Nutritional stimulation of cholecystokinin receptors inhibits inflammation via the vagus nerve

Abstract

The immune system in vertebrates senses exogenous and endogenous danger signals by way of complex cellular and humoral processes, and responds with an inflammatory reaction to combat putative attacks. A strong protective immunity is imperative to prevent invasion of pathogens; however, equivalent responses to commensal flora and dietary components in the intestine have to be avoided. The autonomic nervous system plays an important role in sensing luminal contents in the gut by way of hard-wired connections and chemical messengers, such as cholecystokinin (CCK). Here, we report that ingestion of dietary fat stimulates CCK receptors, and leads to attenuation of the inflammatory response by way of the efferent vagus nerve and nicotinic receptors. Vagotomy and administration of antagonists for CCK and nicotinic receptors significantly blunted the inhibitory effect of high-fat enteral nutrition on hemorrhagic shock-induced tumor necrosis factor-alpha and interleukin-6 release (P < 0.05). Furthermore, the protective effect of high-fat enteral nutrition on inflammation-induced intestinal permeability was abrogated by vagotomy and administration of antagonists for CCK and nicotinic receptors. These data reveal a novel neuroimmunologic pathway, controlled by nutrition, that may help to explain the intestinal hyporesponsiveness to dietary antigens, and shed new light on the functionality of nutrition.

Figures

Figure 1.

Vagotomy blunts the inhibitory effect of high-fat enteral nutrition on the inflammatory response and preserves gut barrier function. Rats (n = 6 per group) were fasted or fed low-fat or high-fat enteral nutrition before (Sham) vagotomy (VGX) and hemorrhagic shock (Hem. Shock). Inhibition of TNF-α (a), IL-6 (b), leakage of HRP in ileum (c) and endotoxin (d) after hemorrhagic shock by high-fat nutrition is reversed by vagotomy. Data are solid dots, mean (dashed line), median (solid line), 25th and 75th percentiles. *P < 0.01 versus fasted Sham + Hem. Shock; **P < 0.01 versus high-fat treated Sham + Hem. Shock; †P < 0.05 versus low-fat treated Sham + Hem. Shock.

Figure 2.

CCK-receptor antagonists increase the inflammatory response and deteriorate gut barrier function in high-fat treated rats subjected to sham vagotomy and hemorrhagic shock. High-fat treated rats (n=6 per group) were intravenously injected with CCK-receptor A+B antagonist (CCK-ra) or vehicle before hemorrhagic shock. TNF-α (a), IL-6 (b), leakage of HRP in ileum (c) and endotoxin (d) were increased after hemorrhagic shock in high-fat treated rats injected with CCK-receptor A+B antagonists in high-fat treated rats vagotomized before hemorrhagic shock. Data are solid dots, mean (dashed line), median (solid line), 25th and 75th percentiles. *P < 0.01 versus vehicle treated group.

Figure 3.

Inhibition of nicotinic receptors increases inflammation and deteriorates gut barrier function in high-fat treated rats subjected to sham vagotomy and hemorrhagic shock. High-fat treated rats (n = 6 per group) were injected intravenously with chlorisondamine (Chlorison.) or vehicle before hemorrhagic shock. TNF-α (a), IL-6 (b), leakage of HRP in ileum (c) and endotoxin (d) were increased after hemorrhagic shock in rats injected with chlorisondamine. There were no significant differences between fasted and high-fat treated rats treated with chlorisondamine. Data are solid dots, mean (dashed line), median (solid line), 25th and 75th percentiles. *P < 0.01 versus vehicle treated group. Treatment with chlorisondamine did not affect mean arterial pressure (MAP) before and just after hemorrhagic shock (e), although there was a significant difference in MAP between chlorisondamine and vehicle treated rats from 10 to 50 min during the observation period (P < 0.05).

Figure 4.

Dietary fat inhibits the inflammatory response by way of stimulation of CCK-receptors leading to activation of nicotinic receptors by vagal efferents. Ingestion of high amounts of fat induces release of cholecystokinin (CCK) that binds to CCK-A and CCK-B receptors (CCK-r) located centrally or on peripheral vagal afferents. Activation of CCK-receptors triggers vagal efferents leading to an increase of acetylcholine (Ach), the principal parasympathetic neurotransmitter. Release of inflammatory cytokines such as TNF-α and IL-6 after activation of Toll-like receptors by bacterial products is inhibited by way of binding of acetylcholine to α-7 nicotinic (α7-nAch) receptors.