Anorexia of infection: Current prospects

The anorexia of infection is part of the host's acute phase response (APR). despite being beneficial in the beginning, long lasting anorexia delays re covery and is ultimately deleterious. Microbial products such as bacterial cell wall compounds (e.g., lipopolysaccharides and peptidoglycans), microbi al nucleic acids (e.g., bacterial DNA and viral double-stranded RNA), and v iral glycoproteins trigger the APR and presumably also the anorexia during infections. Microbial products stimulate the production of proinflammatory cytokines (e.g., interleukins [ILs], tumor necrosis factor-alpha, interfero ns), which serve as endogenous mediators. Several microbial products and cy tokines reduce food intake after parenteral administration, suggesting a ro le of these substances in the anorexia during infection. Microbial products are mainly released and cytokines are produced in the periphery during mos t infections; they might inhibit feeding through neural and humoral pathway s activated by their peripheral actions. Activation of peripheral afferents by locally produced cytokines is involved in several cytokine effects, but is not crucial for the anorectic effect of microbial products and IL-1 bet a. Cytokines increase leptin expression in the adipose tissue, and leptin m ay contribute to, but is also not essential for, the anorectic effects of m icrobial products and cytokines. In addition, a direct action of cytokines and microbial products on the central nervous system (CNS) is presumably in volved in the anorexia during infection. Cytokines can reach CNS receptors through circumventricular organs and through active or passive transport me chanisms or they can act through receptors on endothelial cells of the brai n vasculature and stimulate the release of subsequent mediators such as eic osanoids. De novo CNS cytokine synthesis occurs in response to peripheral i nfections, but its role in the accompanying anorexia is still open to discu ssion. Central mediators of the anorexia during infection appear to be neur ochemicals involved in the normal control of feeding, such as serotonin, do pamine, histamine, corticotropin releasing factor, neuropeptide Y, and cr-m elanocyte-stimulating hormone. Reciprocal, synergistic, and antagonistic in teractions between various pleiotropic cytokines, and between cytokines and neurochemicals, form a complex network that mediates the anorexia during i nfection. Current knowledge on the mechanisms involved suggests some therap eutic options for treatment. Substances that block common key steps in cyto kine synthesis or cytokine action, or inhibitors of eicosanoid synthesis, m ay hold more promise than attempts to antagonize specific cytokines. To tar get the neurochemical mediation of the anorexia during infection may be eve n more efficient. Future research should address these neurochemical mechan isms and the cytokine actions at the blood-brain barrier. Further unanswere d questions concern the modulation of the anorexia during infection by gend er and nutritional state. Nutrition 2000;16:996-1005. (C) Elsevier Science Inc. 2000.