Sphingolipids from a Symbiotic Microbe Regulate Homeostasis of Host Intestinal Natural Killer T Cells

• Published in: Cell Vol. 156; no. 1-2; pp. 123 - 133
• Main Authors: An, Dingding, Oh, Sungwhan F., Olszak, Torsten, Neves, Joana F., Avci, Fikri Y., Erturk-Hasdemir, Deniz, Lu, Xi, Zeissig, Sebastian, Blumberg, Richard S., Kasper, Dennis L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.01.2014
• Subjects: Animals; Animals, Newborn; Bacteroides fragilis; Bacteroides fragilis - metabolism; Cell Proliferation; Colitis - chemically induced; Colitis - immunology; Colitis - prevention & control; Colon - growth & development; Colon - microbiology; Glycosphingolipids - metabolism; Mice; Mice, Inbred C57BL; Natural Killer T-Cells - cytology; Natural Killer T-Cells - immunology; Oxazolone
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2013.11.042

Coevolution of beneficial microorganisms with the mammalian intestine fundamentally shapes mammalian physiology. Here, we report that the intestinal microbe Bacteroides fragilis modifies the homeostasis of host invariant natural killer T (iNKT) cells by supplementing the host’s endogenous lipid antigen milieu with unique inhibitory sphingolipids. The process occurs early in life and effectively impedes iNKT cell proliferation during neonatal development. Consequently, total colonic iNKT cell numbers are restricted into adulthood, and hosts are protected against experimental iNKT cell-mediated, oxazolone-induced colitis. In studies with neonatal mice lacking access to bacterial sphingolipids, we found that treatment with B. fragilis glycosphingolipids—exemplified by an isolated peak (MW = 717.6) called GSL-Bf717—reduces colonic iNKT cell numbers and confers protection against oxazolone-induced colitis in adulthood. Our results suggest that the distinctive inhibitory capacity of GSL-Bf717 and similar molecules may prove useful in the treatment of autoimmune and allergic disorders in which iNKT cell activation is destructive. [Display omitted] [Display omitted] •Symbiotic bacterial glycosphingolipids modulate host iNKT cell homeostasis•Early exposure to these lipids protects the host from later colitis challenges•These lipids inhibit iNKT cell proliferation•Treatment with microbial sphingolipids protects the host from colitis The common intestinal bacterium Bacteroides fragilis produces an inhibitory glycosphingolipid that limits proliferation of invariant natural killer T (iNKT) cells in mice. This irreversible immunomodulation occurs only during a brief window of early life and protects the hosts into adulthood from iNKT cell-mediated colitis.