Review article: probiotics and prebiotics in irritable bowel syndrome

Background  The human gut harbours a complex community of bacteria whose relationship with their host is normally mutually beneficial. Recent studies suggest a disturbance of this relationship in irritable bowel syndrome (IBS) and the potential to correct this using prebiotics and probiotics.
Aim  To review the mechanisms of action of probiotics and prebiotics in IBS and to assess their performance in clinical trials.
Methods  Articles relating to modes of action and randomized control trials of treatment were reviewed by searching PubMed using terms 'probiotic', 'prebiotic' and 'irritable bowel'. Small uncontrolled studies in IBS were excluded.
Results  Probiotics can enhance gut barrier function, inhibit pathogen binding and modulate gut inflammatory response. They can also reduce visceral hypersensitivity associated with both inflammation and psychological stress. Probiotics can alter colonic fermentation and stabilize the colonic microbiota. Several large randomized, placebo-controlled trials of adequate design have shown an improvement in flatulence and abdominal distension with a reduction in composite IBS symptoms scores.
Conclusions  Each probiotic has unique features and IBS patients are heterogeneous. Future efforts should be directed to identifying biomarkers of responsiveness to facilitate better targeting of treatment and hence improved efficacy.     

槲皮素与5-氨基水杨酸协同治疗感染后肠易激综合征大鼠的药效机制

目的：研究槲皮素与5-氨基水杨酸（5-ASA）对感染后肠易激综合征（PI-IBS）的治疗作用及其机制。方法：PI-IBS大鼠模型分别灌胃给予5-ASA、槲皮素或5-ASA联合槲皮素,连续给药2周。腹壁收缩实验测定内脏痛阈值,水应激法评价结肠运动;收集血液和结肠,液质联用法测定5-ASA及其代谢物N-乙酰-5-ASA含量。结果：与正常组相比,PI-IBS组内脏痛阈值显著降低,结肠排便增多（P<0.05）。与模型组相比,5-ASA联合槲皮素可显著提高PI-IBS大鼠内脏痛阈值并明显减少结肠排便数量,其作用优于各单独用药组。槲皮素可明显增加PI-IBS大鼠结肠5-ASA含量并显著降低N-乙酰-5-ASA含量（P<0.05）。结论：槲皮素联合5-ASA对PI-IBS大鼠具有协同治疗作用,其机制可能与槲皮素抑制5-ASA代谢酶,提高结肠5-ASA浓度从而增强其治疗效果有关。     

Review article: new receptor targets for medical therapy in irritable bowel syndrome

Background  Despite setbacks to the approval of new medications for the treatment of irritable bowel syndrome, interim guidelines on endpoints for irritable bowel syndrome (IBS) trials have enhanced interest as new targets for medical therapy are proposed based on novel mechanisms or chemical entities.
Aims  To review the approved lubiprostone, two targets that are not meeting expectations (tachykinins and corticotrophin-releasing hormone), the efficacy and safety of new 5-HT₄ agonists, intestinal secretagogues (chloride channel activators, and guanylate cyclase-C agonists), bile acid modulation, anti-inflammatory agents and visceral analgesics.
Methods  Review of selected articles based on PubMed search and clinically relevant information on mechanism of action, safety, pharmacodynamics and efficacy.
Results  The spectrum of peripheral targets of medical therapy addresses chiefly the bowel dysfunction of IBS and these effects are associated with pain relief. The pivotal mechanisms responsible for the abdominal pain or visceral sensation in IBS are unknown. The new 5-HT₄ agonists are more specific than older agents and show cardiovascular safety to date. Secretory agents have high specificity, low bioavailability and high efficacy. The potential risks of agents 'borrowed' from other indications (such as hyperlipidaemia, inflammatory bowel disease or somatic pain) deserve further study.
Conclusions  There is reason for optimism in medical treatment of IBS with a spectrum of agents to treat bowel dysfunction. However, visceral analgesic treatments are still suboptimal.     

冬凌草片对炎症后肠易激综合征大鼠的治疗作用

目的 研究冬凌草片对炎症后肠易激综合征（Post-inflammatory Irritable Bowel Syndrome,PI-IBS）大鼠的治疗作用及其机制。方法 用2,4,6-三硝基苯磺酸制备PI-IBS大鼠模型,动物灌胃给予冬凌草片0.4,0.8,1.2 g·kg^-1·d^-1,连续2周。采用腹壁收缩实验测内脏痛阈值;水应激法评价结肠运动;免疫组化法考察嗜铬细胞数;液质联用法测血清素含量,并用免疫印迹法考察色氨酸羟化酶的表达。结果 与正常对照组相比,PI-IBS大鼠内脏痛阈值明显降低、结肠排便增多、肠嗜铬细胞增生、色氨酸羟化酶表达增多及血清素含量增高（P<0.05）。冬凌草片高剂量和中剂量给药可显著提高PI-IBS大鼠内脏痛阈值;显著减少结肠排便数量、肠嗜铬细胞数量、血清素含量和色氨酸羟化酶表达（P<0.05）。结论 冬凌草片通过减少肠道嗜铬细胞增生和血清素含量治疗PI-IBS大鼠内脏痛及结肠运动障碍。     

CRF1 receptors as a therapeutic target for irritable bowel syndrome

The characterization of the corticotropin-releasing factor (CRF) family of neuroendocrine regulatory peptides, the cloning and pharmacological characterization of two CRF receptor subtypes (CRF(1) and CRF(2)), and the development of selective CRF receptor antagonists provided new insight to unravel the mechanisms of stress and the potential involvement of the CRF system in different pathophysiological conditions, including functional gastrointestinal disorders, mainly irritable bowel syndrome (IBS), and psychopathologies such as anxiety/depression. Compelling pre-clinical data showed that brain CRF administration mimics acute stress-induced colonic responses and enhances colorectal distension-induced visceral pain in rats through CRF(1) receptors. Similarly, peripheral CRF reduced the pain threshold to colonic distension and increased colonic motility in humans and rodents. These observations mimic the manifestations of IBS, characterized by abdominal bloating/discomfort and altered bowel habits. Moreover, CRF-CRF(1) pathways have been implicated in the development of anxiety/depression. These psychopathologies, together with stressful life events, have high comorbidity with IBS, and are considered significant components of the disease. From these observations, CRF(1) receptors have been suggested as a target to treat IBS. Peripherally acting CRF(1) antagonists might directly improve IBS symptoms, as related to motility, secretion and immune response. On the other hand, central actions will be beneficial as to prevent the psychopathologies that co-exist with IBS and as a way to modulate the central processing of stress- and visceral pain-related signals. Here, we review the pre-clinical and clinical data supporting these assumptions, and address the efforts done at a pharmaceutical level to develop effective therapies targeting CRF(1) receptors for functional gastrointestinal disorders.     

Review article: gender-related differences in functional gastrointestinal disorders

Many functional gastrointestinal disorders and other chronic visceral pain disorders such as interstitial cystitis and chronic pelvic pain are more common in women than in men. In irritable bowel syndrome (IBS) there is a 2 : 1 female to male ratio in prevalence of symptoms in community samples. Female irritable bowel syndrome patients are more likely to be constipated, complain of abdominal distension and of certain extracolonic symptoms.
While animal studies have clearly demonstrated gender-related differences in pain perception and antinociceptive mechanisms, unequivocal evidence for gender-related differences in human pain perception or modulation has only been provided recently. Gender-related differences may be related to constant differences in the physiology of pain perception, such as structural or functional differences in the visceral afferent pathways involved in pain transmission or modulation, and/or they may be related to fluctuations in female sex hormones.
Preliminary evidence suggests that female irritable bowel syndrome patients show specific perceptual alterations in regards to rectosigmoid balloon distension and that they show differences in regional brain activation measured by positron emission tomography. This preliminary evidence suggests that gender-related differences in symptoms and in the perceptual responses to visceral stimuli exist in IBS patients and can be detected using specific stimulation paradigms and neuroimaging techniques.     

Pioglitazone improves visceral sensation and colonic permeability in a rat model of irritable bowel syndrome

Visceral hypersensitivity and impaired gut barrier with minor inflammation are considered to play an important role in the pathophysiology of irritable bowel syndrome (IBS). Since pioglitazone is known to have anti-inflammatory property, we hypothesized that pioglitazone is beneficial for treating IBS. In this study, the effect was tested in rat IBS models such as lipopolysaccharide or repeated water avoidance stress-induced visceral allodynia and increased colonic permeability. Pioglitazone blocked these visceral changes, and GW9662, a peroxisome proliferator-activated receptor gamma (PPAR-γ) antagonist fully reversed the effect by pioglitazone. These results suggest that PPAR-γ activation by pioglitazone may be useful for IBS treatment.     

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).
Aim  To assesses the effect of mesalazine (mesalamine) on mucosal immune cells in patients with IBS, through a pilot study.
Methods  A randomized, double-blind, placebo-controlled trial in 20 patients with IBS in tertiary care setting. Patients were randomized to receive placebo or 800 mg mesalazine three times daily for 8 weeks. The primary endpoint was a significant reduction in total colonic immune cells on biopsies obtained at the end of treatment compared to baseline. Secondary endpoints included effects on subsets of immune cells, inflammatory mediators and symptom severity. Intention-to-treat analysis was performed.
Results  Mesalazine markedly reduced immune cells as compared with placebo ( P  = 0.0082); this effect was ascribed to a marked inhibition of mast cells ( P  = 0.0014). Mesalazine significantly increased general well-being ( P  = 0.038), but had no significant effects on abdominal pain ( P  = 0.084), bloating ( P  = 0.177) or bowel habits. No serious drug-related adverse events were reported during the study.
Conclusions  Mesalazine is an effective and safe approach to reduce mast cell infiltration and may improve general well-being in patients with IBS. These results support the hypothesis that immune mechanisms represent potential therapeutic targets in IBS.     

Amitriptyline modifies the visceral hypersensitivity response to acute stress in the irritable bowel syndrome

Background  Acute physical stress causes alteration in gut autonomic function and visceral hypersensitivity in patients with irritable bowel syndrome (IBS). We have developed a model to measure this stress response.
Aim  To assess whether treatment with a drug effective in treating IBS (amitriptyline) alters the response to acute stress in IBS patients.
Methods  Nineteen patients with IBS were given amitriptyline 25–50 mg. Patients underwent physical stress (cold pressor) test at baseline and after 3 months of treatment. Physiological parameters measured were: stress perception; systemic autonomic tone [heart rate (HR) and blood pressure (BP)]; gut specific autonomic innervation [rectal mucosal blood flow (RMBF)] and visceral sensitivity (rectal electrosensitivity).
Results  Fourteen of 19 (74%) patients improved symptomatically after 3 months of amitriptyline. Acute stress induced increased perception of stress and systemic autonomic tone and reduced RMBF in symptomatic responders and nonresponders ( P  > 0.05 for all). All nonresponders but only 3 of 14 responders continued to exhibit stress-induced reduced pain threshold at 3 months (change from baseline −31% vs. +2%, P  < 0.03 respectively).
Conclusion  In this open study, amitriptyline appears to decrease stress-induced electrical hypersensitivity; this effect is independent of autonomic tone. The gut response to acute stress deserves further study as a model to study drug efficacy in IBS.     

Reactivity to images in health and irritable bowel syndrome

Background  We have been using a medical artist to record and paint the images patients have of their irritable bowel syndrome (IBS) and have hypothesized that the reaction to such images might differ in health and IBS, which could have practical implications for future research.
Aim  To examine reactivity to images in health and IBS.
Methods  Twelve paintings of IBS were shown to 70 patients to determine the four most evocative images. The spontaneous response to these images and four 'non-IBS painful' and four neutral paintings was assessed in another 100 IBS patients and 100 controls. The prompted reaction in terms of whether an image evoked the notion of pain, bloating or discomfort and to what degree was also recorded.
Results  Four images depicting bloating and pain scored the highest. These IBS images triggered significantly different reactivity between patients and controls in terms of their spontaneous and prompted responses. Even 'non-IBS painful' and neutral images resulted in exaggerated and frequently significantly different responses in patients than in controls.
Conclusions  Visual hypersensitivity appears to be another manifestation of the tendency of IBS patients to react adversely to a variety of endogenous and exogenous stimuli. Identifying how individuals relate to different images might also give useful insights into understanding gastrointestinal symptoms.     

Review article: the psychoneuroimmunology of irritable bowel syndrome--an exploration of interactions between psychological, neurological and immunological observations

Background The pathogenesis of irritable bowel syndrome (IBS) is founded on interactive mechanisms. Disentangling these processes is a prerequisite for the development of effective drug therapy. Aim To identify the interaction between the various factors implicated in IBS. Methods Articles pertaining to IBS pathogenesis focusing on psychoneuroimmunology were identified using following search terms: IBS, animal models, microbiota, probiotics, immunology, visceral hypersensitivity, imaging, psychology and visceral pain. Results Cerebral imaging using MRI and proton emission tomography scanning has revealed differential regional cerebral activation, whereas stimuli induced activation has been captured by both MRI and cortical evoked potentials. At the peripheral neurological level, the concept of visceral hypersensitivity has been challenged as perhaps representing psychological traits with symptom over‐reporting or hyper‐vigilance. Gut mucosal immunology is thought to be relevant with immunological changes reflected as peripheral blood cytokine level changes. Molecular technology advances suggest a role for microbiota by activating the gut immunological system. These interactions have been examined in IBS animal models. Conclusions Translation of animal model findings to humans is needed to link the various psychological, neurological and immunological changes noted in IBS. This analysis may identify patient sub‐groups, which will ultimately be critical for drug testing to be focused accordingly.     

Relationship between rectal sensitivity, symptoms intensity and quality of life in patients with irritable bowel syndrome

Background  Relationships between pain threshold during rectal distension and both symptoms intensity and alteration in quality of life (QoL) in irritable bowel syndrome (IBS) patients have been poorly evaluated.
Aim  To evaluate relationships between rectal sensitivity, IBS symptom intensity and QoL in a multicentre prospective study.
Methods  Rectal threshold for moderate pain was measured during rectal distension in IBS patients (Rome II), while IBS symptoms intensity was assessed by a validated questionnaire and QoL by the Functional Digestive Disorder Quality of Life questionnaire.
Results  Sixty-eight patients (44.2 ± 12.7 years, 48 women) were included. The mean rectal distending volume for moderate pain was 127 ± 35 mL while 45 patients (66%) had rectal hypersensitivity (pain threshold <140 mL). Rectal threshold was not significantly related either to overall IBS intensity score ( r  = −0.66, P  =   0.62) or to its different components, or to FDDQL score ( r  = 0.30, P  =   0.14). Among FDDQL domains, only anxiety ( r  = 0.30, P  =   0.01) and coping ( r  = 0.31, P  =   0.009) were significantly related with pain threshold.
Conclusions  In this study, two-thirds of IBS patients exhibited rectal hypersensitivity. No significant correlation was found between rectal threshold and either symptom intensity or alteration in QoL.     

New insights into the pathophysiology of IBS: intestinal microflora, gas production and gut motility

Irritable bowel syndrome (IBS) is a complex disorder clinically characterized by abdominal pain and altered bowel habit. Its pathogenetic mechanisms are still incompletely known; genes, psychosocial factors, changes in gastrointestinal motility and visceral hypersensitivity are traditionally thought to play a crucial role in symptom generation. Recent studies have identified new additional factors that can interact with the established mechanisms. Dysregulation of brain-gut axis, gastrointestinal infection, low-grade infiltration and activation of mast cells in the intestinal mucosa with consequent release of bioactive substances, and altered serotonin metabolism are the emerging factors of IBS pathogenesis. Finally, modification of small bowel and colonic microflora and altered gas balance may be of relevance in at least some subgroups of IBS patients. New therapies can be developed only on the basis of a better understanding of the heterogeneous picture of the pathophysiology of IBS.     

Review article: an integrated approach to the irritable bowel syndrome

Our understanding of the pathophysiology of irritable bowel syndrome (IBS) has evolved from a disorder of motility to a more integrated understanding of enhanced motility and visceral hypersensitivity associated with brain–gut dysfunction. Psychosocial factors contribute to the predisposition, precipitation and perpetuation of IBS symptoms, and affect the clinical outcome. Newer brain imaging techniques (e.g. PET, fMRI) may help us understand the relationship between altered emotional states with pain enhancement and other gastrointestinal symptoms. Diagnosis using symptom-based (e.g. Rome) criteria and a conservative diagnostic approach is recommended. Treatment is based on an effective physician–patient relationship and a combined pharmacological and behavioural approach. Newer medications acting at the 5-HT receptor may help in reducing pain and bowel dysfunction. For more severe pain, antidepressants may be considered.     

Tachykinin receptor antagonists in irritable bowel syndrome

Tachykinins (TKs) are abundantly expressed in the gastrointestinal (GI) tract in intrinsic excitatory motor neurons, interneurons, sensory neurons and extrinsic sensory neurons. Their role in the regulation of enteric secretomotor functions is well established, especially following pathophysiological stimuli. Recent evidence emphasizes the role of TKs in the sensitization of peripheral branches of visceral afferent neurons, implying a role in determining visceral hypersensitivity. Furthermore, the involvement of both CNS and peripheral TK receptors in autonomic reactions to stress, render these receptors an appealing target for the development of drugs aimed at the treatment of irritable bowel syndrome (IBS), a functional GI disorder. The available preclinical evidence indicates that TK receptor antagonists could normalize motor disturbance (diarrhea and constipation) and reduce the painful symptoms that characterize IBS.     

Achieving translation in models of visceral pain

The failure of drugs to modify pain end points in clinical trials for irritable bowel syndrome (IBS) highlights the knowledge gap that exists in the translation of efficacy in animal models of visceral pain into the clinic. Recent progress has been made towards improving the translation of visceral pain, particularly with regard to the activation of the sensory nerves which relay pain from the gut to the brain. This review will focus on studies which have identified the presence of an altered gastrointestinal and immune environment in IBS patients. The development of human gastrointestinal visceral afferent recordings has allowed direct comparison between sensory nerve studies in animals and human, as well as important advances in our understanding of the ion channels that underpin the changes in sensory nerve excitability.     

Clinical trial: dextofisopam in the treatment of patients with diarrhoea-predominant or alternating irritable bowel syndrome

Background  Dextofisopam modulates stimulated activity in animal models of stress, altered bowel motility, and visceral hypersensitivity.
Aim  To evaluate the effects of dextofisopam in men and women with diarrhoea-predominant or alternating irritable bowel syndrome (IBS) (d-IBS or a-IBS).
Methods  In this double-blind, placebo-controlled study, patients were randomly assigned to receive dextofisopam 200 mg b.d. or placebo for 12 weeks. The prospectively defined primary endpoint was number of months of adequate overall relief of IBS symptoms. Bowel function was assessed primarily via stool frequency and consistency.
Results  Of 140 enrolled patients, 66 received dextofisopam and 74 placebo; 73% of the patients were women, and 78% had d-IBS. Dextofisopam was superior to placebo on the primary endpoint ( P  = 0.033). In d-IBS patients treated with dextofisopam, both men and women had improved stool consistency, but stool frequency was reduced only in women. Benefit diminished over time on the primary endpoint, but persisted on frequency and consistency. Dextofisopam and placebo had similar rates and types of adverse events, with more events of worsening abdominal pain with dextofisopam (12% vs. 4%) and more headaches with placebo (12% vs. 5%). Constipation was rare.
Conclusion  Dextofisopam should be further evaluated as a new treatment for men and women with d-IBS and a-IBS.     

Protease activated receptor 2: a new target for IBS treatment

Proteinase-activated receptors (PARs) are G-protein-coupled receptors that are activated by the proteolytic cleavage of their N-terminal domain. The new N-terminal sequence that is exposed by proteolysis acts as a tethered ligand, which binds to and activates the receptor. PAR-2 is highly expressed in the gastrointestinal tract, where it is found in endothelial cells, colonic myocytes, enterocytes (both on basolateral and apical membranes), enteric neurons, terminals of mesenteric afferent nerves and immune cells. In the gastrointestinal tract, PAR-2 may be activated by tryptase from mast cells but also by luminal proteases such as trypsin and possibly bacterial proteases. In addition to effects on motility, ion and mucus secretion, activation of PAR-2 receptors from luminal affects visceral pain. In rats, the intracolonic infusion of PAR-2 agonists (SLIGRL, trypsin) initiates a delayed hypersensitivity to colonic distension. These effects are locally mediated since they are not observed for systemic administration. Interestingly, such pronociceptive effect of local activation of PAR-2 is associated with increased colonic paracellular permeability. Blockade of such increase in permeability, prevents the occurrence of hypersensitivity to rectal distension suggesting that activation of the local immune system by luminal toxins and antigens is responsible for the sensitization of primary afferent terminals to mechanical stimuli. Consequently, blockade of PAR-2 receptors at the periphery and/or inhibition of colonic luminal protease activity may be new interesting targets for the treatment of gut hypersensitivity and IBS. A recent study has evidenced that stool supernatants from diarrhea predominant IBS patients have a high level of serine-protease activity that increases permeability and colonic hypersensitivity when infused intra-colonically in mice, and these effects are linked to activation of PAR-2 receptors. These data support a possible role of luminal proteases in the pathogenesis of IBS and give a rationale to target PARs and more specifically PAR-2 as future treatment of IBS.     

Relationship between symptoms and hypersensitivity to rectal distension in patients with irritable bowel syndrome

BACKGROUND: Visceral hypersensitivity is considered an important pathophysiological mechanism in irritable bowel syndrome, yet its relationship to symptoms is unclear. AIM: To detect possible associations between symptoms and the presence of hypersensitivity to rectal distension in patients with irritable bowel syndrome. METHODS: Ninety-two irritable bowel syndrome patients and 17 healthy volunteers underwent a rectal barostat study. The association between specific irritable bowel syndrome symptoms and the presence of hypersensitivity was examined using Area under the Receiver Operating Characteristic curves. RESULTS: Irritable bowel syndrome patients had significantly lower thresholds for discomfort/pain than healthy volunteers: 24 (18-30) and 30 (27-45) mmHg above minimal distending pressure, respectively. Forty-one patients (45%) showed hypersensitivity to rectal distension. Proportions of patients with different predominant bowel habits were similar in hypersensitive and normosensitive subgroups (diarrhoea predominant: 39 and 41%, respectively; alternating type: 27 and 28%, respectively; constipation predominant: 34 and 31%, respectively). Severe abdominal pain was more frequent in hypersensitive, compared with normosensitive patients (88% vs. 67%, P = 0.02), but none of the individual irritable bowel syndrome symptoms could accurately predict the presence of hypersensitivity, as assessed by Area under the Receiver Operating Characteristic curve analysis. CONCLUSIONS: Hypersensitive and normosensitive irritable bowel syndrome patients present with comparable, heterogeneous symptomatology. Therefore, selection based on clinical parameters is unlikely to discriminate individual irritable bowel syndrome patients with visceral hypersensitivity from those with normal visceral sensitivity.     

Milnacipran is active in models of irritable bowel syndrome and abdominal visceral pain in rodents

The role of antidepressants in the treatment of visceral pain has not been extensively examined. Milnacipran, a serotonin/noradrenalin reuptake inhibitor, has recently been approved in the USA for fibromyalgia, a chronic pathology characterized by diffused/chronic musculoskeletal pain, and a high prevalence of irritable bowel syndrome. Here, we determined its antinociceptive efficacy in two visceral pain tests in rodents: the acetic acid-induced writhing model in mice and the butyrate/colonic distension assay in rats, a model of irritable bowel syndrome. Acute milnacipran (5-40 mg/kgi.p.) significantly and dose-dependently reduced writhing (72.2 ± 3.2 versus 17.0 ± 4.1 writhes at 40 mg/kg). Following repeated administration (40 m/kgi.p. for 5 days), milnacipran preserved its ability to significantly reduce writhing (76 ± 8.3 versus 21.1 ± 6.7 writhes). Similarly, in the butyrate model, acute milnacipran (17.5 and 35 mg/kg, i.p.) significantly and dose-dependently increased cramps induction thresholds (from 45.7 ± 5.7 to 66.3 ± 4.8 and 75.6 ± 2.9 mm Hg, for 17.5 and 35 mg/kg, respectively) and reduced the number of cramps (from 3.0 ± 0.8 to 1.2 ± 0.8 and 0.3 ± 0.3 following inflation of an intra-rectal balloon. To summarise, milnacipran was efficacious in the writhing test, after acute and semi-chronic administration. This effect was confirmed after acute administration in a more specific model of colonic hypersensitivity induced by butyrate. This suggests that milnacipran has potential clinical application in the treatment of visceral pain, such as in irritable bowel syndrome, highly co-morbid with fibromyalgia.