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.     

Role of antispasmodics in the treatment of irritable bowel syndrome

Irritable bowel syndrome (IBS) is a long-lasting, relapsing disorder characterized by abdominal pain/discomfort and altered bowel habits. Intestinal motility impairment and visceral hypersensitivity are the key factors among its multifactorial pathogenesis, both of which require effective treatment. Voltage-gated calcium channels mediate smooth muscle contraction and endocrine secretion and play important roles in neuronal transmission. Antispasmodics are a group of drugs that have been used in the treatment of IBS for decades. Alverine citrate, a spasmolytic, decreases the sensitivity of smooth muscle contractile proteins to calcium, and it is a selective 5-HT_1A receptor antagonist. Alverine, in combination with simethicone, has been demonstrated to effectively reduce abdominal pain and discomfort in a large placebo-controlled trial. Mebeverine is a musculotropic agent that potently blocks intestinal peristalsis. Non-placebo-controlled trials have shown positive effects of mebeverine in IBS regarding symptom control; nevertheless, in recent placebo-controlled studies, mebeverine did not exhibit superiority over placebo. Otilonium bromide is poorly absorbed from the GI tract, where it acts locally as an L-type calcium channel blocker, an antimuscarinic and a tachykinin NK2 receptor antagonist. Otilonium has effectively reduced pain and improved defecation alterations in placebo-controlled trials in IBS patients. Pinaverium bromide is also an L-type calcium channel blocker that acts locally in the GI tract. Pinaverium improves motility disorders and consequently reduces stool problems in IBS patients. Phloroglucinol and trimethylphloroglucinol are non-specific antispasmodics that reduced pain in IBS patients in a placebo-controlled trial. Antispasmodics have excellent safety profiles. T-type calcium channel blockers can abolish visceral hypersensitivity in animal models, which makes them potential candidates for the development of novel therapeutic agents in the treatment of IBS.     

New insights into visceral hypersensitivity--clinical implications in IBS

A subset of patients with IBS have visceral hypersensitivity and/or somatic hypersensitivity. Visceral hypersensitivity might have use as a clinical marker of IBS and could account for symptoms of urgency for bowel movements, bloating and abdominal pain. The mechanisms that lead to chronic visceral hypersensitivity in patients who have IBS are unclear. However, several working models may be considered, including: nociceptive input from the colon that leads to hypersensitivity; increased intestinal permeability that induces a visceral nociceptive drive; and alterations in the expression of microRNAs in gastrointestinal tissue that might be delivered via blood microvesicles to other target organs, such as the peripheral and/or central nervous system. As such, the chronic visceral hypersensitivity that is present in a subset of patients with IBS might be maintained by both peripheral and central phenomena. The theories underlying the development of chronic visceral hypersensitivity in patients with IBS are supported by findings from new animal models in which hypersensitivity follows transient inflammation of the colon. The presence of somatic hypersensitivity and an alteration in the neuroendocrine system in some patients who have IBS suggests that multisystemic factors are involved in the overall disorder. Thus, IBS is similar to other chronic pain disorders, such as fibromyalgia, chronic regional pain disorder and temporomandibular joint disorder, as chronic nociceptive mechanisms are activated in all of these disorders.     

Visceral hypersensitivity in irritable bowel syndrome

Altered central processing, abnormal gastrointestinal motility and visceral hypersensitivity may be possible major pathophysiology of irritable bowel syndrome (IBS). These factors affect each other and are probably associated with development of IBS symptoms. It has been confirmed that lower pain threshold to colonic distention was observed in most of patients with IBS than healthy subjects. We have investigated pain perception of the descending colon among different subtypes of IBS. There was no difference in pain threshold to colonic distention between IBS with diarrhea and constipation. Some brain regions such as the anterior cingulate cortex (ACC) may play a major role for generating pain and/or pain-related emotion in humans. IBS patients showed greater activation in the perigenual ACC during painful rectal distention compared with healthy subjects. Inflammation, stress and the combination of both stimuli can induce significant increase in visceral sensitivity in animal models. Serotonin (5-HT) can modulate visceral perception. It has been thought that 5-HT(3) receptors may play an important role for conveying visceral sensation from the gut. Corticotropin-releasing hormone (CRH) may also modulate visceral pain hypersensitivity in IBS. CRH receptor-1 antagonist significantly prevented an increase in gut sensitivity in rats. It has been demonstrated that non-specific CRH receptor antagonist α-helical CRH significantly reduced abdominal pain score during gut stimulus in patients with IBS. In conclusion, visceral hypersensitivity is common in IBS patients and probably plays a major role in development of the symptoms and both central and peripheral factors may enhance the pain sensitivity.     

Role of stress in functional gastrointestinal disorders. Evidence for stress-induced alterations in gastrointestinal motility and sensitivity.

Psychological stress is widely believed to play a major role in functional gastrointestinal (GI) disorders, especially irritable bowel syndrome (IBS), by precipitating exacerbation of symptoms. The available data clearly demonstrate that inhibition of gastric emptying and stimulation of colonic transit is the most consistent pattern in the motility response of the GI tract to acute or short-term stress. Thus, one might propose that these alterations might play a pathophysiological role in dyspeptic symptoms and alterations in stool frequency and consistency in patients with stress-related functional GI disorders. Taken together, the above-mentioned studies suggest that the colonic motor response to stress is exaggerated in IBS. There is evidence that an increased emotional response is associated with this difference in colonic, and perhaps also gastric motor responses to certain stressors. However, almost no valid data are available so far from human studies addressing the question if differences in motility responses to stress between patients with functional GI disorders and healthy subjects are due to an altered stress response associated with an imbalance of the autonomic nervous system or increased stress susceptibility. We can summarize that in experimental animals the most consistent pattern of GI motor alterations induced by various psychological and physical stressors is that of delaying gastric emptying and accelerating colonic transit. Endogenous corticotropin-releasing factor (CRF) in the brain plays a significant role in the central nervous system mediation of stress-induced inhibition of upper GI and stimulation of lower GI motor function through activation of brain CRF receptors. The inhibition of gastric emptying by CRF may be mediated by interaction with the CRF-2 receptor, while CRF-1 receptors are involved in the colonic and anxiogenic responses to stress. Endogenous serotonin, peripherally released in response to stress, seems to be involved in stress- and central CRF-induced stimulation of colonic motility by acting on 5HT-3 receptors. Taken together, the limited data available from investigations in healthy subjects and patients with functional GI disorders provide some evidence that stress affects visceral sensitivity in humans. Acute psychological stress seems to facilitate increased sensitivity to experimental visceral stimuli, if the stressor induces a significant emotional change. In summary, studies in experimental animals suggest that stress-induced visceral hypersensitivity is centrally mediated by endogenous CRF and involvement of structures of the emotional motor system, e.g. the amygdala. Stress-induced activation or sensitization of mucosal mast cells in the GI tract seem to be involved in stress-associated alterations of visceral sensitivity.     

Low-grade inflammation plays a pivotal role in gastrointestinal dysfunction in irritable bowel syndrome

The pathogenesis of irritable bowel syndrome (IBS) is considered to be multifactorial and includes psychosocial factors, visceral hypersensitivity, infection, microbiota and immune activation. It is becoming increasingly clear that low-grade inflammation is present in IBS patients and a number of biomarkers have emerged. This review describes the evidence for low-grade inflammation in IBS and explores its mechanism with particular focus on gastrointestinal motor dysfunction. Understanding of the immunological basis of the altered gastrointestinal motor function in IBS may lead to new therapeutic strategies for IBS.     

New insights into the pathogenesis and pathophysiology of irritable bowel syndrome.

The pathogenesis and pathophysiology of irritable bowel syndrome is complex and still incompletely known. Potential pathogenetic factors include genes, infectious events, psychological symptoms and other loosely defined environmental factors. Both alterations at the central and peripheral level are thought to contribute to the symptoms of irritable bowel syndrome, including psychosocial factors, abnormal gastrointestinal motility and secretion, and visceral hypersensitivity. Today irritable bowel syndrome is viewed upon as a disorder of dysregulation of the so-called brain-gut axis, involving abnormal function in the enteric, autonomic and/or central nervous systems, with peripheral abnormalities probably dominating in some patients and disturbed central processing of signals from the periphery in others. Lines of evidence also suggest that inflammation within the gastrointestinal tract may be of great importance in at least subgroups of irritable bowel syndrome patients. To conclude, a complex picture of the pathogenesis and pathophysiology of irritable bowel syndrome is emerging, with interactions between several different alterations resulting in the divergent symptom pattern in these patients.     

5-羟色胺信号系统在炎症性肠病发病机制中的地位

炎症性肠病(IBD)患者较易出现功能性肠道症状,这些症状往往与肠道活动性炎症关系不大,却与肠功能紊乱有关,说明IBD的发病在某些方面与肠易激综合征(IBS)相似。5-羟色胺(5-HT)信号系统异常可致胃肠动力、分泌功能异常和内脏高敏感性,与多种功能性胃肠病密切相关。而IBD的发病机制中亦存在功能性因素,提示IBD与IBS可能存在某些分子水平的联系,有必要对5-HT信号系统在IBD发病机制中的作用进行研究。     

Alterations of sensori-motor functions of the digestive tract in the pathophysiology of irritable bowel syndrome

Pathophysiology of irritable bowel syndrome (IBS) is based upon multiple factors that have been organised in a comprehensive model centred around the brain-gut axis. The brain-gut axis encompasses nerve pathways linking the enteric and the central nervous systems and contains a large proportion of afferent fibres. Functionally and anatomically, visceral nerves are divided in to two categories: the parasympathetic pathways distributing to the upper gut through the vagi and to the hindgut, through the pelvic and pudendal nerves, and the sympathetic pathways, arising form the spinal cord and distributing to the midgut via the paravertebral ganglia. Several abnormalities of gut sensori-motor function have been described in patients with IBS. Abnormal motility patterns have been described at the intestinal and colonic levels. Changes in colonic motility are mainly related to bowel disturbances linked to IBS but do not correlate with pain. More recently, visceral hypersensitivity has been recognised as a main characteristic of patients with IBS. It is defined by an exaggerated perception of luminal distension of various segments of the gut and related to peripheral changes in the processing of visceral sensations as well as modulation of perception by centrally acting factors including mood and stress. Viscero-visceral reflexes link the two edges of the brain-gut axis and may account for the origin of symptoms in some pathological conditions. Recent advances in the understanding of the role of myenteric plexus allowed recognition of several neurotransmitters involved at the level of both the afferent and efferent pathways. Targeting the receptors of these neurotransmitters is a promising way for development of new treatments for IBS.     

Mechanisms Underlying Visceral Hypersensitivity in Irritable Bowel Syndrome

Visceral hypersensitivity is currently considered a key pathophysiological mechanism involved in pain perception in large subgroups of patients with functional gastrointestinal disorders, including irritable bowel syndrome (IBS). In IBS, visceral hypersensitivity has been described in 20%–90% of patients. The contribution of the central nervous system and psychological factors to visceral hypersensitivity in patients with IBS may be significant, although still debated. Peripheral factors have gained increasing attention following the recognition that infectious enteritis may trigger the development of persistent IBS symptoms, and the identification of mucosal immune, neural, endocrine, microbiological, and intestinal permeability abnormalities. Growing evidence suggests that these factors play an important role in pain transmission from the periphery to the brain via sensory nerve pathways in large subsets of patients with IBS. In this review, we will report on recent data on mechanisms involved in visceral hypersensitivity in IBS, with particular attention paid to peripheral mechanisms.     

Psychosocial factors and visceral hypersensitivity in irritable bowel syndrome]

Most studies provide strong support for an etiologic role of stressful life events in irritable bowel syndrome (IBS). Consistent with the observations in both patients and doctors that psychosocial disturbances seem to precede the onset or exacerbation of gut symptoms, researches have consistently found high levels of emotional distress in a proportion of patients with IBS and other functional gastrointestinal disorders. Moreover, a variety of other potentially psychiatric diseases such as anxiety, depression, and sleep disorder also coexist frequently with IBS. In recent literatures, some studies have shown altered mechanoelastic properties such as colonic tone, compliance, and accommodation. The demonstrated differences in colonic compliance and accommodation suggest peripheral neuromuscular substrate contributing to the pathogenesis of IBS. However, until now, attention has focused on the disturbances of visceral hypersensitivity rather than on gastrointestinal motor function as a hallmark of IBS pathophysiology. But not all IBS patients show decreased rectosigmoid pain thresholds. Recent advances in brain imaging have allowed investigators to measure changes in regional cerebral blood flow during stimulation. Those methods have extended our understanding of brain function and brain-gut interaction. IBS is characterized by hypersensitivity to visceral sensation and augmented response to stress. Studies on the disorders of sensori-motor function have also contributed to understand the knowledge of neurotransmitters involved in the function of the enteric nervous system and to identify targets for the development of new treatments for IBS.     

肠易激综合征发病机制的研究进展

肠易激综合征（IBS）是一种常见的功能性胃肠病,其发病机制尚未完全阐明,可能与胃肠动力异常、内脏高敏感、精神心理应激、脑．肠轴功能紊乱、免疫和内分泌系统紊乱等有关。本文就IBS发病机制的相关研究进展作一综述。     

Acupuncture-moxibustion in treating irritable bowel syndrome: How does it work?

Irritable bowel syndrome (IBS) is a functional intestinal disease characterized by abdominal pain or discomfort and altered bowel habits. It has drawn great attention because of its high prevalence, reoccurring symptoms, and severe influence on patients’ lives. Many clinical studies have demonstrated the efficacy of acupuncture-moxibustion in treating IBS. Increasing attention has been paid to research regarding the action mechanisms of acupuncture-moxibustion for IBS, and the adoption of modern techniques has achieved some progress. This article reviews the latest advances among action mechanism studies from the perspectives of gastrointestinal motility, visceral hypersensitivity, the brain-gut axis, the neuroendocrine system, and the immune system. It is shown that acupuncture-moxibustion can effectively regulate the above items, and thus, this treatment should have a high efficacy in the treatment of IBS. This article also identifies existing problems in current mechanism research and raises several ideas for future studies. Further revelations regarding these action mechanisms will promote the application of acupuncture-moxibustion in treating IBS.     

肠易激综合征发病机理的研究进展

肠易激综合征的发病机制至今仍不明确，目前比较一致的观点认为IBS是胃肠动力异常、内脏感觉敏感性增高、肠道感染、炎症、心理社会精神因素、神经免疫内分泌及基因遗传等多种发病机制共同参与共同作用的结果，本文就近年来有关IBS发病机制的研究进展作一综述。     

肠易激综合征动物模型研制现状和进展

肠易激综合征(IBS)是一种常见的肠功能紊乱性疾病,特点是慢性反复发作的腹痛、腹部不适及排便习惯的改变。发病机制目前尚未阐明。研究显示IBS可能与肠道动力、内脏感觉过敏和肠道感染等因素有关。此文对IBS动物模型研制现状及展望作一综述。     

Funktionelle Magen-Darm-Erkrankungen

Functional dyspepsia (FD) and irritable bowel syndrome (IBS) are the most important functional gastrointestinal diseases (FGID), and both affect about 5–15?% of the German population. The patients’ symptoms are caused by disturbances of gastrointestinal (GI) motility, secretion and sensitivity. Central processing of visceral afferences is disturbed, and the course of the disease and individual symptom perception are influenced by psychosocial factors. Diagnosis of FD and IBS is based on a compatible symptom pattern, absence of alarm symptoms and exclusion of relevant differential diagnoses. The diagnosis of FD requires a normal upper GI endoscopy. Current German guidelines also demand a normal colonoscopy for diagnosis of IBS. Basic therapeutic measures include explanation of the nature of the disease and its harmlessness quo ad vitam . Individual trigger factors should be identified and eliminated if possible. Drug therapy of persisting complaints is guided by the dominant symptom.     

Abnormal endogenous pain modulation and somatic and visceral hypersensitivity in female patients with irritable bowel syndrome

AIM： To investigate the role of endogenous pain modulatory mechanisms in the central sensitization implicated by the visceral hypersensitivity demonstrated in patients with irritable bowel syndrome （IBS）. Dysfunction of modulatory mechanisms would be expected to also result in changes of somatic sensory function.
METHODS： Endogenous pain modulatory mechanisms were assessed using heterotopic stimulation and somatic and visceral sensory testing in IBS. Pain intensities （visual analogue scale, VAS 0-100） during suprathreshold rectal distension with a barostat, cold pressor stimulation of the foot and during both stimuli simultaneously （heterotopic stimulation） were recorded in 40 female patients with IBS and 20 female healthy controls.
RESULTS： Rectal hypersensitivity （defined by 95% Cl of controls） was seen in 21 （53%）, somatic hypersensitivity in 22 （55%） and both rectal and somatic hypersensitivity in 14 of these IBS patients. Heterotopic stimulation decreased rectal pain intensity by 6 （-11 to -1） in controls, but increased rectal pain by 2 （-3 to ＋6） in all IBS patients （P 〈 0.05） and by 8 （-2 to ＋19） in IBS patients with somatic and visceral hypersensitivity （P 〈 0.02）.
CONCLUSION： A majority of IBS patients had abnormal endogenous pain modulation and somatic hypersensitivity as evidence of central sensitization.     

Possible role of intestinal stem cells in the pathophysiology of irritable bowel syndrome

The pathophysiology of irritable bowel syndrome(IBS) is not completely understood. However, several factors are known to play a role in pathophysiology of IBS such as genetics, diet, gut microbiota, gut endocrine cells,stress and low-grade inflammation. Understanding the pathophysiology of IBS may open the way for new treatment approaches. Low density of intestinal stem cells and low differentiation toward enteroendocrine cells has been reported recently in patients with IBS. These abnormalities are believed to be the cause of the low density of enteroendocrine cells seen in patients with IBS.Enteroendocrine cells regulate gastrointestinal motility, secretion, absorption and visceral sensitivity. Gastrointestinal dysmotility, abnormal absorption/secretion and visceral hypersensitivity are all seen in patients with IBS and haven been attributed to the low density the intestinal enteroendocrine cells in these patients.The present review conducted a literature search in Medline(Pub Med) covering the last ten years until November 2019, where articles in English were included.Articles about the intestinal stem cells and their possible role in the pathophysiology of IBS are discussed in the present review. The present review discusses the assumption that intestinal stem cells play a central role in the pathophysiology of IBS and that the other factors known to contribute to the pathophysiology of IBS such as genetics, diet gut microbiota, stress, and lowgrade inflammation exert their effects through affecting the intestinal stem cells.It reports further the data that support this assumption on genetics, diet, gut microbiota, stress with depletion of glutamine, and inflammation.     

5-羟色胺信号系统与肠易激综合征

5-羟色胺(5-HT)是参与调节胃肠道运动和分泌功能的重要神经递质,5-HT信号系统异常可导致胃肠动力及分泌功能异常、内脏高敏感性,与IBS的病理生理改变相关。此文旨在探讨5-HT信号系统在IBS肠道运动和感觉的调节、脑肠轴异常、精神症状、神经保护等方面的作用。     

Irritable bowel syndrome: new pharmaceutical approaches to treatment.

The irritable bowel syndrome (IBS) is a consortium of symptoms including abdominal pain and alterations in the pattern of defaecation. There is no single pathophysiological marker of IBS although it is generally accepted that some patients do have abnormalities of intestinal motility and/or enhanced visceral sensitivity. There is also an increasing acceptance that the central nervous system, an important component of the brain-gut axis, also plays an important role in symptom production both in the response to stress and when there is an underlying affective disorder. During the past decade new therapeutic targets have been identified that have permitted the development of new drugs with therapeutic potential for IBS. Identification and characterization of 5-hydroxytryptamine (5-HT) receptors in the gastrointestinal tract particularly 5-HT3 and 5-HT4 receptors, which are involved not only in modulating gut motility but in visceral sensory pathways, has led to a number of studies of 5-HT3 (Alosetron, Granisetron and Ondansetron) and 5-HT4 (SB-207266A) antagonists. Both classes of drug appear to reduce visceral sensitivity and have inhibitory effects on motor activity in the distal intestine. Early clinical studies suggest that these agents may have a role in painful, diarrhoea-predominant IBS. 5-HT4 agonists (HTF919, Zelmac) may improve constipation-predominant IBS by normalizing bowel habit and thereby reducing abdominal pain. Alternative approaches to reducing visceral sensation include the use of the opioid kappa agonists, which have no central opioid effects although clinical trials have suggested that these agents are not highly effective in relieving IBS pain. There are in addition, new approaches to modify intestinal motility including the development of gut selective muscarinic M3 receptor antagonists such as zamifenacin and the 5-HT4 partial agonist, HTF919. Preliminary studies suggest that these agents may have therapeutic potential in IBS. Anti-depressants are increasingly used to treat affective disorder in IBS but in addition appear to have added value because of their ability to reduce visceral hypersensitivity and alter gut transit. Therapeutic effects are often obtained at doses below those normally used to treat depression. IBS continues to be a therapeutic challenge because of its diverse symptomatology and lack of a single pathophysiological target for drug intervention.