Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine

Abstract

Growing empirical evidence suggests that nutrition and bacterial metabolites might impact the systemic immune response in the context of disease and autoimmunity. We report that long-chain fatty acids (LCFAs) enhanced differentiation and proliferation of T helper 1 (Th1) and/or Th17 cells and impaired their intestinal sequestration via p38-MAPK pathway. Alternatively, dietary short-chain FAs (SCFAs) expanded gut T regulatory (Treg) cells by suppression of the JNK1 and p38 pathway. We used experimental autoimmune encephalomyelitis (EAE) as a model of T cell-mediated autoimmunity to show that LCFAs consistently decreased SCFAs in the gut and exacerbated disease by expanding pathogenic Th1 and/or Th17 cell populations in the small intestine. Treatment with SCFAs ameliorated EAE and reduced axonal damage via long-lasting imprinting on lamina-propria-derived Treg cells. These data demonstrate a direct dietary impact on intestinal-specific, and subsequently central nervous system-specific, Th cell responses in autoimmunity, and thus might have therapeutic implications for autoimmune diseases such as multiple sclerosis.

Western lifestyle and immunopathology of multiple sclerosis

“…Fatty acids can be classified into short‐ (SCFA, <10 carbon atoms), medium‐ (MCFA, 10–14 carbon atoms), long‐ (LCFA, 16–20 carbon atoms), and very‐long‐chain fatty acids (VLCFA, >20 carbon atoms). SCFAs were recently found to ameliorate EAE, as well as other autoimmune diseases, such as type 1 diabetes, by expanding lamina propria–derived T reg cells through suppression of the JNK1 and p38 pathway 98, 125. In line with these studies, SFCAs also increase the number of colonic T reg cells in an experimental model of inflammatory bowel disease 126, 127.…”

“…This argues for a dysfunctional microbiome being a possible culprit for MS disease initiation or progression. SCFAs, MCFAs, and LCFAs, the most abundant components of a Western diet, worsen EAE severity by enhancing T H 1 and T H 17 differentiation and proliferation and possibly by decreasing intestinal SCFA levels 98. In line with this finding, LCFA also induced the polarization of human naive T cells toward T H 1 and T H 17 fates in vitro 98.…”

“…Similarly, the precise underlying pathogenic molecular mechanisms remain largely unknown. Recently, increased consumption of saturated medium‐ and long‐chain fatty acids was found to worsen autoimmunity in the EAE model 98. The exacerbated EAE severity was paralleled by increased T H 17 cell frequencies in the CNS and elevated T H 1 and T H 17 cell numbers in the spleen.…”

“…An increasing amount of literature shows that fat‐induced alterations in T cell lineages and the activation status of macrophages and microglia exacerbate neuroinflammation in MS and the EAE model 98, 99, 100, 101, 102, 103. Interestingly, excessive fat consumption is also a key factor inducing obesity, which increases the risk of developing MS 60, 61, 62.…”

“…SCFAs, MCFAs, and LCFAs, the most abundant components of a Western diet, worsen EAE severity by enhancing T H 1 and T H 17 differentiation and proliferation and possibly by decreasing intestinal SCFA levels 98. In line with this finding, LCFA also induced the polarization of human naive T cells toward T H 1 and T H 17 fates in vitro 98. In addition to its effects on T cells, MCFA may also affect macrophage physiology through the activation of G protein‐coupled receptor 84 (GPR84) 132.…”