The enteric nervous system neuropeptide, bombesin, reverses innate immune impairments during parenteral nutrition.

Background: Lack of enteral stimulation during parenteral nutrition (PN) impairs mucosal immunity. Bombesin (BBS), a gastrin-releasing peptide analogue, reverses PN-induced defects in acquired immunity. Paneth cells produce antimicrobial peptides (AMPs) of innate immunity for release after cholinergic stimulation.

Objective: Determine if BBS restores AMPs and bactericidal function during PN.

Methods: Intravenously cannulated male ICR mice were randomized to Chow, PN, or PN+BBS (15 μg 3 times daily, n = 7 per group) for 5 days. Ileum was analyzed for AMPs (Protein: sPLA2 by fluorescence, lysozyme and RegIII-γ by western andcryptdin-4 by ELISA; mRNA: all by RT-PCR). Cholinergic stimulated (100 μM bethanechol) ileal specimens assessed Pseudomonas bactericidal activity. Ileum (Chow: n = 7; PN: n = 9; PN+BBS: n = 8) was assessed for Escherichia coli invasion in ex-vivo culture.

Results: PN significantly decreased most AMPs versus Chow while BBS maintained Chow levels (sPLA2: Chow: 107 + 14*, PN: 44.6 + 7.2, PN+BBS: 78.7 + 13.4* Fl/min/μL/total protein; Lysozyme: Chow: 63.9 + 11.9*, PN: 26.8 + 6.2; PN+BBS: 64.9 + 13.8* lysozyme/total protein; RegIII-γ: Chow: 51.5 + 10.0*, PN: 20.4 + 4.3, PN+BBS: 31.0 + 8.4 RegIII-γ/total protein; Cryptdin-4: Chow: 18.4 + 1.5*, PN: 12.7 + 1.6, PN+BBS: 26.1 + 2.4*† pg/mg [all *P < 0.05 vs PN and †P < 0.05 vs Chow]). Functionally, BBS prevented PN loss of bactericidal activity after cholinergic stimulation (Chow: 25.3 + 3.6*, PN: 13.0 + 3.2; PN+BBS: 27.0 + 4.7* percent bacterial killing, *P < 0.05 vs PN). BBS reduced bacterial invasion in unstimulated tissue barely missing significance (P = 0.06).

Conclusions: The enteric nervous system (ENS) controls AMP levels in Paneth cells during PN but mucosal protection by innate immunity requires both ENS and parasympathetic stimulation.