Role of Sphingolipids in Infant Gut Health and Immunity

Abstract

Sphingomyelin (SM), glycosphingolipids, and gangliosides are important polar lipids in the milk fat globule membrane but are not found in standard milk replacement formulas. Because digestion and absorption of SM and glycosphingolipids generate the bioactive metabolites ceramide, sphingosine, and sphingosine-1-phosphate (S1P), and because intact gangliosides may have beneficial effects in the gut, this may be important for gut integrity and immune maturation in the neonate. The brush border enzymes that hydrolyze milk SM, alkaline sphingomyelinase (nucleotide phosphodiesterase pyrophosphatase 7), and neutral ceramidase are expressed at birth in both term and preterm infants. Released sphingosine is absorbed, phosphorylated to S1P, and converted to palmitic acid via S1P-lyase in the gut mucosa. Hypothetically, S1P also may be released from absorptive cells and exert important paracrine actions favoring epithelial integrity and renewal, as well as immune function, including secretory IgA production and migration of T lymphocyte subpopulations. Gluco-, galacto-, and lactosylceramide are hydrolyzed to ceramide by lactase-phlorizin hydrolase, which also hydrolyzes lactose. Gangliosides may adhere to the brush border and is internalized, modified, and possibly transported into blood, and may exert protective functions by their interactions with bacteria, bacterial toxins, and the brush border.

Dietary Milk Sphingomyelin Reduces Systemic Inflammation in Diet-Induced Obese Mice and Inhibits LPS Activity in Macrophages

“…Feeding mice an HFD has also been shown to reduce the expression of the key enzyme in SM digestion, alkaline sphingomyelinase [46,47]. Therefore, it is possible that the use of a high-fat lard diet with added cholesterol in this study influenced ileal and colonic exposure to SM and bioactive metabolic products (ceramide, sphingosine, and sphingosine-1-phosphate), which in turn could affect colon inflammation [48,49].…”

Breast Milk Lipids and Fatty Acids in Regulating Neonatal Intestinal Development and Protecting against Intestinal Injury

“…Breast milk sphingolipids, such as sphingomyelin and gangliosides, are important modulators of neonatal intestinal development, the establishment of the gut microbiome, and inflammation [117]. Sphingomyelin is digested by nucleotide phosphodiesterase pyrophosphatase 7 (NPP7), a brush border enzyme of the intestinal epithelium, and generates ceramide, sphingosine, and sphingosine-1phosphate [118,119]. In contrast to sphingomyelin and ceramide, sphingosine is rapidly absorbed and largely converted to palmitic acid in the mucosa [120].…”

“…NPP7 possesses phospholipase C activity against platelet activating factor, a pro-inflammatory lipid mediator produced by gut epithelial cells [121]. Higher levels of platelet activating factor have been shown in inflammatory bowel disease, ischemic colitis and NEC [118]. Intrarectal administration of recombinant NPP7 significantly reduced the intestinal injury and inflammation against colitis in an adult rat model [122].…”

Benefits of Lactoferrin, Osteopontin and Milk Fat Globule Membranes for Infants

“…A major class of compounds are sphingolipids, which are based on a sphingosine backbone and according to the head group can be differentiated into sphingomyelin (phosphocholine), ceramide (H), glycosylceramides (glucose or lactose), lactosylceramides (lactose) and with more complex glycosyl residues gangliosides (monosaccharides, N-acetylgalactoseamine, sialic acid and others) [ 135 ]. A series of biological functions have been ascribed to ceramides, including regulation of cell growth, apoptosis and inflammation, but cellular uptake seems limited [ 136 ]. Similarly, intact sphingomyelin is not absorbed, but it accelerates maturation of the intestine of rat pups [ 137 ].…”