The
neuropeptide Pituitary adenylate cyclase-activating polypeptide (
PACAP) is well-known for its important functions in immunity and
inflammation. Data regarding anti-inflammatory properties of
PACAP in the intestinal tract are limited, however. In our present preclinical intervention study we addressed whether
PACAP treatment could alleviate experimental subacute
ileitis mimicking human gut microbiota conditions. Therefore, secondary abioitic mice were subjected to human
fecal microbiota transplantation (FMT) and perorally infected with low-dose Toxoplasma gondii to induce subacute
ileitis on day 0. From day 3 until day 8 post-
infection, mice were either treated with synthetic
PACAP38 or placebo. At day 9 post-
infection, placebo, but not
PACAP treated mice exhibited overt macroscopic sequelae of intestinal immunopathology.
PACAP treatment further resulted in less distinct apoptotic responses in ileal and colonic epithelia that were accompanied by lower T cell numbers in the mucosa and lamina propria and less secretion of pro-inflammatory
cytokines in intestinal ex vivo biopsies. Notably,
ileitis-associated gut microbiota shifts were less distinct in
PACAP as compared to placebo treated mice.
Inflammation-ameliorating effects of
PACAP were not restricted to the intestines, but could also be observed in extra-intestinal including systemic compartments as indicated by lower apoptotic cell counts and less pro-inflammatory
cytokine secretion in liver and lungs taken from
PACAP treated as compared to placebo control mice, which also held true for markedly lower serum TNF and
IL-6 concentrations in the former as compared to the latter. Our preclinical intervention study provides strong evidence that synthetic
PACAP alleviates subacute
ileitis and extra-intestinal including systemic sequelae of T cell-driven immunopathology. These findings further support
PACAP as a novel treatment option for intestinal
inflammation including
inflammatory bowel diseases (IBD).