Substance P activation of enteric neurons in response to intraluminal Clostridium difficile toxin A in the rat ileum.
OBJECTIVE
Nerves have been suggested to mediate the effects of bacterial toxins in intestinal diseases. However, the mechanisms involved are unknown. This study examined endogenous substance P (SP) activation of the substance P receptor (SPR) on enteric neurons in the rat ileum after exposure to intraluminal Clostridium difficile toxin A.


METHODS
After intraluminal injection of toxin A in ileal loops, tissue was examined for pathological changes by histology and for SPR activation by immunocytochemical analysis of SP-induced SPR endocytosis.


RESULTS
After toxin A administration, > 70% of enteric neurons showed SPR endocytosis and became swollen with thickened dendrites. In contrast, SPRs in control rats were largely confined to the plasma membrane. Rats denervated of primary afferent fibers with neonatal capsaicin injection and animals pretreated with a nonpeptide SPR antagonist showed few endosomal SPRs, and the pathological inflammatory effects of toxin A were ablated.


CONCLUSIONS
Intraluminal toxin A causes the release of SP from primary afferent neurons: this endogenous SP then acts on enteric neurons in the submucosal and myenteric plexuses. SP is the primary mediator of an axon reflex mediating neurogenic inflammation in the intestine. SPR blockade may prove to be a novel therapy used to prevent intestinal inflammation.
Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
C R
CR
Mantyh
T N
TN
Pappas
J A
JA
Lapp
M K
MK
Washington
L M
LM
Neville
J R
JR
Ghilardi
S D
SD
Rogers
P W
PW
Mantyh
S R
SR
Vigna
D000818:Animals; D001427:Bacterial Toxins; D002211:Capsaicin / Q000494:pharmacology; D016360:Clostridioides difficile / Q000472:pathogenicity*; D004768:Enterotoxins / Q000633:toxicity*; D005260:Female; D007082:Ileum / Q000737:chemistry / Q000187:drug effects* / Q000294:innervation; D008297:Male; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000032:analysis / Q000187:drug effects* / Q000276:immunology; D013373:Substance P / Q000502:physiology*
D001427:Bacterial Toxins; D004768:Enterotoxins; D018040:Receptors, Neurokinin-1; C041348:tcdA protein, Clostridium difficile; D013373:Substance P; D002211:Capsaicin