Bacterial immunogenic α-galactosylceramide identified in the murine large intestine: dependency on diet and inflammation

Abstract

Supplementary key words glycolipids • sphingolipids • mass spectrometry • immunology • bacteria • invariant natural killer T cells • Western diet • experimental colitis • influenza A virus • cluster of differentiation 1d Besides recognition of classical major histocompatibility complex class I or II molecules presenting oligopeptides by T lymphocytes, a wide variety of nonclassical nearly monomorphic major histocompatibility complex molecules, including CD1, may be recognized by  and  T cells as Abstract The glycosphingolipid, -galactosylceramide (GalCer), when presented by CD1d on antigen-presenting cells, efficiently activates invariant natural killer T (iNKT) cells. Thereby, it modulates immune responses against tumors, microbial and viral infections, and autoimmune diseases. Recently, the production of GalCer by Bacteroidetes from the human gut microbiome was elucidated. Using hydrophilic interaction chromatography coupled to MS 2 , we screened murine intestinal tracts to identify and quantify GalCers, and we investigated the GalCer response to different dietary and physiologic conditions. In both the cecum and the colon of mice, we found 1-15 pmol of GalCer per milligram of protein; in contrast, mice lacking microbiota (germ-free mice) and fed identical diet did not harbor GalCer. The identified GalCer contained a (R)-hydroxylated hexadecanoyl chain N-linked to C18-sphinganine, which differed from what has been reported with Bacteroides fragilis. Unlike -anomeric structures, but similar to GalCers from B. fragilis, the synthetic form of the murine GalCer induced iNKT cell activation in vitro. Last, we observed a decrease in GalCer production in mice exposed to conditions that alter the composition of the gut microbiota, including Western type diet, colitis, and influenza A virus infection. Collectively, this study suggests that GalCer is produced by commensals in the mouse intestine and reveals that stressful conditions causing dysbiosis alter its synthesis. The consequences of this altered production on iNKT cell-mediated local and systemic immune responses are worthy of future

The lung–gut axis during viral respiratory infections: the impact of gut dysbiosis on secondary disease outcomes

“…Infection with IAV also resulted in a shift in glycolipid metabolism. Interestingly, IAV infection altered the synthesis of alpha-galactosylceramides 53 which are known ligands for invariant natural killer T cells and play an important role in the immune system in rodents and humans. 54 It is not clear whether these metabolic changes influence gut homeostasis and function.…”

NKT cells and the regulation of intestinal immunity: a two‐way street

“…Conversely, B. fragilis has been reported to have a direct effect on the homeostasis of colonic iNKT cells by providing inhibitory sphingolipids that negatively modulate cell proliferation in the neonatal period . Interestingly, the presence of αGalCers in the murine intestinal compartment is strongly decreased in response to Western‐type diet, dextran sodium sulfate (DSS)‐induced colitis or influenza A virus infection, potentially impacting the function of intestinal iNKT cells . Altogether, these studies support a model by which the commensal microbiota can control the iNKT cell compartment by providing either inhibitory or stimulatory lipid antigens.…”

The role and research progress of the balance and interaction between regulatory T cells and other immune cells in obesity with insulin resistance

“…More importantly, Lynch et al [ 80 ]. treated high-fat diet-fed mice with sphingolipids (αGalCer), which effectively activated iNKT cells when presented by CD1d on APCs [ 81 ]. They found that three days after treatment with αGalCer, the number of Treg cells in the adipose tissue of wild-type mice was significantly increased, suggesting that the activation of iNKT cells promoted the proliferation and activation of Treg cells.…”