New insights of disorders of gastroduodenal-Oddi sphincter coordination

The coordination and acceptance relationship between the stomach and duodenum affects the speed at which food enters the duodenum. The latter is closely related to the opening degree of the Oddi sphincter, which affects the release of bile and digestive enzymes into the intestinal lumen. The motility of the duodenum also determines the mixing ratio, residence time, and contact area of chyme and digestive enzymes within the lumen. These factors collectively influence the efficiency of digestion and absorption after meals. From the perspective of gastrointestinal (GI) motility, disorders of gastroduodenal coordination can lead to (i) increased gastric emptying resistance and the resultant duodeno-gastric reflux, playing an important role in the pathogenesis of gastroesophageal reflux disease (GERD) and other esophageal diseases, and (ii) abnormal small intestinal motility and gastriccolonic reflex, contributing to pathophysiological mechanisms for the overlap of upper GI symptoms such as functional dyspepsia (FD) with lower GI symptoms including abdominal pain, bloating, constipation, and diarrhea. The decreased efficiency of digestion and absorption disrupts the nutritional and metabolic environment in the distal small intestine and colon, leading to microbial overgrowth, mucosal inflammation, increased permeability, and alterations in the humoral regulation of the portal vein, liver, and even the whole body. Therefore, disorders of gastroduodenal-Oddi sphincter coordination (DGDOC) are among the most important pathogenic factors leading to dysfunction of the entire GI tract.

In recent years, breakthroughs have been made in the basic and clinical research of GI diseases, such as gut-brain interactions, duodenal inflammation (DI), gut dysbiosis, and leaky gut syndrome (LGS). These advancements have prompted us to look for a deeper understanding of the mechanisms of GDODC and to improve clinical management strategies. This mini-review combines the latest advancements in both basic and clinical aspects of digestive diseases, addresses the mechanisms and clinical relevance of GDODC, and explores new ideas for drug therapy related to clinical issues (focusing on the application of neuromodulators).

The duodenum, with a length of approximately 25 cm, is the shortest, widest, and deepest part of the small intestine. It is crucial for digestion as it receives gastric juice,

pancreatic juice, and bile. Key factors that affect the efficiency of digestion and absorption in the duodenum include the speed of gastric emptying (influenced by gastric peristalsis and the intraduodenal pressure), the rate of digestive enzyme and bile discharge (influenced by the degree of opening of the sphincter of Oddi), and the retention time of chyme in the duodenum. The regulatory mechanisms of the coordinated movement of the stomach-duodenum-Oddi sphincter, dominated by duodenal motility, involves two systems:

(1) Endocrine and paracrine systems. They include: (i) Peptide hormones including gastrin, cholecystokinin (CCK), ghrelin, vasoactive intestinal peptide (VIP), gastric inhibitory polypeptide (GIP)/glucose-dependent insulinotropic peptide (GIP), and motilin [1, 2]. Recently, new factors involved in the regulation of gastric and duodenal motility have been discovered, such as angiotensin II, which can be produced by the mucosal cells of the small intestine and locally inhibits sodiumdependent glucose co-transporter-1 (SGLT-1) mediated glucose uptake [3, 4], and glucagon-like peptide-1 (GLP1), which is released by the enteroendocrine L cells. Another peptide hormone, preproglucagon, is the precursor of GLP-1, GLP-2, etc [5]. (ii) Non-peptide hormones including glucocorticoids (such as cortisol) and mineralocorticoids (such as aldosterone), etc. Vitamin D3, or 1,25-dihydroxyvitamin D3, is also a steroid hormone that may affect intestinal Ca2+ absorption and the proliferation and differentiation of intestinal mucosal cells [6]. Other active substances derived from single amino acids, such as epinephrine, dopamine, norepinephrine, nitric oxide, histamine, etc [7-10]. Nitric oxide is considered a major non-adrenergic, non-cholinergic (NANC) neurotransmitter, which is an important modulator of intestinal motility and mesenteric blood flow. Additionally, active substances derived from mucosal fatty acids, such as plateletactivating factor (PAF), are also involved in the regulation of mucosal inflammatory responses, gastric acid secretion, and gastroduodenal motility [11-14].

(2) Neuro-smooth muscle regulatory system. In the gastric antrum, food is ground and chemically coped to form particles about 1-2 mm in size and then enters the duodenum through the pylorus. The neural control of this process is mediated by the vagus nerve and cholinergic neurons within the muscle layer. It also relies on the inhibitory effect of nitrergic neurons. Contraction of the upstream smooth muscles triggers the inhibition of downstream smooth muscles by nitrergic neurons, which is crucial for the coordinated relaxation and accommodation of the pylorusduodenum. 

These inhibitory and excitatory neural effects are paced and transmitted through interstitial cells of Cajal (ICCs) and other fibroblast-like cells that may have similar functions. The common feature of the aforementioned cells is the presence of the plateletderived growth factor receptor-α (PDGFRα) [15].

Coordination of gastric and duodenal motility involves complex regulatory mechanisms. Currently, clinical intervention drugs are ineffective. Recent studies on the brain-gut axis have provided valuable clues for elucidating these mechanisms. The latest research findings suggest that psychosocial stress may primarily regulate gastric and duodenal motility through the following mechanisms [16-18]. (i) The interactions between the central nervous system (CNS) and the enteric nervous system (ENS) affect GI motility, secretion, and visceral sensory functions. (ii) The neuro-immune and endocrine networks influence the metabolism and micro-ecological environment in the GI tract, thus affecting mucosal inflammatory responses, permeability, microcirculation, as well as proliferation, differentiation, and repair. These influences cover almost all local humoral and neural mechanisms regulating gastric and duodenal motility. The correspondence between psychosocial stress types, functional brain region localization, and clinical manifestations of the GI symptoms has been suggested.

(1) Emotional and affective stress. The affected brain regions include the prefrontal cortex, cingulate gyrus, insula, and other central areas for emotional and affective responses. This type of stress can cause abnormal sensory responses to noxious stimuli in the GI tract, GI dysmotility, and mucosal immune inflammatory responses [17]. Clinical manifestations can be divided into the following 2 types. (i) Emotional responses such as anxiety and irritability, corresponding to pathological states caused by the lack of coordination between visceral hypersensitivity, motility, secretion, and other functions of the GI tract (such as gastroesophageal reflux, peptic ulcers, increased borborygmi, and diarrhea). They may cause mucosal inflammatory responses (tend to be autoimmune in nature) and abnormal increased GDODC in the postprandial phase, with elevated intraluminal pressure of the duodenum, increased resistance to gastric emptying, and abnormal opening of the Oddi sphincter, leading to increased reflux from the intestine to the stomach and from the duodenum to the biliary and pancreatic ducts. If required, NMs, i.e., antidepressants with sedative and anti-anxiety effects (such as tricyclic antidepressants, fluvoxamine, paroxetine, and duloxetine), can be used. (ii) Emotional responses such as depression and suppression,

corresponding to the generalization of GI discomfort (inaccurate location, difficulty in describing characteristics, etc.), and reduced GI motility and secretion functions (such as loss of appetite, postprandial fullness, and lack of defecation desire). The corresponding form of GDODC is the lack of duodenal motility (in both the postprandial phase and fasting phase). If required, antidepressants that mainly enhance mental drive (such as fluoxetine, sertraline, citalopram, and venlafaxine) can be chosen.

(2) Stress with abnormal brain-using patterns and thinking modes. The affected functional brain areas include the orbital frontal region, striatum, ventral tegmental area, suprachiasmatic nucleus, and amygdala [17]. Corresponding GI problems usually manifest as complicated inflammatory responses and impaired mucosal repair.

In clinical practice, the psychosocial stress associated with GDODC often coexists in the above two categories. When applying NMs, in addition to using the aforementioned antidepressants or anxiolytics, it is also necessary to use multi-target NMs (such as antidepressants acting on 5-HT2 receptors, atypical antipsychotics, circadian rhythm regulators, and sedatives).

Recent evidence shows that DI is frequently found in patients with FD, particularly in those exhibiting overlapping symptoms of other functional GI disorders (FGIDs) [19]. DI is one of newly identified key contributors to the pathogenesis of FGIDs. FDassociated DI displays several characteristics [20-22]. (i) The activation of the eosinophil-mast cell axis is a key mechanism of DI, indicating a correlation between DI and psychological stress or food-related immunological reactions. (ii) DI is accompanied by changes in gut microbiota and metabolome.

DI also plays an important role in the development of GDODC. DI triggers local neuroendocrine and inflammatory responses, altering the levels of peptide hormones and non-peptide active substances that regulate duodenal motility. It also leads to changes in the levels of luminal bile acids (which induce motility and sensory dysregulation through FXR receptors distributed in the mucosa) and other metabolic products, as well as alterations in the composition of luminal microbiota, and thus affects the duodenal movement. Low-grade mucosal inflammation can lead to changes in the postprandial motility pattern of duodenum, causing increased resistance within the duodenum and the accompanied gastroduodenal bile reflux. For drug therapy, smooth muscle antispasmodic drugs, especially calcium channel antagonists locally released into the lumen, can be applied.

In summary, GDODC may deteriorate the luminal microenvironment in the distal intestine via affecting the absorption and digestion efficiency of the proximal small intestine. This can trigger LGS and negative regulatory consequences in the gut-brain axis. Therefore, duodenal dysmotility may greatly contribute to the disruption of gut-brain interactions. And, the reduced digestive efficiency may serve as a potential intervention target for the related clinical issues. In addition to the aforementioned drugs with potential values, supplementation of digestive enzymes could improve the absorption and digestion efficiency of the upper small intestine, thereby improving the distal intestinal environment and preventing the overgrowth of harmful bacteria in the small intestine, and thus lowers the risk of increased mucosal permeability and reduces the occurrence of LGS. Therefore, supplementation of digestive enzymes could also be considered for treatment of GDODC.

The author declares no conflicting interest.

This study were supported by the National Natural Science Foundation of China (Grant Nos. 82170554, 81970473, 81970472, and 81670484).

1. Camilleri M. Peripheral mechanisms in appetite regulation. Gastroenterology. 2015; 148(6): 1219- 33.

2. Deloose E, Janssen P, Depoortere I, et al. The migrating motor complex: control mechanisms and its role in health and disease. Nat Rev Gastroenterol Hepatol. 2012; 9(5): 271-85.

3. Leung PS. Local RAS. Adv Exp Med Biol. 2010; 690: 69-87.

4. Lu HL, Wang ZY, Huang X, et al. Excitatory regulation of angiotensin II on gastric motility and its mechanism in guinea pig. Regul Pept. 2011;167(2-3): 170-6.

5. Schalla MA, Taché Y, Stengel A. Neuroendocrine Peptides of the Gut and Their Role in the Regulation of Food Intake. Compr Physiol. 2021;11(2): 1679- 1730.

6. Barbáchano A, Fernández-Barral A, Ferrer-Mayorga G, et al. The endocrine vitamin D system in the gut. Mol Cell Endocrinol. 2017; 453: 79-87.

7. M i t t a l R , D e b s L H , P a t e l A P, e t a l . Neurotransmitters: The Critical Modulators Regulating Gut-Brain Axis. J Cell Physiol. 2017;232(9): 2359-2372.

8. Idrizaj E, Traini C, Vannucchi MG, et al. Nitric Oxide: From Gastric Motility to Gastric Dysmotility. Int J Mol Sci. 2021; 22(18): 9990.

9. Verbeure W, van Goor H, Mori H, et al. The Role of Gasotransmitters in Gut Peptide Actions. Front Pharmacol. 2021;12: 720703

10.Naganuma S, Shiina T, Yasuda S, et al. Histamine-enhanced contractile responses of gastric smooth muscle via interstitial cells of Cajal in the Syrian hamster. Neurogastroenterol Motil. 2018;30(4): e13255.

11.Borthakur A, Bhattacharyya S, Kumar A, et al. Lactobacillus acidophilus alleviates plateletactivating factor-induced inflammatory responses in human intestinal epithelial cells. PLoS One. 2013; 8(10): e75664.

12.Sobhani I, Bado A, Cherifi Y, et al. Helicobacter pylori stimulates gastric acid secretion via platelet activating factor. J Physiol Pharmacol. 1996;47(1): 177-85.

13.Yan ZY, Wood JG, Cheung LY. Platelet activating factor-induced changes in gastric motility and vascular resistance. Am J Surg. 1992;163(1): 23-7.

14.Yildirim G, Koç E, Baştug M, et al. Effects of platelet-activating factor and hyperbaric oxygenation on antioxidant defense and duodenal contractility. Undersea Hyperb Med. 2000; 27(3): 155-8.

15.Vannucchi MG, Traini C. Interstitial cells of Cajal and telocytes in the gut: twins, related or simply neighbor cells? Biomol Concepts. 2016;7(2): 93- 102.

16.Konturek PC, Brzozowski T, Konturek SJ. Stress and the gut: pathophysiology, clinical consequences,diagnostic approach and treatment options. J Physiol Pharmacol. 2011;62(6): 591-9.

17.Weltens N, Iven J, Van Oudenhove L, et al. The gut-brain axis in health neuroscience: implications for functional gastrointestinal disorders and appetite regulation. Ann N Y Acad Sci. 2018;1428(1): 129- 150.

18.Martin CR, Osadchiy V, Kalani A, et al. The BrainGut-Microbiome Axis. Cell Mol Gastroenterol Hepatol. 2018;6(2): 133-148.

19.Zhang SH, Guo XX, Wei JJ, et al. Changes and significance of duodenal eosinophils and chromogranin A positive cells in patients with functional dyspepsiaet. Gastroenterology (in Chinese) 2018;23(01): 18-23.

20.Wauters L, Burns G, Ceulemans M, et al. Duodenal inflammation: an emerging target for functional dyspepsia? Expert Opin Ther Targets. 2020; 24(6): 511-523.

21.Wauters L, Talley NJ, Walker MM, et al. Novel concepts in the pathophysiology and treatment of functional dyspepsia. Gut. 2020; 69(3): 591-600.

22.Wauters L, Ceulemans M, Frings D, et al. Proton Pump Inhibitors Reduce Duodenal Eosinophilia, Mast Cells, and Permeability in Patients With Functional Dyspepsia. Gastroenterology. 2021;160(5): 1521-1531.e9.