Postoperative Ileus and Postoperative Gastrointestinal Tract Dysfunction: Pathogenic Mechanisms and Novel Treatment Strategies Beyond Colorectal Enhanced Recovery After Surgery Protocols

Abstract

Postoperative ileus (POI) and postoperative gastrointestinal tract dysfunction (POGD) are well-known complications affecting patients undergoing intestinal surgery. GI symptoms include nausea, vomiting, pain, abdominal distention, bloating, and constipation. These iatrogenic disorders are associated with extended hospitalizations, increased morbidity, and health care costs into the billions and current therapeutic strategies are limited. This is a narrative review focused on recent concepts in the pathogenesis of POI and POGD, pipeline drugs or approaches to treatment. Mechanisms, cellular targets and pathways implicated in the pathogenesis include gut surgical manipulation and surgical trauma, neuroinflammation, reactive enteric glia, macrophages, mast cells, monocytes, neutrophils and ICC's. The precise interactions between immune, inflammatory, neural and glial cells are not well understood. Reactive enteric glial cells are an emerging therapeutic target that is under intense investigation for enteric neuropathies, GI dysmotility and POI. Our review emphasizes current therapeutic strategies, starting with the implementation of colorectal enhanced recovery after surgery protocols to protect against POI and POGD. However, despite colorectal enhanced recovery after surgery, it remains a significant medical problem and burden on the healthcare system. Over 100 pipeline drugs or treatments are listed in Clin.Trials.gov. These include 5HT₄R agonists (Prucalopride and TAK 954), vagus nerve stimulation of the ENS-macrophage nAChR cholinergic pathway, acupuncture, herbal medications, peripheral acting opioid antagonists (Alvimopen, Methlnaltexone, Naldemedine), anti-bloating/flatulence drugs (Simethiocone), a ghreline prokinetic agonist (Ulimovelin), drinking coffee, and nicotine chewing gum. A better understanding of the pathogenic mechanisms for short and long-term outcomes is necessary before we can develop better prophylactic and treatment strategies.

Keywords: 5HT4 receptor; colorectal enhanced recovery after surgery; enteric glia; gastrointestinal surgery; mechanosensation; postoperative gastrointestinal tract dysfunction; postoperative ileus; prokinetic agents.

FIGURE 1

Cellular mechanisms and Pathways involved in the Pathogenesis of POI and POGD. Gut manipulation and surgical trauma triggers an inflammatory response in the muscularis externa. A variety of immune, inflammatory cells, enteric glia, neurons, smooth muscle cells, ICCs, enteroendocrine cells and microbes in the lumen of the gut, all contribute to the inflammatory response. Interactions in both directions exist between these cells in the intestinal wall but the precise trigger mechanisms activated for the cascade of events leading to POI are not known. In the context of inflammation, immune cell activation in coordination with reactive glia, promote monocyte and neutrophil infiltration, and all together produce a neuroinflammatory response leading to smooth muscle dysfunction and postoperative ileus. In contrast to chronic intestinal inflammation such as in IBD, after the surgery, in the absence of intestinal surgical manipulation, the ENS and intestinal motility eventually recover. The vagus—ENS—macrophage cholinergic (nAChR) pathway is a protective anti-inflammatory pathway, and vagus nerve stimulation can protect against development of POI and POGD.

FIGURE 2

Working hypothesis of proposed glial pathogenic mechanism of postoperative ileus—Enteric glia are very sensitive to mechanical stimulation and mechanical forces generated during peristalsis. Touch, stretch, shear stress, pressure, compression, membrane perturbations and centrifugal forces all operate during peristalsis. Mechanosensation is a normal function of enteric glia in the modulation of motility through interactions with the ENS. Abnormal mechanical forces encountered during GI surgery such as gut manipulation, surgical insult, fluid edema or high pressure pneumoperitoneum encountered in minimal invasive laparoscopic surgery, may activate enteric glia (and immune cells) in the muscularis externa contributing to the induction of a reactive enteric glial cell phenotype. Reactive glia in coordination with immune cells release pro-inflammatory mediators that disrupt the ENS to cause GI dysmotility associated with POI and POGD. Signs and symptoms include nausea, vomiting, Pain distention, bloating and constipation. Pain pathways also activate the sympathetic nervous system which has inhibitory effects on GI motility. Additionally, opioids, commonly used during the perioperative period to treat pain, activate peripheral µ opioid receptors in the ENS and further depress peristalsis.

FIGURE 3

Working hypothesis of Glial Molecular Mechanisms Implicated in the Pathogenesis of POI. Under normal physiological conditions, glial cells modulate motility by interacting with neural-motor components of the gut. Glia communicate with each other and the ENS via Ca²⁺ waves and release of gliotransmitters. Recent evidence has revealed a number of potential glial targets implicated in the pathogenesis of POI and POGD. Gut surgical trauma and manipulation induces a reactive enteric glial phenotype that contributes to the overall neuroinflammation and GI dysmotility. Experimental evidence in reactive glia suggests that a variety of glial molecular signaling mechanisms may be operating in POI. These include 1) abnormal mechanosensation, 2) purinergic pathways via ATP, 3) the IL1β/IL1R Signaling Pathway, 4) the ET-1/ETBR signalling pathway, 5) the s100β-RAGE/iNOS/NO signaling pathway, and 6) a PPARα signaling pathway targeted by PEA to inhibit inflammation.