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Dingding An, Sungwhan Oh, Dennis Kasper, P-174 YI Commensal Bacteria Play an Important Role in Ulcerative Colitis via Bacterial Sphingolipids-Mediated Regulation of Host Invariant Natural Killer T Cells, Inflammatory Bowel Diseases, Volume 18, Issue suppl_1, 1 December 2012, Page S84, https://doi.org/10.1097/00054725-201212001-00207
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Our group has shown previously that microbiota can impact ulcerative colitis disease phenotypes by modulating invariant natural killer T (iNKT) cell functions. We further found that chemokine CXCL16 is responsible for this modulation, with germ-free (GF) mice having high CXCL16 level, large iNKT cell numbers and severe experimental ulcerative colitis outcome. In this study, we hypothesized that in addition to CXCL16 regulated functions, intestinal microbiota can directly impact iNKT cells by providing bacterial antigen, such as glycosphingolipids.
We generated a Bacteroides fragilis mutant (del SPT) that no longer produces any sphingolipids. We then mono-colonized GF mice using wild-type or del SPT mutant. Theses mice were further challenged with an experimental ulcerative colitis model—oxazolone colitis model and the disease phenotypes were evaluated.
Results: We found that the wild-type B. fragilis mono-colonized mice have significantly lower colonic iNKT cell numbers than the mutant mono-colonized mice, which are similar to the GF mice. CXCL16 levels in both of the mono-colonized mice are as low as that of the conventional mice, indicating the existence of a new pathway for colonic iNKT cell regulation. When challenged in the oxazolone colitis model, the mutant-colonized mice were much more susceptible than the wild-type-colonized mice. These phenotypes were diminished when the mice were treated with CD1d antibody, indicating iNKT cell-specific functions were involved.
Our study demonstrated that microbiota regulate colonic iNKT cells via a new and unknown pathway. This pathway uses components in bacterial sphingolipid biosynthesis and it points to a new direction for therapeutic intervention of ulcerative colitis.
- phenotype
- chemokines
- ulcerative colitis
- antigens, bacterial
- bacteroides fragilis
- cell count
- colitis
- glycosphingolipids
- infectious mononucleosis
- intestines
- oxazolone
- sphingolipids
- antibodies
- bacteria
- colon
- mice
- sphingolipid biosynthesis
- therapeutic intervention
- microbial colonization
- microbiome
- natural killer t-cells
- host (organism)
