# Mechanisms and therapeutic interventions of postoperative gastric ileus

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2020 · —

## Abstract

Postoperative ileus (POI) is one of the main complication associated with abdominal surgery (AS) procedures.
A number of Veterans deployed in the war zones undergo injuries requiring AS. After AS, patients usually
develop nausea, vomiting, bloating, and abdominal pain which are major contributing factors to postoperative
discomfort. The incidence of ileus is highest in gastrointestinal (GI) surgery with 24% of patients developing
ileus and can be as high as 40% in laparotomy patients. The health burden and the cost of prolonged
hospitalization due to POI have been estimated to be as much as $1.47 billion annually in the USA, illustrating
its large socioeconomic impact. The lack of effective treatments has prompted novel experimental studies to
elucidate the underlying mechanisms. Recent insight in the pathophysiology of POI induced by AS have
identified intestinal inflammation triggered by handling of the intestine as a contributing mechanism which is
clinically a relevant target for treatment. In other inflammatory conditions, there is evidence that resident
macrophages within the GI muscularis contribute to both the initiation and the resolution of inflammation
through activations of M1 and M2 phenotypes secreting pro- and anti-inflammatory cytokines respectively.
Recent studies point to the vagus nerve controlling a cholinergic anti-inflammatory pathway. We previously
established that thyrotropin-releasing hormone (TRH) in the brainstem plays a physiological role (including in
the cephalic phase) to stimulate the vagus innervating the GI tract. In the last granting period, we reported that
intracisternal (ic) injection of TRH prevents the neurogenic (early phase) of POI occurring within 2-h of AS. Our
preliminary data obtained at 6-h post-surgery indicate that 1) AS increases M1 but not M2 macrophages and
the infiltration of neutrophils in the gastric muscularis externa along with delay gastric emptying (GE); 2) central
vagal activation by ic injection of the stable TRH agonist, RX77368 prevents the above increases and reduces
the delayed GE induced by AS without modifying basal GE in sham group. In the last granting period, we also
established that AS induces a sharp reduction of plasma levels of the prokinetic hormone, ghrelin known to
influence vagal activity and the response is prevented by ic TRH before AS. In addition, we obtained
preliminary data showing that the novel long acting and brain penetrant ghrelin agonist, HM01 administered
orally activates vagal preganglionic motor neurons in the brainstem and prevents AS-induced delayed GE.
Based on these reports and exciting supportive preliminary data, we will test 3 HYPOTHESES: Aim 1. AS
induces inflammation in the rat gastric muscularis externa through changes in the activation status of M1 or M2
macrophages in the rat gastric muscularis externa. 2. Central vagal stimulation prevents AS-induced delayed
GE by activating cholinergic anti-inflammatory pathway with the deactivation of M1 an...

## Key facts

- **NIH application ID:** 9933786
- **Project number:** 5I01BX003951-04
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** YVETTE FRANCE TACHE
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933786

## Citation

> US National Institutes of Health, RePORTER application 9933786, Mechanisms and therapeutic interventions of postoperative gastric ileus (5I01BX003951-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9933786. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*