The science of fatty acids and inflammation

Abstract

Inflammation is believed to play a central role in many of the chronic diseases that characterize modern society. In the past decade, our understanding of how dietary fats affect our immune system and subsequently our inflammatory status has grown considerably. There are compelling data showing that high-fat meals promote endotoxin [e.g., lipopolysaccharide (LPS)] translocation into the bloodstream, stimulating innate immune cells and leading to a transient postprandial inflammatory response. The nature of this effect is influenced by the amount and type of fat consumed. The role of various dietary constituents, including fats, on gut microflora and subsequent health outcomes in the host is another exciting and novel area of inquiry. The impact of specific fatty acids on inflammation may be central to how dietary fats affect health. Three key fatty acid-inflammation interactions are briefly described. First, the evidence suggests that saturated fatty acids induce inflammation in part by mimicking the actions of LPS. Second, the often-repeated claim that dietary linoleic acid promotes inflammation was not supported in a recent systematic review of the evidence. Third, an explanation is offered for why omega-3 (n-3) polyunsaturated fatty acids are so much less anti-inflammatory in humans than in mice. The article closes with a cautionary tale from the genomic literature that illustrates why extrapolating the results from inflammation studies in mice to humans is problematic.

Keywords: endotoxin; fatty acids; inflammation; linoleic acid; lipopolysaccharide; microflora; omega-3.

FIGURE 1

Pathway from consuming milk fat to colitis by way of altered bile acid production and subsequent shifts in gut microbial populations. Reproduced from reference with permission.

FIGURE 2

LA and AA metabolites play roles in both inflammation and resolution. Solid lines indicate proinflammatory pathways, and dotted/dashed lines represent anti-inflammatory/proresolving pathways. AA, arachidonic acid; CYP₄₅₀, cytochrome P₄₅₀; EET, epoxyeicosatrienoic acids; HETE, hydroxyeicosatetraenoic acid; HODE, hydroxyoctadecadienoic acid; LA, linoleic acid; LO, lipoxygenase; LTB₄, leukotriene B₄; LTX, leukotoxin; NO, nitrosylated; PGE₂, prostaglandin E₂.

FIGURE 3

Quantitative comparison of dietary DHA with immune cell DHA from mice, rats, and humans. The data were from studies that met the following criteria: 1) dietary n–3 PUFA (i.e., EPA and/or DHA) intake was a dependent variable in the study design, 2) the FA profile of an identifiable immune cell population was reported, and 3) data were published and identified in PubMed (National Library of Medicine) through December 2005. n–3 PUFA intake is expressed as a percentage of total energy consumed (i.e., en%). In most studies, daily caloric intake was not reported. Thus, the following assumptions were made: 1) human subjects consumed 2000 kcal/d and 2) rodents consumed the same calories across diet treatment groups. Best-fit lines/curves with 95% CI displayed by dotted lines were generated by using Prism software version 4.0b (GraphPad). Reproduced from reference with permission.

FIGURE 4

Putative model for the effect of n–3 PUFAs on lipid rafts. Lipid rafts are nanoscale regions of the plasma membrane, enriched in cholesterol, sphingomyelin, and phospholipids containing saturated acyl chains. Both transmembrane and peripheral membrane proteins can be localized to lipid rafts. Upon treatment with a combination of n–3 PUFAs or DHA alone, these PUFAs are incorporated into phospholipids, which are inserted into both raft and nonraft regions of the plasma membrane. This results in enhanced clustering of lipid raft regions, which are depleted of cholesterol and sphingomyelin. In addition, many lipid raft–associated proteins “mislocalize” to the bulk membrane domain. This results in a suppression of lipid raft–mediated processes, including T cell activation and downstream signal transduction. Reproduced from reference with permission.

FIGURE 5

Comparison of the genomic response in circulating leukocytes to severe acute inflammation from 6 distinct causes in human and murine models. GEO was queried for studies in the white blood cells of severe acute inflammatory diseases (i.e., burns, endotoxemia, trauma, sepsis, ARDS, and infection) in humans and mice. The fold-change of each gene measured was calculated between patients and controls in a human study or between treated and control groups in a murine model study; and for a time-course data set, the maximum fold-change was calculated. The gene response in each data set was then compared with the 5554 genes that were significantly changed in human trauma, burns, and endotoxemia. Shown are correlations (x axis) and directionality (y axis) of gene response from the resulting multiple published data sets in GEO compared with human burn injury. ARDS, acute respiratory distress syndrome; GEO, Gene Expression Omnibus. Reproduced from reference with permission.