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The Enteric Nervous System (ENS) Neuropeptide, Bombesin (BBS), Reverses Innate Immune Impairments during Parenteral Nutrition (PN)
Kenneth A Kudsk, Rebecca A Busch*, Aaron F Heneghan*, Joseph F Pierre*, Xinying Wang*
University of Wisconsin-Madison, Madison, WI
OBJECTIVE(S): Lack of enteral stimulation during PN impairs acquired (e.g. IgA) and innate mucosal immunity providing a cogent explanation for increased infections in PN fed patients compared to enteral feeding. Experimentally, BBS,a gastrin-releasing neuropeptide analogue, reverses PN-induced defects in gut and respiratory acquired immunity. Paneth cells produce and store the key bactericidal peptides of innate immunity for
release into the lumen after cholinergic stimulation. We hypothesized that BBS during PN restores antimicrobial peptides and the bactericidal function of innate immunity.
METHODS: IV cannulated male ICR mice were randomized to Chow, PN, or PN + 15 ug TID BBS (n=7/group) for 5 days. Ileal tissue was analyzed for antimicrobial peptides (sPLA2 fluorescent activity, lysozyme protein by Western, and RegIII-ɤ by RT-PCR and all by IHC). Ileal tissue stimulated with a cholinergic agonist (100 µM bethanechol) assessed Pseudomonas bactericidal activity. Additional mice (Chow:n=7; PN: n=9; PN+BBS: n=8) were assessed for E. coli intestinal invasion in ex-vivo culture.
RESULTS: Compared to chow, PN significantly decreased cellular levels
of all antimicrobial peptides while BBS maintained them at Chow levels. Functionally, BBS prevented PN loss of bactericidal
activity after cholinergic stimulation but failed to improve bacterial enteroinvasion in unstimulated tissue.
CONCLUSIONS:The ENS controls antimicrobial peptide levels in Paneth cellsduring PN but both ENS and parasympathetic stimulation are required for mucosal protection by innate immunity.
| Chow | PN | PN+BBS | |
| sPLA2 fluorescent activity (Fl/min/µL/total protein) | 1070 + 140 | 450 + 72a | 790 + 130 |
| Lysozyme protein (lysozyme/total protein) | 6390 + 1200 | 2680 + 620a | 6490 + 1400 |
| RegIII-γ by RT-PCR (RegIII-γ/b-actin expression) | 2.4 + 0.1 | 1.3 + 0.1a | 2.7 + 0.6 |
| Bactericidal activity (%) | 25.3 + 3.6 | 13.0 + 3.2a | 27.0 + 4.7 |
| Enteroinvasion (x103 CFU) | 3.3 + 1.1 | 63.9 + 20.0b | 24.5 + 10.6 |
| (mean + SEM) a P <0.05 vs. Chow and BBS, b P <0.05 vs. Chow |
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