TY - JOUR
AU - Dennis, Kasper
AB - Background The role microbes play in shaping host immune system and intestinal health has been increasingly appreciated. However, the majority of the evidences are from epidemiological studies with only limited insights on molecular mechanisms. We have previously uncovered that symbiotic microbes regulate the host invariant natural killer T (iNKT) cell homeostasis and experimental colitis phenotypes via the CXCL16-CXCR6 mediated pathway. Here we provide evidence that a separate mechanism exists, in which glycosphingolipids produced by symbionts are important mediators for host iNKT cell biology and host susceptibility to iNKT cell-mediated, human ulcerative colitis-like disease. Methods Bacteroides fragilis was used as a model system to study bacterial sphingolipids. An isogenic B. fragilis mutant was constructed, which did not produce any sphingolipids. Both the wild-type and the mutant B. fragilis strains were used to monocolonize the germ-free mice. Together with the germ-free and the specific pathogen-free mice, we performed a series of in vitro and in vivo immunological studies and oxazolone colitis experiments. Glycosphingolipids were also purified from the wild-type bacteria and subjected to chemical analysis and identification. Finally, the identified active α-galactosylceramide molecules were applied to the mutant mono-associated mice to test whether these molecules alone can mediate regulation on host iNKT cell homeostasis and colitis phenotypes. Results We discovered that B. fragilis produces immunomodulatory α-galactosylceramide molecules. These molecules modulate iNKT cell proliferation by competing for limited agonist-binding space on the antigen-presenting CD1d protein. As a result, if the host is exposed to the wild-type B. fragilis or its α-galactosylceramide molecules early in life when iNKT cells actively proliferate, the expansion of colonic iNKT cells in response to endogenous antigens is modulated, resulting in a lower homeostatic colonic iNKT cell level in adult life. Consequently, the host becomes more resistant to the iNKT cell-dependent colitis challenge. Conclusions These results suggest an unexpected mechanism by which symbionts can help the host attain immune balance by supplementing the endogenous lipid antigen milieu with unique inhibitory α-galactosylceramide molecules in early life. These Bacteroides glycosphingolipids provide the second known example of immunomodulatory molecules produced by a symbiont (the first being a zwitterionic polysaccharide also produced by B. fragilis). Our results suggest that the distinctive inhibitory power of these lipids may be useful in treating autoimmune and allergic disorders in which iNKT cell activation is destructive. Copyright © 2014 Crohn's & Colitis Foundation of America, Inc.
TI - O-037 Symbiotic Bacteria Modulate the Host Colitis Phenotype via α-Galactosylceramide Molecules in Early Life
JO - Inflammatory Bowel Diseases
DO - 10.1097/01.MIB.0000456695.47986.04
DA - 2014-12-01
UR - https://www.deepdyve.com/lp/oxford-university-press/o-037-symbiotic-bacteria-modulate-the-host-colitis-phenotype-via-Xw0t6ev3b0
SP - S19
EP - S19
VL - 20
IS - suppl_1
DP - DeepDyve
ER -