Enteric autoantibodies and gut motility disorders

Increasing evidence suggests that a subset of gastrointestinal motility disorders is associated with the presence of circulating antibodies. These antibodies are directed against various molecular targets, the best known being anti-neuronal nuclear antibody (ANNA-1 or anti-Hu) associated with paraneoplastic motility disorders. There is also evidence that the presence of distinct autoantibody profiles is associated with non-paraneoplastic motility disorders. This review focuses on the types of antibodies associated with gastrointestinal motility disorders and the significance of these antibodies. Algorithms are suggested for the work-up and treatment of patients with circulating antibodies associated with gastrointestinal motility disorders.     

Autoantibodies in patients with gut motility disorders and enteric neuropathy

OBJECTIVE: Enteric neuropathy with mild inflammation (ganglionitis) has been described in several motility disorders including irritable bowel syndrome (IBS), enteric dysmotility (ED), slow-transit constipation (STC) and chronic intestinal pseudo-obstruction (CIPO). The purpose of this study was to test the hypothesis that autoantibodies directed against specific neural antigens including ion channels may be associated with this finding. MATERIAL AND METHODS: Comprehensive routine and immunohistochemical analyses of full-thickness jejunal laparoscopic biopsies were performed on patients fulfilling the international criteria for IBS, ED, STC and CIPO. Patients with ganglionitis had sera screened for specific antibodies to voltage-gated calcium channels (VGCCs) of P/Q- and N-type, voltage-gated potassium channels (VGKCs), glutamic acid decarboxylase (GAD) and neuronal alpha3-AChR by validated immunoprecipitation assays. RESULTS: Thirty-three patients were included in the study. Two of them, both with IBS, were found to have positive antibody titres. One had anti-VGKC antibodies and one had anti-alpha3-AChR antibodies. No antibodies were detected in GAD or VGCCs (case reports presented). CONCLUSIONS: A small proportion of patients with inflammatory enteric neuropathy have antibodies directed towards neuronal ion channels. The pathogenic role of such antibodies requires determination but may represent a possible aetiology of severe functional symptoms in these groups of patients.     

Autoantibodies in patients with gut motility disorders and enteric neuropathy

Objective. Enteric neuropathy with mild inflammation (ganglionitis) has been described in several motility disorders including irritable bowel syndrome (IBS), enteric dysmotility (ED), slow-transit constipation (STC) and chronic intestinal pseudo-obstruction (CIPO). The purpose of this study was to test the hypothesis that autoantibodies directed against specific neural antigens including ion channels may be associated with this finding. Material and methods. Comprehensive routine and immunohistochemical analyses of full-thickness jejunal laparoscopic biopsies were performed on patients fulfilling the international criteria for IBS, ED, STC and CIPO. Patients with ganglionitis had sera screened for specific antibodies to voltage-gated calcium channels (VGCCs) of P/Q- and N-type, voltage-gated potassium channels (VGKCs), glutamic acid decarboxylase (GAD) and neuronal α3-AChR by validated immunoprecipitation assays. Results. Thirty-three patients were included in the study. Two of them, both with IBS, were found to have positive antibody titres. One had anti-VGKC antibodies and one had anti-α3-AChR antibodies. No antibodies were detected in GAD or VGCCs (case reports presented). Conclusions. A small proportion of patients with inflammatory enteric neuropathy have antibodies directed towards neuronal ion channels. The pathogenic role of such antibodies requires determination but may represent a possible aetiology of severe functional symptoms in these groups of patients.     

Upper gut motility of Hirschsprung's disease and its allied disorders in adults

BACKGROUND/AIMS: To clarify the significance of upper gut motility for Hirschsprung's disease and its allied disorders in adults, we studied the upper esophagogastroduodenal motility of adult patients with Hirschsprung's disease and its allied disorders such as hypoganglionosis and intestinal neuronal dysplasia. METHODOLOGY: Twelve patients (7 men and 5 women, aged between 20 and 55 years with a mean age of 39.6 years) with Hirschsprung's disease (2 cases) or its allied disorders (8 cases of hypoganglionosis and 2 cases of intestinal neuronal dysplasia) were studied. As a control, 15 healthy volunteers (8 men and 7 women aged between 27 and 69 years with a mean age of 49.0 years) were also examined. To obtain the upper gut motility in Hirschsprung's disease, hypoganglionosis, and intestinal neuronal dysplasia, we performed gastrointestinal transit time study, esophageal manometry, and gastroduodenal manometry. RESULTS: On gastrointestinal transit time, barium stagnated in the upper jejunum in 2 cases of hypoganglionosis, in the terminal ileum in one case of hypoganglionosis and intestinal neuronal dysplasia, and in the colon in the remaining patients. In two of the 12 cases of Hirschsprung's disease and its allied disorders such as hypoganglionosis and intestinal neuronal dysplasia, abnormal esophageal motilities, and absence of interdigestive migrating motor complex, phase III from the stomach were observed. These findings suggested that the entire digestive tract might have been affected in these two cases, i.e., these 2 patients had total gut involvement type of hypoganglionosis. CONCLUSIONS: Gastrointestinal transit time and upper esophagogastroduodenal manometry should be performed because of the relatively frequent association of upper gut dysmotilities with these disorders.     

Esophageal motility disorders

Esophageal motility abnormalities are usually diagnosed when esophageal manometry is performed in patients with unexplained non-cardiac chest pain, non obstructive dysphagia or as a part of the preoperative evaluation for surgery of gastroesophageal reflux. Classification of these abnormalities has been a subject of controversy. These esophageal contraction abnormalities can be separated manometrically from the motor pattern seen in normal subjects, however, their clinical relevance is still unclear and debated. Many patients demonstrate motility abnormalities in the manometry laboratories, but may lack correlation with their presenting symptoms. Medical treatment can decrease symptoms particularly chest pain or acid reflux but there is no significant changes in the manometric patterns. Such motor abnormalities may not reflect a true disease state, but they could be markers of other abnormalities and they can modify the initial manometric findings in time.     

Oesophageal motility disorders

Oesophageal motility disorders comprise various abnormal manometric patterns which usually present with dysphagia or chest pain. Some, such as achalasia, are diseases with a well defined pathology, characteristic manometric features, and good response to treatments directed at the pathophysiological abnormalities. Other disorders, such as diffuse oesophageal spasm and hypercontracting oesophagus, have no well defined pathology and could represent a range of motility changes associated with subtle neuropathic changes, gastro-oesophageal reflux, and anxiety states. Although manometric patterns have been defined for these disorders, the relation with symptoms is poorly defined and the response to medical or surgical therapy unpredictable. Hypocontracting oesophagus is generally caused by weak musculature commonly associated with gastro-oesophageal reflux disease. Secondary oesophageal motility disorders can be caused by collagen vascular diseases, diabetes, Chagas' disease, amyloidosis, alcoholism, myxo-oedema, multiple sclerosis, idiopathic pseudo-obstruction, or the ageing process.     

Esophageal motility disorders

Esophageal symptoms are most often related to gastroesophageal reflux disease and other mucosal or structural processes in the tubular esophagus. When these have been appropriately ruled out with careful endoscopy, or when motility disorders are suspected based on persistent symptoms or endoscopic findings, esophageal motility testing is performed. High resolution manometry has been shown to be superior and has largely replaced conventional esophageal manometry, as it provides more detailed evaluation of esophageal motor function and results in an accurate diagnosis more often. Using innovative and intuitive software tools applied to the electronic pressure data from high resolution manometry, esophageal outflow obstruction (including achalasia spectrum disorders), major motor disorders (hypercontractile esophagus, distal esophageal spasm, and absent contractility), and minor disorders (ineffective esophageal motility and fragmented peristalsis) can be diagnosed. Provocative testing (multiple rapid swallows, rapid drink challenge, and solid test meal) can provide additional gain in motor diagnoses in symptomatic patients with normal or inconclusive standard manometry, but the clinical value is still controversial. New metrics have been introduced to characterize the esophagogastric junction in terms of barrier function and morphology, which are relevant in the context of gastroesophageal reflux disease. Barium radiography has a complementary role in the evaluation and follow-up in patients with symptoms suggestive of esophageal motility disorders. Symptomatic patients with minor motor disorders or normal motility, especially when response to provocative testing is normal, may have a functional basis for symptoms.     

Gastrointestinal motility disorders

A classification of gastrointestinal motility disorders is offered based upon the type of disorder in transit (delay or acceleration), and the region of the gastrointestinal tract affected. Specific abnormalities of myoelectrical patterns are identified when possible and related to disturbances in transit in the stomach and small bowel.     

Role of bile in regulation of gut motility

Abstract. Bile empties into the duodenum not only after a meal but also in the interdigestive state. In man, inter-digestive biliary emptying is related to fasting motor activity, the migrating motor complex (MMC), in the stomach and small bowel and generally occurs during phase 2 preceding a gastroduodenal phase 3 activity (activity front). It seems that the main regulatory peptide to initiate phase 3 is motilin. During a period with 13 phase 3 activities of MMC, 18 episodes of gall-bladder emptying and 19 motilin peaks were observed. Such a peak of plasma motilin usually took place 25 ± 11 min after onset of biliary emptying. In conclusion, data indicate that motilin is released to the circulation by the biliary output and induces phase 3 of MMC. The induced phase 3 propels bile acids along the gut to promote their absorption in the distal intestine. The choleretic action of recycling of bile acids may cause subsequent episodes of biliary emptying with motilin release by the action of the enterohepatic circulation of bile acids. In such a manner the MMC may be withheld as a recycling motility pattern.     

Upper esophageal motility disorders

This article begins with a summary of the anatomy and physiology of the upper esophageal region. The appropriate diagnostic tools used in the evaluation of upper esophageal motility disorders are then detailed including cineradiography, manometry, and other modalities. Specific clinical disorders associated with pharyngeal, UES, or upper esophageal dysfunction are described followed by a section on treatment.     

Nutrition and motility disorders

The purpose of this article is to give an overview of the relation between feeding and gastrointestinal symptoms and complaints, and to review different motility disorders that have implications for food intake. We also report the consequences for nutrition state and the evidence-based principles of dietary modification in patients with motility disorders.     

Pediatric intestinal motility disorders

Pediatric intestinal motility disorders affect many children and thus not only impose a significant impact on pediatric health care in general but also on the quality of life of the affected patient.Furthermore,some of these conditions might also have implications for adulthood.Pediatric intestinal motility disorders frequently present as chronic constipation in toddler age children.Most of these conditions are functional,meaning that constipation does not have an organic etiology,but in 5% of the cases,an underlying,clearly organic disorder can be identified.Patients with organic causes for intestinal motility disorders usually present in early infancy or even right after birth.The most striking clinical feature of children with severe intestinal motility disorders is the delayed passage of meconium in the newborn period.This sign is highly indicative of the presence of Hirschsprung disease(HD),which is the most frequent congenital disorder of intestinal motility.HD is a rare but important congenital disease and the most significant entity of pediatric intestinal motility disorders.The etiology and pathogenesis of HD have been extensively studied over the last several decades.A defect in neural crest derived cell migration has been proven as an underlying cause of HD,leading to an aganglionic distal end of the gut.Numerous basic science and clinical research related studies have been conducted to better diagnose and treat HD.Resection of the aganglionic bowel remains the gold standard for treatment of HD.Most recent studies show,at least experimentally,the possibility of a stem cell based therapy for HD.This editorial also includes rare causes of pediatric intestinal motility disorders such as hypoganglionosis,dysganglionosis,chronic intestinal pseudo-obstruction and ganglioneuromatosis in multiple endocrine metaplasia.Underlying organic pathologies are rare in pediatric intestinal motility disorders but must be recognized as early as possible.     

Gastrointestinal motility and the brain‐gut axis

The role of the brain‐gut axis in gastrointestinal motility is discussed according to the specific organs of the gastrointestinal tract. Not only clinical studies but basic animal research are reviewed. Although the mechanism of functional gut disorders remains to be clarified, recent data suggest that there is evidence that the brain‐gut axis has significant effects on gastrointestinal motility. The major role of endoscopy in the diagnosis of functional gastrointestinal disorders is to exclude organic gastrointestinal disorders. In the esophagus, the lower esophageal sphincter and a gamma‐aminobutyric acid B mechanism are considered to play important roles in gastroesophageal reflux disease. In the stomach, corticotropin‐releasing factor, neuropeptide Y and other substances might be involved in the pathogenesis of non‐ulcer dyspepsia. In the small intestine, corticotropin‐releasing factor, gamma‐aminobutyric acid B and other substances are considered to modulate intestinal transit via central mechanisms. In the colon, it is known that psychiatric factors are related to the onset and clinical course of irritable bowel syndrome. Serotonin, corticotropin‐releasing factor, gamma‐aminobutyric acid, orphanin FQ and neuropeptide Y have been reported as putative neurotransmitters. More efforts in basic science studies and animal and human studies of physiology of the gastointestinal tract are still required. These efforts will elucidate further mechanisms to clarify the etiology of motility disorders and encourage the investigation of new therapies in this field.     

Ghrelin family of peptides and gut motility

Acyl ghrelin, des-acyl ghrelin, and obestatin are three peptides isolated from the gastrointestinal tract and encoded by the same preproghrelin gene. Three ghrelin gene products participate in modulating appetite, adipogenesis, glucose metabolism, cell proliferation, immune, sleep, memory, anxiety, cognition, and stress. We have investigated the effects of ghrelin family of peptides on fed and fasted motor activities in the stomach and duodenum of freely moving conscious rats by manometric method. Intracerebroventricular (ICV) and intravenous (IV) administration of acyl ghrelin induced fasted motor activity in the duodenum in fed rats. ICV and IV administration of des-acyl ghrelin disrupted fasted motor activity in the antrum. Changes in gastric motility induced by IV administration of des-acyl ghrelin were antagonized by ICV administration of a corticotropin-releasing factor (CRF) 2 receptor antagonist. IV administration of obestatin decreased the percentage motor index in the antrum and prolonged the time taken to return to fasted motility in the duodenum in fed rats. ICV administration of CRF 1 and 2 receptor antagonists prevented the effects of obestatin on gastroduodenal motility. Ghrelin gene products regulate feeding-associated gastroduodenal motility. Stomach may regulate various functions including gastrointestinal motility via acyl ghrelin, des-acyl ghrelin and obestatin as an endocrine organ. Increasing knowledge of the effects of ghrelin family of peptides on gastrointestinal motility could lead to innovative new therapies for functional gastrointestinal disorders.