intestinal lumen of v-IL-15tg mice is the result of intrinsic alterations in the microbiota induced by IL-15. This reconfiguration of the microbiota is associated with increased susceptibility to dextran sodium sulfate-induced colitis. Altogether, this study reveals that IL-15 impacts butyrate-producing bacteria and lowers butyrate levels in the absence of overt pathology, which represent events that precede and promote intestinal inflammatory diseases.
- Published
- 2017
- Full Text
- View/download PDF