Preoperative administration of the 5-HT4 receptor agonist prucalopride reduces intestinal inflammation and shortens postoperative ileus via cholinergic enteric neurons

Abstract

ObjectivesVagus nerve stimulation (VNS), most likely via enteric neurons, prevents postoperative ileus (POI) by reducing activation of alpha7 nicotinic receptor (α7nAChR) positive muscularis macrophages (mMφ) and dampening surgery-induced intestinal inflammation. Here, we evaluated if 5-HT4 receptor (5-HT4R) agonist prucalopride can mimic this effect in mice and human.DesignUsing Ca2+ imaging, the effect of electrical field stimulation (EFS) and prucalopride was evaluated in situ on mMφ activation evoked by ATP in jejunal muscularis tissue. Next, preoperative and postoperative administration of prucalopride (1–5 mg/kg) was compared with that of preoperative VNS in a model of POI in wild-type and α7nAChR knockout mice. Finally, in a pilot study, patients undergoing a Whipple procedure were preoperatively treated with prucalopride (n=10), abdominal VNS (n=10) or sham/placebo (n=10) to evaluate the effect on intestinal inflammation and clinical recovery of POI.ResultsEFS reduced the ATP-induced Ca2+ response of mMφ, an effect that was dampened by neurotoxins tetrodotoxin and ω-conotoxin and mimicked by prucalopride. In vivo, prucalopride administered before, but not after abdominal surgery reduced intestinal inflammation and prevented POI in wild-type, but not in α7nAChR knockout mice. In humans, preoperative administration of prucalopride, but not of VNS, decreased Il6 and Il8 expression in the muscularis externa and improved clinical recovery.ConclusionEnteric neurons dampen mMφ activation, an effect mimicked by prucalopride. Preoperative, but not postoperative treatment with prucalopride prevents intestinal inflammation and shortens POI in both mice and human, indicating that preoperative administration of 5-HT4R agonists should be further evaluated as a treatment of POI.Trial registration numberNCT02425774.

Lack of mucosal cholinergic innervation is associated with increased risk of enterocolitis in Hirschsprung’s disease

“…6a and f). In contrast, other receptors reported to be involved in cholinergic immune suppression such as receptors for serotonin 56 , catecholamine (ADRB2) 50, 57 , or neuropeptides (NMUR1, VIPR1, SSTR2, and CALCRL) 58–65 were not upregulated in fiber-high LPMΦ compared to fiber-low LPMΦ or were not expressed (NMUR1) (Fig. 6b, c and f).…”

“…Upon Salmonella typhimurium infection, MMΦ interact with sympathetic adrenergic neurons via β2 adrenergic receptors to induce a tissue- and neuron-protective gene expression program 50 . In a model of POI which is characterized by surgery-induced inflammatory response of MMΦ and impaired motility, VN stimulation or pharmacologic triggering of cholinergic enteric neurons prevented MΦ activation and reduced POI in a α7nAChR-dependent manner in both mice and humans 56 . However, anti-inflammatory neuro-immune modulation seems to involve different neuronal receptors in type 2-mediated intestinal disease models.…”

The clinical and economical impact of postoperative ileus in patients undergoing colorectal surgery

“…In animal studies, interventions have been explored aiming to reduce the early inflammatory responses that lie at the basis of POI. For instance, prucalopride, a5‐Ht4 receptor agonist, and vagus nerve stimulation, either electrical or via lipid‐enriched nutrition inhibits inflammation in an early stage and can prevent experimental POI 18,34,35 . Interestingly, two recent clinical pilot studies by Stakenborg et al showed promising results in patients.…”

“…The reason for this discrepancy between the experimental data and the implementation into clinical practice may be twofold; on the one hand there is a lack of consensus amongst physicians toward the clinical features of POI, its impact, and its management, resulting in few high quality clinical studies also in a surgical setting 14 . On the other hand, it is uncertain whether the mechanisms found in rodent models can be completely translated into the clinical setting 15‐18 . The aim of the current study is to address whether inflammatory processes such as those found in experimental studies, occur in patients undergoing colorectal surgery.…”

Concise Review: Cellular and Molecular Mechanisms of Postnatal Injury-Induced Enteric Neurogenesis

“…In dogs, mosapride ameliorates gastric hypomotility following vincristine‐induced colitis, whereas in human patients, mosapride increased gastric emptying and decreases full bowel transit time during capsule endoscopy . Preoperative administration of prucalopride shortens postoperative ileus and reduces intestinal inflammation in clinical patients with decreases in IL‐6 and IL‐8 expression . Utilizing the 5‐HT4 agonists in the treatment of acute inflammatory colitis is a promising option when prokinetic and neurogenic effects are desirable.…”