E-Letter responses to:

special/review: Michael K. Badman and Jeffrey S. Flier The Gut and Energy Balance: Visceral Allies in the Obesity Wars Science 2005; 307: 1909-1914 [Abstract] [Full text] [PDF]

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Gut-Brain Interaction in Sepsis

Michael Miksa   (21 April 2005)

Gut-Brain Interaction in Sepsis 21 April 2005
Michael Miksa, Investigator North Shore-Long Island Jewish Health System, Manhasset, NY Respond to this E-Letter: Re: Gut-Brain Interaction in Sepsis	Michael Badman and Jeffrey Flier comprehensively reviewed the molecular modulation of energy maintenance through direct and indirect interaction with neurons in the hypothalamus. Among others, leptin and ghrelin have been discussed as modulators of satiety and hunger, respectively. Except for ghrelin’s potential role in carcinoma-induced cachexia, the authors focused on the pathogenesis of obesity. Yet, cachexia plays an important role in severe morbid conditions such as sepsis. Although, due to the short course of the disease it is not as obvious as in oncologic patients, pro-anorexic peptide patterns can be found in sepsis. Leptin- levels increase in sepsis while ghrelin is decreased (1, 2). One effect of this state is the activation of sympathetic outflow, which increases energy expenditure in brown adipose tissue. While leptin has been shown to act as a pro-inflammatory cytokine (3), ghrelin has clear anti- inflammatory effects that are not mediated by direct influence on immune cells. Ghrelin contains a systemic inflammatory response in sepsis that is thought to have detrimental effects by inducing septic shock and organ dysfunction. This is achieved by centrally activating the vagus nerve and at the same time inhibiting sympathetic outflow. Activation of the vagus nerve decreases the pro-inflammatory response of macrophages via a7- cholinergic receptors (4). Ghrelin also abrogates the sympathetic excitotoxic effect in sepsis mediated by norepinephrine-primed macrophages (5). Catecholamines have been shown to inhibit inflammation in therapeutic doses via activation of b2-adrenoceptors on mononuclear cells. However, ogan dysfunction in severe sepsis is mediated in part by an increase in pro-inflammatory cytokine release, which is caused in turn by priming of macrophages via gut-derived norepinephrine at subtherapeutic levels. This mediates the pro-inflammatory priming by activating a2A- adrenoceptors on Kupffer cells. These orexigenic peptides thus are linked with the activation of the autonomous nervous system and the regulation of inflammatory responses. The energy requirements in sepsis might be only marginally elevated, yet the sympathoinhibitory and anti-inflammatory effect of a “fed state” should not be underestimated in the severely injured or multi-morbid patient. 1. R. E. Landman et al., J Clin Endocrinol Metab 88, 1285-91 (Mar, 2003). 2. Y. Hataya et al., Endocrinology 144, 5365-71 (Dec, 2003). 3. M. Otero et al., FEBS Lett 579, 295-301 (Jan 17, 2005). 4. K. J. Tracey, Nature 420, 853-9 (Dec 19-26, 2002). 5. M. Miksa, R. Wu, M. Zhou, P. Wang, Front Biosci 10, 2217- 2229 (Sep 1, 2005).