Dietary Ganglioside Inhibits Acute Inflammatory Signals in Intestinal Mucosa and Blood Induced by Systemic Inflammation of Escherichia Coli Lipopolysaccharide

Abstract

Our previous study demonstrated that feeding ganglioside increased total ganglioside content while decreasing cholesterol and caveolin-1 content in developing rat intestinal lipid microdomains. Cholesterol or caveolin depletion in membranes inhibits inflammatory signaling by disrupting microdomain structure. We hypothesized that dietary ganglioside-induced reduction in cholesterol content will reduce proinflammatory mediators in the intestinal mucosa after acute exposure to bacterial endotoxin. Weanling rats were fed semipurified diets with 0.1% (wt/wt of total fat) gangliosides (treatment) or without ganglioside (control). After 2 weeks of feeding, half of animals from each diet group were injected with saline or lipopolysaccharide (LPS) endotoxin (Escherichia coli serotype O111:B4, intraperitoneal, 3 mg/kg body weight) to induce acute gut inflammation. Intestinal mucosa and blood were collected after 6 h. The effect of dietary ganglioside on proinflammatory mediators including cholesterol, platelet-activating factor, prostaglandin E2, leukotriene B4 (LTB4), interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha) was determined in inflamed mucosa and blood. Feeding animals the control diet increased cholesterol content in intestinal lipid microdomains by 92% after LPS injection compared with saline injection. Animals fed the ganglioside diet significantly decreased cholesterol content in lipid microdomains by 60% compared with animals fed the control diet. Feeding animals the ganglioside diet increased total ganglioside content by 90% while decreasing platelet-activating factor content by 45% in the inflamed mucosa by acute systemic exposure to LPS compared with animals fed the control diet. When animals were fed the ganglioside diet, the levels of prostaglandin E2, LTB4, IL-1beta, and TNF-alpha were lower in inflamed mucosa, and LTB4, IL-1beta, and TNF-alpha were decreased in plasma by 41%, 58%, and 55% compared with control animals, respectively. The present study demonstrates that dietary gangliosides inhibit proinflammatory signals in the intestine and blood induced by acute inflammation of LPS and suggests therapeutic potential in the treatment and management of acute local and systemic inflammatory diseases.

Nutraceutical Properties of Milk Fat Globular Membrane

“…The decreased serum levels of several cytokines in mice fed the experimental diet suggest that MFGM reduces the inflammatory response following stress. Our results are consistent with those investigating the effects of sphingolipids and gangliosides on inflammation (Dalbeth et al 2009;El Alwani et al 2006;Park et al 2007;Park et al 2005), suggesting that the high sphingolipid content of MFGM could be responsible for the lowered inflammatory response. Gut barrier dysfunction has been identified as a result of cytokine induction due to inflammation (Sun et al 1999).…”

“…While the mechanism of how gut barrier dysfunction occurs is unclear, pro-inflammatory cytokines, such as, IL-4, IL-13, IFN-, and TNF-α, have been reported to increase the permeability of intestinal epithelia (Fink 2003;Lewis and McKay 2009;Yajima et al 2009). Several studies suggest that various milk sphingolipids, including sphingomyelin and gangliosides, positively affect the gut by exhibiting a protective effect against colon cancer (Dillehay et al 1994;Duan and Nilsson 2009;Nilsson and Duan 2006;Schmelz et al 1996;Schmelz et al 2000), and other studies have linked sphingolipids and other milk fat fractions containing phospholipids and gangliosides to the inhibition of a pro-inflammatory response and gut barrier protection (Dalbeth et al 2009;El Alwani et al 2006;Park et al 2007;Park et al 2005;. One source of a variety of dietary sphingolipids is MFGM.…”

The Nutritional Significance of Lipid Rafts

“…However, whether these effects in any way involve modulation of cell composition or behavior by gangliosides is not known; it is notable that the carbohydrate portions resemble those of free oligosaccharides with proven prebiotic capabilities (119). Nevertheless, dietary gangliosides have been shown to modify the composition of the brush border membrane in intestinal mucosa (106,107), and an increase in ganglioside content decreased the cholesterol and caveolin-1 content of lipid microdomains (108). Cholesterol depletion in membranes inhibits cellular entry of pathogens and generation of inflammatory signals by disrupting microdomain structure; thus, the authors went on to demonstrate that feeding dietary gangliosides resulted in reduced generation of inflammatory eicosanoids and cytokines by intestinal mucosa following acute exposure to bacterial endotoxin (108).…”

Intestinal alkaline phosphatase prevents metabolic syndrome in mice

“…Also, it has been shown that an HFD causes local intestinal inflammation (11). Systemic and local inflammation lead to overexpression of proinflammatory cytokines (12), which cause increased gut permeability (13) and an acceleration of endotoxin translocation (14), resulting in a vicious cycle of endotoxemia. A central role of LPS in the pathogenesis of metabolic syndrome is also supported by the observation that mice lacking toll-like receptor 4 (TLR4), the receptor for LPS, are resistant to HFD-induced inflammation, obesity, and insulin resistance (15).…”