功能性胃肠病的根源——脑肠轴神经系统记忆假说

功能性胃肠病(functionalgastrointestinaldisorders,FGID)以消化道动力与内脏感觉异常为主要病理生理特征并有多种症状重叠、多变或相互转换以及反复发作、较难治愈等特点;其病因和发病机制目前仍未完全清楚.本文将大脑记忆外延提出FGID的根源是脑肠轴神经系统记忆的假说,并用这个假说解释说明FGID的各种特点,以及治疗FGID的思路和方法.     

脑肠互动与针刺治疗功能性胃肠病的相关性

功能性胃肠病是临床上常见的消化系统疾病,也是针刺治疗的优势病种.近年来的研究表明,脑肠轴功能失调是功能性胃肠病发病的重要原因,而针刺对脑肠轴的调节作用是其治疗功能性胃肠病的主要着眼点.随着脑功能成像技术的发展和脑肠肽研究的进展,功能性胃肠病与中枢神经系统及脑肠肽代谢相关性的研究日益增多.针灸作为传统中医疗法的一部分,治疗功能性胃肠病疗效显著,被广泛运用于临床.大量研究显示,针刺既能调节中枢神经系统,也能调控脑肠肽代谢.本文拟从中枢神经系统、脑肠肽代谢两方面,探讨脑肠互动与针刺治疗功能性胃肠病的相关性.     

The microbiota-gut-brain axis in functional gastrointestinal disorders

Functional gastrointestinal disorders (FGIDs) are highly prevalent and pose a significant burden on health care and society, and impact patients’ quality of life. FGIDs comprise a heterogeneous group of disorders, with unclear underlying pathophysiology. They are considered to result from the interaction of altered gut physiology and psychological factors via the gut-brain axis, where brain and gut symptoms are reciprocally influencing each other’s expression. Intestinal microbiota, as a part of the gut-brain axis, plays a central role in FGIDs. Patients with Irritable Bowel Syndrome, a prototype of FGIDs, display altered composition of the gut microbiota compared with healthy controls and benefit, at the gastrointestinal and psychological levels, from the use of probiotics and antibiotics. This review aims to recapitulate the available literature on FGIDs and microbiota-gut-brain axis.     

The origin of symptoms on the brain-gut axis in functional dyspepsia

It was hypothesized that symptoms in functional dyspepsia are originated by an altered mechanism at the brain-gut axis (one or several) in the process of gastric accommodation to a meal. To test the key mechanisms potentially involved in symptomatic gastric accommodation, the sensorial responses (on a 0-10 perception score) and the gastric tone responses (by electronic barostat) to either gastric accommodation (n = 10) or to cold stress (n = 10) were measured in 20 patients with functional dyspepsia and 20 healthy controls. The mechanical accommodation of the stomach to gastric distention (compliance) was similar in patients (52 +/- 8 mL/mm Hg) and controls (57 +/- 6 mL/mm Hg). However, isobaric gastric distention elicited more upper abdominal discomfort in dyspeptics than in controls (perception scores, 4.7 +/- 0.9 vs. 1.1 +/- 0.5, respectively; mean +/- SE; P less than 0.005). Cold stress induced a similar gastric relaxatory response in dyspeptics and controls (delta vol, 145 mL +/- 40 mL vs. 141 mL +/- 42 mL, respectively); hand perception (scores, 8.3 +/- 0.4 vs. 7.9 +/- 0.4, respectively) and autonomic responses were also similar. It is concluded that an abnormal afferent sensorial pathway (altered gastric perception) may be a major mechanism of symptom production in functional dyspepsia.     

Orexins in the brain-gut axis

Orexins (hypocretins) are a novel pair of neuropeptides implicated in the regulation of energy balances and arousal. Previous reports have indicated that orexins are produced only in the lateral hypothalamic area, although orexin-containing nerve fibers were observed throughout the neuroaxis. Recent evidence shows that orexins and functional orexin receptors are found in the periphery. Vagal and spinal primary afferent neurons, enteric neurons, and endocrine cells in both the gut and pancreas display orexin- and orexin receptor-like immunoreactivity. Orexins excite secretomotor neurons in the guinea pig gut and modulate gastric and intestinal motility and secretion. In addition, orexins modulate hormone release from pancreatic endocrine cells. Moreover, fasting up-regulates the phosphorylated form of cAMP response element binding protein in orexin-immunoreactive enteric neurons, indicating a functional response to food status in these cells. The purpose of this article is to summarize evidence for the existence of a brain-gut network of orexin-containing cells that appears to play a role in the acute regulation of energy homeostasis.     

Adaptive cytoprotection and the brain-gut axis

Adaptive cytoprotection is a concept to counteract against the gastric mucosal injury caused by stress, strong irritants and drugs such as non-steroidal anti-inflammatory drugs. The process is mediated through diverse mediators and mechanisms. Studies on adaptive cytoprotection began from the discovery of prostaglandin (PG)-dependent and PG-independent pathways, followed by the investigation on the types and concentrations of mild irritants to be used. Upon the confirmation on the importance of the vagus nerve and the vago-vagal pathway in regulating the mucosal protective actions of the mild irritants, individual participating mediators for the neuronal modulatory processes were explored, including peptide neurotransmitters such as calcitonin gene-related peptide and substance P. Further correlation with the sympathetic nervous system, the sensory afferent neurons and the enteric nervous system of the gastric mucosa had been made. A close working relationship between the hypothalamic-pituitary-adrenal axis, the autonomic nervous system and the enteric nervous system was then proposed, with concurrent regulation of PG, nitric oxide and sensory neuropeptides by different mild irritants. Apart from these conventional concepts, there are now contemporary ideas on newer forms of adaptive cytoprotection such as ischemic preconditioning and heat-shock proteins, which will cast new light to novel approaches in facilitating gastric mucosal protection.     

儿童功能性胃肠疾病3:功能性腹泻

儿童功能性腹泻是指发生在幼儿或学龄前儿童中的再发性无痛性排便次数增多 ,每天 3次或 3次以上 ,持续四周或四周以上 ,大便不成形 ,也被称为婴幼儿腹泻 (Ｔｏｄｄｌｅｒ’ｓｄｉａｒｒｈｅａ)、慢性非特异性腹泻、儿童结肠激惹。如果饮食中有足够热量 ,往往不影响患儿生长发育[1,2 ] 。当父母发现孩子解下的或遗留在尿布上的未成形大便中含有数小时前吃下的未消化的蔬菜时 ,才开始意识到出了问题。孩子却不会因排松散便而有丝毫不适 ,并且这些现象到学龄时会自发缓解。一、临床特征　功能性腹泻患儿的肠道转运功能并无缺陷 ,水、电解质的分…     

Pediatric functional gastrointestinal disorders

Opinion statement  

Age-related functional gastrointestinal disorders

The demographic development will lead to a disproportionate increase of older people and to a significant increase of functional gastrointestinal disorders including dysphagia due to motility and reflux-related disorders, nausea and vomiting by gastrointestinal dysfunction and abdominal and pelvic pain caused by chronic obstipation, stool impaction and incontinence. This implies significant consequences with regard to the development of weight loss, anorexia, social disadvantages and increased mortality with serious socio-economic burden. Ageing processes are determined by differentiated neurogeneration of the myenteric plexus (cholinergic degeneration) through reactive oxygen and nitrogen species and alteration of protective and regenerative processes. Age-related gastrointestinal dysfunctions may be caused by the ageing gastrointestinal tract itself or by other age-related diseases such as tumour, neurological or inflammatory diseases, anatomic changes, therapeutic medication, polymorbidity or malnutrition. Because of the significant therapeutic options, differential diagnostic work-up is mandatory also in elderly patients.     

New technologies to investigate the brain-gut axis

Functional gastrointestinal disorders are commonly encountered in clinical practice, and pain is their commonest presenting symptom. In addition, patients with these disorders often demonstrate a heightened sensitivity to experimental visceral stimulation, termed visceral pain hypersensitivity that is likely to be important in their pathophysiology. Knowledge of how the brain processes sensory information from visceral structures is still in its infancy. However, our understanding has been propelled by technological imaging advances such as functional Magnetic Resonance Imaging, Positron Emission Tomography, Magnetoencephalography, and Electroencephalography （EEG）. Numerous human studies have non-invasively demonstrated the complexity involved in functional pain processing, and highlighted a number of subcortical and cortical regions involved. This review will focus on the neurophysiological pathways （primary afferents, spinal and supraspinal transmission）, brainimaging techniques and the influence of endogenous and psychological processes in healthy controls and patients suffering from functional gastrointestinal disorders. Special attention will be paid to the newer EEG source analysis techniques. Understanding the phenotypic differences that determine an individual＇s response to injurious stimuli could be the key to understanding why some patients develop pain and hyperalgesia in response to inflammation/injury while others do not. For future studies, an integrated approach is required incorporating an individual＇s psychological, autonomic, neuroendocrine, neurophysiological, and genetic profile to define phenotypic traits that may be at greater risk of developing sensitised states in response to gut inflammation or injury.     

儿童功能性胃肠疾病1:呕吐

呕吐是一个病因复杂的症状 ,在罗马Ⅱ标准中 ,与呕吐有关的儿童功能性胃肠疾病包括[1] :一、婴儿反流[1～ 3 ]反流 (ｒｅｇｕｒｇｉｔａｔｉｏｎ)是指咽下的食物或分泌物不自主性地反流人口 ,它是胃食管反流的一部分 ,当它引起食管组织损害或炎症时 ,就称为胃食管反流症 ,它不同于呕吐 (ｖｏｍｉｔｉｎｇ)。呕吐是在自主神经和骨骼肌参与下的中枢神经系统受到刺激而引发的一种防御性反射活动 ,胃内容物在小肠、胃、食管和膈肌的协调运动下被强力经口排出。反流也不同于反刍 (ｒｕｍｉｎａｔｉｏｎ) ,反刍是指刚摄入的食物自主地返流到口腔中…     

Neuropathophysiology of functional gastrointestinal disorders

The investigative evidence and emerging concepts in neurogastroenterology implicate dysfunctions at the levels of the enteric and central nervous systems as underlying causes of the prominent symptoms of many of the functional gastrointestinal disorders. Neurogastroenterological research aims for improved understanding of the physiology and pathophysiology of the digestive subsystems from which the arrays of functional symptoms emerge. The key subsystems for defecation-related symptoms and visceral hyper- sensitivity are the intestinal secretory glands, the musculature and the nervous system that controls and integrates their activity. Abdominal pain and discomfort arising from these systems adds the dimension of sensory neurophysiology. This review details current concepts for the underlying pathophysiology in terms of the physiology of intestinal secretion, motility, nervous control, sensing function, immuno-neural communication and the brain-gut axis.     

Obesity and functional gastrointestinal disorders

Obesity is prevalent in Korea. An increase in food intake and a decrease in energy expenditure are responsible for obesity. Gut hormones play a role in controlling food intake. Obesity is suggested to be linked to common gastrointestinal functional disorders. Obesity is associated with an increased risk of gastroesophageal reflux disease, Barrett esophagus and esophageal adenocarcinoma. Epidemiologic studies indicate that obesity is associated with chronic gastrointestinal symptoms. This association suggests the possibility that obesity and functional gastrointestinal disorders may be pathophysiologically linked. However, data on the relationship between obesity and functional gastrointestinal disorders are inconsistent. In this paper, we review the role of gastrointestinal hormones in food intake and the relationship between obesity and functional gastrointestinal disorders.     

Acupuncture for functional gastrointestinal disorders

Functional gastrointestinal (GI) symptoms are common in the general population. Especially, motor dysfunction of the GI tract and visceral hypersensitivity are important. Acupuncture has been used to treat GI symptoms in China for thousands of years. It is conceivable that acupuncture may be effective in patients with functional GI disorders because it has been shown to alter acid secretion, GI motility, and visceral pain. Acupuncture at the lower limbs (ST-36) causes muscle contractions via the somatoparasympathetic pathway, while at the upper abdomen (CV-12) it causes muscle relaxation via the somatosympathetic pathway. In some patients with gastroesophageal reflux disease (GERD) and functional dyspepsia (FD), peristalsis and gastric motility are impaired. The stimulatory effects of acupuncture at ST-36 on GI motility may be beneficial to patients with GERD or FD, as well as to those with constipation-predominant irritable bowel syndrome (IBS), who show delayed colonic transit. In contrast, the inhibitory effects of acupuncture at CV-12 on GI motility may be beneficial to patients with diarrhea-predominant IBS, because enhanced colonic motility and accelerated colonic transit are reported in such patients. Acupuncture at CV-12 may inhibit gastric acid secretion via the somatosympathetic pathway. Thus, acupuncture may be beneficial to GERD patients. The antiemetic effects of acupuncture at PC-6 (wrist) may be beneficial to patients with FD, whereas the antinociceptive effects of acupuncture at PC-6 and ST-36 may be beneficial to patients with visceral hypersensitivity. In the future, it is expected that acupuncture will be used in the treatment of patients with functional GI disorders.     

Hypersensitivity in functional gastrointestinal disorders

Patients with functional gastrointestinal disorders may have visceral sensory dysfunction so that physiological stimuli induce their symptoms. The clinical significance of altered perception-that is, its relation to clinical symptoms-remains unclear. Data indicate that sensory dysfunction is associated with altered reflex activity. Hence evidence of combined sensory-reflex dysfunction as a common pathophysiological mechanism in various functional gastrointestinal disorders would suggest that they are different forms of the same process. Altered reflex activity and altered conscious perception of gastrointestinal stimuli may combine to differing degrees, and their interaction may produce clinical symptoms.     

A new twist in the brain-gut axis.

Gastrointestinal functions are precisely regulated by hormonal and neural negative feedback loops. In addition to the classic hormonal and vago-vagal reflex mechanisms, these studies indicate that there are direct actions of gut hormones on the dorsal vagal complex. The current data demonstrate that pancreatic polypeptide is released into the circulation by vagal-cholinergic dependent mechanisms. It travels to the brainstem in the circulation, transverses the blood-brain barrier through "leaky" regions of this barrier in the area postrema and nucleus of the tractus solitarius and binds to specific receptors in the dorsal vagal complex. By binding to these sites, pancreatic polypeptide can directly inhibit vagal input to the pancreas and other gastrointestinal organs. These observations provide an anatomic basis to explain why pancreatic polypeptide is a more potent inhibitor of the action of central stimulants of pancreatic secretion than it is of the response to peripheral secretagogues. They also establish a novel mechanism by which gut peptides can influence brain function directly.