Cholecystokinin/Cholecystokinin-1 receptor-mediated peripheral activation of the afferent vagus by enteral nutrients attenuates inflammation in rats.
OBJECTIVE
The current study investigates activation of the nutritional anti-inflammatory pathway by lipid-rich nutrition.


BACKGROUND
Enteral nutrition activates humoral and neural pathways to regulate food intake and sustain energy balance. Recently, we demonstrated that enteral nutrition and in particular lipid-rich nutrition modulates inflammation and prevents organ damage.


METHODS
Male rats were fasted or fed lipid-rich nutrition before hemorrhagic shock. Disruption of afferent vagal fibers with capsaicin (deafferentation) was used to investigate involvement of afferent fibers. Peripheral activation of afferent vagal fibers via cholecystokinin (CCK)-mediated activation of CCK-1 receptors was investigated using administration of the selectively peripheral acting CCK-1 receptor antagonist, A70104 and PEGylated-CCK9. Tissue and blood were collected 90 minutes after shock to assess systemic inflammation and intestinal integrity.


RESULTS
Deafferentation reversed the inhibitory effect of lipid-rich nutrition on systemic levels of tumor necrosis factor-alpha and interleukin-6, and on intestinal leakage of horseradish peroxidase and bacterial translocation. Furthermore, the protective effects of lipid-rich nutrition were negated by A70104, indicating that lipid-rich nutrition triggers peripheral CCK-1 receptors on vagal afferents to modulate inflammation. These findings were substantiated by the fact that pretreatment of fasted rats with PEGylated-CCK9, which acts on peripheral CCK-1 receptors, attenuated systemic inflammation, and loss of intestinal integrity.


CONCLUSIONS
These data demonstrate that enteral lipid-rich nutrition modulates inflammation and preserves intestinal integrity via CCK release which activates CCK-1 receptors located on afferent vagal fibers. Taken together, the current study reveals a novel gut-brain-immune axis and provides new insight into the applicability of enteral nutrition to treat inflammatory conditions.
Lubbers
Tim
T
Department of Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands.
de Haan
Jacco J
JJ
Luyer
Misha D P
MD
Verbaeys
Isabelle
I
Hadfoune
M'hamed
M
Dejong
Cornelis H C
CH
Buurman
Wim A
WA
Greve
Jan Willem M
JW
D000818:Animals; D018988:Bacterial Translocation; D002211:Capsaicin; D002766:Cholecystokinin / Q000494:pharmacology / Q000502:physiology*; D004750:Enteral Nutrition; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects; D008055:Lipids / Q000494:pharmacology*; D008297:Male; D009434:Neural Pathways; D010446:Peptide Fragments / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012771:Shock, Hemorrhagic / Q000378:metabolism; D014630:Vagus Nerve / Q000503:physiopathology*
D008055:Lipids; D010446:Peptide Fragments; D011804:Quinolines; D011949:Receptors, Cholecystokinin; C053399:cholecystokinin 9; C063047:A 65186; D002766:Cholecystokinin; D002211:Capsaicin