R. De Giorgio

A role for inflammation in irritable bowel syndrome

Attention has been directed to the putative role of low grade mucosal inflammation in irritable bowel syndrome (IBS) on the basis of evidence showing that some patients with IBS have an increased number of inflammatory cells in the colonic and ileal mucosa. Previous episodes of infectious enteritis, genetic factors, undiagnosed food allergies, and changes in bacterial microflora may all play a role in promoting and perpetuating this low grade inflammatory process. Human and animal studies support the concept that inflammation may perturb gastrointestinal reflexes and activate the visceral sensory system even when the inflammatory response is minimal and confined to the mucosa. Thus abnormal neuroimmune interactions may contribute to the altered gastrointestinal physiology and hypersensitivity that underlies IBS. A brief review of the human and animal studies that have focused on the putative role of intestinal inflammation and infections in the pathogenesis of IBS is given.

New pathophysiological mechanisms in irritable bowel syndrome

Irritable bowel syndrome (IBS) is a functional, multifactorial disease characterized by abdominal pain and erratic bowel habit. Changes in gastrointestinal motor function, enhanced perception of stimuli arising from the gut wall and psychosocial factors are thought to be major contributors for symptom generation. In recent years, several additional factors have been identified and postulated to interact with these classical mechanisms. Reduced ability to expel intestinal gas with consequent gas trapping and bowel distension may contribute to abdominal discomfort/pain and bloating. Abnormal activation of certain brain regions following painful stimulation of the rectum suggests altered processing of afferent signals. An acute gastrointestinal infection is now a recognized aetiological factor for symptom development in a subset of IBS patients (i.e. post‐infectious IBS), who are probably unable to down‐regulate the initial inflammatory stimulus efficiently. Furthermore, low‐grade inflammatory infiltration and activation of mast cells in proximity to nerves in the colonic mucosa may also participate in the frequency and severity of perceived abdominal pain in post‐infectious and non‐specific IBS. Initial evidence suggests the existence of changes in gut microflora, serotonin metabolism and a genetic contribution in IBS pathophysiology. These novel mechanisms may aid a better understanding of the complex pathophysiology of IBS and to develop new therapies.

Human enteric neuropathies: morphology and molecular pathology

Abstract  The aim of this study is to review current understanding of the molecular and morphological pathology of the enteric neuropathies affecting motor function of the human gastrointestinal tract and to evaluate the described pathological entities in the literature to assess whether a new nosology may be proposed. The authors used PUBMED and MEDLINE searches to explore the literature pertinent to the molecular events and pathology of gastrointestinal motility disorders including achalasia, gastroparesis, intestinal pseudo‐obstruction, colonic inertia and megacolon in order to characterize the disorders attributable to enteric gut neuropathies. This scholarly review has shown that the pathological features are not readily associated with clinical features, making it difficult for a patient to be classified into any specific category. Individual patients may manifest more than one of the morphological and molecular abnormalities that include: aganglionosis, neuronal intranuclear inclusions and apoptosis, neural degeneration, intestinal neuronal dysplasia, neuronal hyperplasia and ganglioneuromas, mitochondrial dysfunction (syndromic and non‐syndromic), inflammatory neuropathies (caused by cellular or humoral immune mechanisms), neurotransmitter diseases and interstitial cell pathology. The pathology of enteric neuropathies requires further study before an effective nosology can be proposed. Carefully studied individual cases and small series provide the basic framework for standardizing the collection and histological evaluation of tissue obtained from such patients. Combined clinical and histopathological studies may facilitate the translation of basic science to the clinical management of patients with enteric neuropathies.

Advances in our understanding of the pathology of chronic intestinal pseudo-obstruction

Chronic intestinal pseudo-obstruction (CIP) represents a particularly difficult clinical challenge. It is a rare and highly morbid syndrome characterised by impaired gastrointestinal propulsion together with symptoms and signs of bowel obstruction in the absence of any lesions occluding the gut lumen. CIP can be classified as either “secondary” to a wide array of recognised pathological conditions or “idiopathic” (CIIP). This review will focus on CIIP, and specifically on the underlying pathological abnormalities. Combined clinical and histopathological studies are needed to highlight new perspectives in the understanding and management of chronic intestinal pseudo-obstruction.

Functional gastrointestinal disorders and mast cells: implications for therapy

Abstract  The pathophysiology of functional gastrointestinal disorders is poorly understood. Accepted common mechanisms include psychosocial factors, abnormal gastrointestinal motility and disturbed visceral sensory perception, but the underlying causes remain unclear. Mast cells (MCs) are immunocytes widely distributed throughout the gastrointestinal tract. Several stimuli (e.g. allergens, neuropeptides and stress) lead to MC activation with consequent mediator release (e.g. histamine, tryptase and prostanoids). The MC mediators interact with nerves supplying the gut leading to altered gut physiology and increased sensory perception. The intestinal mucosa of irritable bowel syndrome patients contains on average an increased number of MCs. These cells release an increased amount of mediators in close vicinity to mucosal innervation. The MC activation and their close proximity to nerve fibres is correlated with the severity of perceived abdominal painful sensations. These data provide a strong basis for considering MCs as important participants in visceral hypersensitivity and pain perception in irritable bowel syndrome. Inhibition of MC function may ameliorate irritable bowel symptoms. Novel drugs with an increased potential in the control of MC function (e.g., anti‐IgE antibodies, the intracellular protein tyrosine kinase inhibitor Syk) and mediator release (e.g., second generation antihistamines, proteinase‐activated receptor antagonists) may be useful pharmacological tools for these common disorders.

Chronic intestinal pseudo-obstruction: manifestations, natural history and management

Abstract  Chronic intestinal pseudo‐obstruction (CIPO) is a rare pathological condition characterized by a marked derangement of gut propulsive motility mimicking mechanical obstruction, in the absence of any lesion occluding the gut lumen. This disease is often associated with a disabling and potentially life‐threatening complications and is still too often unrecognized even in referral centres. As a result, patients receive neither appropriate care nor recognition of their severe health condition. Medical and surgical therapies are often unsatisfactory and long‐term outcome turns out to be poor in the vast majority of cases. This article focuses on the main clinical features, the management and long‐term outcome of patients affected by CIPO, with particular emphasis on those aspects which remain a matter of debate.

Effect of mesalazine on mucosal immune biomarkers in irritable bowel syndrome: a randomized controlled proof-of-concept study

Background  Intestinal immune infiltration contributes to symptoms in patients with irritable bowel syndrome (IBS).

Review article: molecular, pathological and therapeutic features of human enteric neuropathies

Background  Considerable information has been gathered on the functional organization of enteric neuronal circuitries regulating gastrointestinal motility. However, little is known about the neuropathophysiological mechanisms underlying gastrointestinal motor disorders.

Role of nitric oxide‐ and vasoactive intestinal polypeptide‐containing neurones in human gastric fundus strip relaxations

The morphological pattern and motor correlates of nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) innervation in the human isolated gastric fundus was explored. By using the nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)‐diaphorase and specific rabbit polyclonal NO‐synthase (NOS) and VIP antisera, NOS‐ and VIP‐containing varicose nerve fibres were identified throughout the muscle layer or wrapping ganglion cell bodies of the myenteric plexus. NOS‐immunoreactive (IR) neural cell bodies were more abundant than those positive for VIP‐IR. The majority of myenteric neurones containing VIP coexpressed NADPH‐diaphorase. Electrical stimulation of fundus strips caused frequency‐dependent NANC relaxations. NG‐nitro‐L‐arginine (L‐NOARG: 300 μM) enhanced the basal tone, abolished relaxations to 0.3–3 Hz (5 s) and those to 1 Hz (5 min), markedly reduced (∼50%) those elicited by 10–50 Hz, and unmasked or potentiated excitatory cholinergic responses at frequencies 1 Hz. L‐NOARG‐resistant relaxations were virtually abolished by VIP (100 nM) desensitization at all frequencies. Relaxations to graded low mechanical distension (1 g) were insensitive to tetrodotoxin (TTX: 1 μM) and L‐NOARG (300 μM), while those to higher distensions (2 g) were slightly inhibited by both agents to the same extent (∼25%). In the human gastric fundus, NOS‐ and VIP immunoreactivities are colocalized in the majority of myenteric neurones. NO and VIP mediate electrically evoked relaxations: low frequency stimulation, irrespective of the duration, caused NO release only, whereas shortlasting stimulation at high frequencies induced NO and VIP release. Relaxations to graded mechanical distension were mostly due to passive viscoelastic properties, with a slight NO‐mediated neurogenic component at 2 g distension. The difference between NO and VIP release suggests that in human fundus accommodation is initiated by NO.

New insights into human enteric neuropathies

The functioning of enteric neuronal circuitries has been elucidated in the recent past. Evidence is now gathering to explain how dysfunction of the enteric nervous system (ENS) may lead to human gastrointestinal motor disorders. These conditions include achalasia, congenital hypertrophic pyloric stenosis, chronic intestinal pseudo‐obstruction, Hirschsprungs disease, chronic idiopathic constipation, and probably irritable bowel syndrome. Degenerative, inflammatory and genetic mechanisms exert a critical role in ENS dysfunction underlying gut dysmotility. The study of the ENS abnormalities in gut dysmotility provides a framework to better understand the mechanisms involved in degeneration and neuronal loss and fosters the development of targeted therapeutic options.