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Infections and glycolipids
  1. N S Radin
  1. Psychiatry Department, University of Michigan, Ann Arbor, Michigan, USA; gluconorm{at}aol.com

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    A recent case report in the journal described a Gaucher’s disease patient, dangerously infected with salmonella that responded poorly to antibiotic treatment.1 However, use of enzyme replacement with glucosylceramide glucosidase lowered tissue levels of glucosylceramide (GlcCer), and produced a slow but dramatic improvement. The article points out that infection is an important aspect of the genetic disorder. I would like to mention important observations that explain this unfortunate complication and their significance for many patients with infections.

    Many research studies have shown that a wide variety of bacterial and viral infections involve binding of the organism to a glucosphingolipid in the cell surface. Patients with Gaucher’s disease accumulate not only GlcCer, but also some of the more complex glucosphingolipids formed from GlcCer. This second order accumulation explains why these patients are susceptible to infection. In the case of salmonella,1 the organism binds to GlcCer and acidic glucosphingolipids.

    It follows then that depleting glucosphingolipids in people should reduce the number of binding sites for infectious agents and, possibly, prevent the development of new infections. If the glucosphingolipids already bound to infectious particles are in a reversible equilibrium, one can expect that a decrease in the body’s total glucosphingolipid content will force the infectious particles to leave the body, one way or another. This, basically, is why enzyme replacement helped the Gaucher’s patient.1

    Lowering cellular glucosphingolipids has indeed been shown to reduce adhesion of pathogens.2 Mice depleted of their glucosphingolipids resisted colonisation of the urinary tract.3 Interference with HIV-1 progression by glucosphingolipid depletion is especially exciting.4 Studies of this sort utilised inhibitors of GlcCer synthase.

    Other approaches can also achieve reductions in cellular glucosphingolipids. Caloric restriction has long been known to extend life, slowing the appearance of infections, cancer, atherosclerosis, and other serious illnesses. Brief fasting or caloric restriction might prove helpful in fighting a current infection. This approach should also be helpful for micro-organisms that bind primarily to glycoproteins.

    Other means of slowing glucosphingolipid synthesis have been described.5 These include the use of chlorpromazine, tamoxifen, verapamil, RU-486 (mifepristone), antiandrogens, all-trans retinoic acid, and cycloserine. Glucosamine, widely used to prevent joint pain, should compete against glucose, lowering the level of uridine diphosphoglucose.

    Biosynthesis of the GlcCer precursor, ceramide, can be slowed by inhibiting sphingomyelin hydrolysis. This can be done by avoiding arachidonic acid, a stimulator of the enzyme. Dietary fats should therefore be restricted to olive and canola oil. Glutathione, the major thiol in cells, slows sphingomyelin hydrolysis and should be maintained at a high level by eating a glutathione precursor, N-acetyl cysteine. 3-O-Methyl sphingomyelin is a direct inhibitor of the hydrolase. Supplementing the diet with modest amounts of antioxidants will protect glutathione against oxidation. Carnitine, available as a food supplement, helps lower tissue fatty acids by speeding their oxidation. (Since ceramide is formed from two molecules of fatty acid, general fat depletion should be helpful.) The level of ceramide can also be lowered by stimulating its conversion to sphingomyelin by reaction with lecithin; ergo, eat extra lecithin. GlcCer, the simplest glucosphingolipid, is normally degraded by hydrolysis, which can be speeded by phosphatidylserine, available as a food supplement.

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