肠道菌群失衡与肠易激综合征

肠易激综合征（irritable bowel syndrome, IBS）是一种常见的功能性胃肠道疾病,其发病机制目前尚不完全清楚,但有越来越多的证据表明IBS可能与肠道菌群谱的改变有关。本文就IBS患者存在的结肠菌群失衡、小肠细菌过度生长及它们可能的致病机制,以及干预肠道菌群失衡等的治疗手段作一综述。     

The shifting interface between IBS and IBD

Recent data developing from the study of postinfectious IBS has challenged the belief that IBS is a purely psychological disorder. Distinct abnormalities of the gut mucosa have been reported including immune activation and increased release of inflammatory mediators with some overlap with IBD. New studies show that genetic factors which predispose to IBD are also associated with IBS. A common feature is impaired gut barrier function which appears to precede the development of IBD while in IBS it may be the result of either a preceding infection or psychosocial stress. Stress can activate mast cells which are a feature in most but not all IBS series. Anti-inflammatory treatments targeting activated mast cells may benefit IBS patients but currently the evidence is weak and larger trials are needed. Changes in the commensal microbiota have been recently described with a "dysbiosis" in CD characterised by reduced diversity. Inconsistent changes have also been described in IBS but studies controlling for antibiotic use and differences in diet and bowel habit are needed before definitive conclusions can be made.     

Rifaximin for the treatment of irritable bowel syndrome – a drug safety evaluation

ABSTRACT

Introduction: Irritable bowel syndrome is a functional gastrointestinal disorder with a multifactorial etiology. Alterations of intestinal motility and immunity, gut-brain interactions, as well as gut microbiota dysbiosis contribute to the development of irritable bowel syndrome. Therefore, gut microbiota modulation by non-absorbable antibiotics is a therapeutic option in patients with IBS.

Areas covered: Published articles including patients with irritable bowel syndrome reporting data about rifaximin activity and safety have been searched throughout the literature and selected.

Expert opinion: The optimal antibiotic molecule should be local-acting, long-acting and safe-acting. Rifaximin is a non-absorbable antibiotic with additional anti-inflammatory and gut microbiota-modulating activity. It is effective in inducing symptoms relief in patients with IBS, even after repeated treatment courses. Rifaximin-related side effects in patients with IBS are reported to be mild and infrequent; microbial resistance is rare and transient, due to the high local concentration of the drug and to the absence of horizontal transmission. Clostridium difficile infection is not usual in patients receiving rifaximin in absence of predisposing conditions such as hospitalization and immunosuppression, which are uncommon in patients affected by irritable bowel syndrome. Nevertheless rifaximin is an antibiotic active against Clostridium difficile infection. Rifaximin has limited metabolic interactions and is not expected to interfere with drug metabolism in patients with normal hepatic function. These properties make rifaximin a safe antibiotic for gut microbiota modulation in patients with IBS.     

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.     

Rationale for using serotonergic agents to treat irritable bowel syndrome.

PURPOSE: The role of serotonin in gastrointestinal (GI)-tract functioning, the pharmacologic rationale for using serotonergic agents in the treatment of irritable bowel syndrome (IBS), and clinical experience with novel serotonergic agents are described. SUMMARY: IBS is a common multisymptom disorder that is associated with a high socioeconomic burden. The goal of treatment is to provide rapid and sustained global relief of the multiple symptoms of IBS with a single, effective, well-tolerated agent. Traditional treatment options target single symptoms, and many patients are dissatisfied with the level of relief achieved and adverse effects. Research has revealed that serotonin is involved in three major actions in the gut: (1) mediating intestinal motility, (2) mediating intestinal secretion in the GI tract, and (3) modulating perception in the bowels. Serotonin is also a vital link in the brain-gut axis. Alterations in key elements of serotonin signaling have been demonstrated in patients with IBS. Tegaserod, a selective serotonin type 4 (5-HT(4))-receptor partial agonist, is indicated for use in women with IBS whose primary bowel symptom is constipation. Alosetron, a 5-HT(3)-receptor antagonist, is indicated for use in women with severe diarrhea-predominant IBS in whom traditional therapies have failed. The clinical usefulness of several other serotonergic agents for IBS is being investigated. CONCLUSION: The use of serotonergic agents in patients with IBS is based on the critical role that serotonin plays in the maintenance of normal gut function and brain-gut communication. Pharmacologic therapies targeting specific serotonin receptors represent an important step in the management of IBS.     

Maternal separation as a model of brain–gut axis dysfunction

Rationale  

Early life stress has been implicated in many psychiatric disorders ranging from depression to anxiety. Maternal separation in rodents is a well-studied model of early life stress. However, stress during this critical period also induces alterations in many systems throughout the body. Thus, a variety of other disorders that are associated with adverse early life events are often comorbid with psychiatric illnesses, suggesting a common underlying aetiology. Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that is thought to involve a dysfunctional interaction between the brain and the gut. Essential aspects of the brain–gut axis include spinal pathways, the hypothalamic pituitary adrenal axis, the immune system, as well as the enteric microbiota. Accumulating evidence suggest that stress, especially in early life, is a predisposing factor to IBS.     

Enterochromaffin cells and 5-HT signaling in the pathophysiology of disorders of gastrointestinal function

Disorders of gastrointestinal function are common and significantly reduce quality-of-life, as well as negatively impacting healthcare costs. Consequently, there is much interest in understanding the pathogenesis of these disorders. Increasing, albeit as yet limited, evidence has implicated alterations in 5-hydroxytryptamine (5-HT) release, and the subsequent interaction of 5-HT with specific 5-HT receptor subtypes, in the altered gut function of patients with irritable bowel syndrome (IBS) and other functional bowel diseases. Alterations to enterochromaffin cells and/or 5-HT signaling can result in gastrointestinal dysmotility, visceral hypersensitivity and secretomotor abnormalities in the gut. Evidence is beginning to link disturbed 5-HT physiology with the pathophysiology of diarrhea and constipation in IBS, and with slow-transit constipation. This review discusses the current evidence on the pathobiology of these systems.     

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.     

Altered peripheral toll-like receptor responses in the irritable bowel syndrome

Aliment Pharmacol Ther 2011; 33: 1045–1052

Summary

Background Irritable bowel syndrome (IBS) is a stress‐related disorder with disturbed brain‐gut communication, gastrointestinal homeostasis and, based on recent evidence, low grade inflammation and an altered microbiota. The immune system is a critical regulator of the brain‐gut axis. Toll‐like receptors (TLRs) are pattern recognition molecules regulating innate immunity. Aim To characterise toll‐like receptor activity in IBS. Methods Thirty IBS patients and 30 healthy controls (HC) were recruited. Venous blood was collected, and cultured with a panel of toll‐like receptor agonists for 24 h. Cell supernatants were analysed using a multiplex ELISA approach to measure IL1β, IL6, IL8 and TNFα. Plasma was analysed for levels of inflammatory cytokines and cortisol. Results Toll‐like receptor agonist‐induced cytokine (IL1β, IL6, IL8 and TNFα) release was markedly enhanced in stimulated whole blood from IBS (n = 30) patients compared with healthy controls (n = 30). An exaggerated response to the TLR8 agonist for all cytokines investigated was seen in IBS patients. In addition, enhanced TLR2‐induced TNFα release, TLR3‐induced IL‐8 release, TLR4‐induced IL1β and TNFα release, TLR5‐induced IL1β and TNFα release and TLR7‐induced IL‐8 release were also observed in IBS patients. No differences in TLR1, TLR6 or TLR9 activity were detected. In addition, plasma levels of cortisol, IL‐6 and IL‐8 were significantly increased in IBS patients. Conclusion Taken together, these data demonstrate elevated cytokine levels and toll‐like receptor activity in the periphery of patients with the irritable bowel syndrome, indicating some immune dysregulation in these patients.     

Emerging drugs for irritable bowel syndrome

Irritable bowel syndrome (IBS) is one of the most common chronic gastrointestinal disorders, yet its pathophysiology is incompletely understood and pharmacological treatments remain unsatisfactory. Current therapeutic choices include a range of drugs aimed at normalising bowel habits, reducing pain or treating comorbid psychological symptoms. However, this individual symptom-targeted approach remains unsatisfactory in terms of global symptom relief and patient satisfaction. In the last decade, further characterisation of IBS pathophysiology has provided new and exciting targets at different levels of the brain–gut axis for the development of several candidate drugs. Advances in clinical trial design will help to evaluate these compounds in different IBS patient populations.     

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.     

Drug treatment options for irritable bowel syndrome: managing for success

Irritable bowel syndrome (IBS) is a functional gut disorder the diagnosis of which is based on clinical symptoms as set forth by the Rome criteria. As the population ages, especially with the population of patients >75 years of age expanding greatly over the next 10 years, IBS is becoming one of the most common diseases of the elderly. Thus far, developing treatment strategies for patients with IBS has been difficult because of the lack of pharmacological targets and the wide range of symptomatology. Additionally, demonstration of a therapeutic benefit is difficult in the presence of a high placebo response observed regardless of the therapy employed. Fibre, antidiarrhoeals and antispasmodics all play some role in the symptomatic treatment of IBS. With the evolution of IBS as a disorder of visceral hypersensitivity, new drugs have been developed that target the enteric nervous system. Tricyclic antidepressants (TCAs) have been found to target the enteric neurons and play a role in pain modulation. Currently, the TCAs are recommended only for severe cases of IBS pain. The newest class of drugs to be approved for use in IBS are the serotonin (5-hydroxytryptamine; 5-HT) antagonists. Specifically, the 5-HT3 receptor antagonists have been shown to decrease symptoms in female patients with IBS. A related class of drugs, the 5-HT4 receptor agonists, is being developed for the treatment of constipation-predominant IBS. Further investigation into the role of spinal afferent neurons in visceral hypersensitivity is at the forefront of IBS research. Several experimental drug therapies for IBS are also discussed in this review including N-methyl-D-aspartate receptor antagonists, neurokinin-1 receptor antagonists, octreotide, clonidine and the selective M3 receptor antagonist, zamifenacin.     

Change over time of bowel habit in irritable bowel syndrome: a prospective, observational, 1-year follow-up study (RITMO study)

BACKGROUND: Evolution of bowel habit in irritable bowel syndrome (IBS) is not well known. AIM: To evaluate the change over time of bowel habit in IBS patients followed-up during 1 year. METHODS: Five hundred and seventeen patients with IBS were prospectively included in an observational study with five evaluations over a 1-year period. Symptoms were recorded daily in diary cards during four 4-week periods along the study. Bristol Stool Scale (BSS) was used to define bowel habit. RESULTS: Four-hundred patients completed the study. Rome II showed low-moderate agreement (42%) with BSS to define bowel habit. Frequency of constipation and diarrhoea showed little changes throughout the study. Over 50% of the patients had the same bowel habit when each diary was compared with the next one. A third of patients maintained the same habit throughout the study. Most changes occurred from/to mixed or unsubtyped IBS. Only 14% of cases changed from constipation to diarrhoea or vice versa. This change was associated to female gender (OR: 2.65). CONCLUSIONS: The frequency of constipation and diarrhoea remains relatively stable over time. Changes in IBS subtypes are common, but changes between constipation and diarrhoea are rare. Alternating IBS is more frequent in women.     

Randomised clinical trial: Bifidobacterium bifidum MIMBb75 significantly alleviates irritable bowel syndrome and improves quality of life--a double-blind, placebo-controlled study

Aliment Pharmacol Ther 2011; 33: 1123–1132

Summary

Background Recent research suggests that an imbalance of the intestinal microbiota and a dysfunctional intestinal barrier might trigger irritable bowel syndrome (IBS). As probiotics have been reported to restore the intestinal microbiota and the gut barrier, the therapeutic potential of probiotics within IBS became of strong interest. Aim To assess the efficacy of Bifidobacterium bifidum MIMBb75 in IBS. Methods A total of 122 patients were randomised to receive either placebo (N = 62) or MIMBb75 (N = 60) once a day for 4 weeks. The severity of IBS symptoms was recorded daily on a 7‐point Likert scale. Results MIMBb75 significantly reduced the global assessment of IBS symptoms by ?0.88 points (95% CI: ?1.07; ?0.69) when compared with only ?0.16 (95% CI: ?0.32; 0.00) points in the placebo group (P < 0.0001). MIMBb75 also significantly improved the IBS symptoms pain/discomfort, distension/bloating, urgency and digestive disorder. The evaluation of the SF12 sum scores showed a significant gain in quality of life within the bifidobacteria group. Furthermore, adequate relief was reported by 47% of the patients in the bifidobacteria and only by 11% of the patients in the placebo group (P < 0.0001). Overall responder rates were 57% in the bifidobacteria group but only 21% in the placebo group (P = 0.0001). MIMBb75 was well tolerated and adverse events were not different from placebo. Conclusions Bifidobacterium bifidum MIMBb75 effectively alleviates global IBS and improves IBS symptoms simultaneously with an improvement of quality of life. Considering the high efficacy of MIMBb75 in IBS along with the good side‐effect profile, MIMBb75 is a promising candidate for IBS therapy.

     

Rifaximin for the treatment of diarrhoea-predominant irritable bowel syndrome

Introduction: Rifaximin is a non-absorbable, semisynthetic antibiotic that acts as an inhibitor of bacterial RNA synthesis, with a broad spectrum of antibacterial activity. Due to its poor absorption, rifaximin has an increased exposure to the intestine, thus it is suitable for the treatment of many gastrointestinal (GI) diseases. In irritable bowel syndrome (IBS) pathogenesis, gut microbiota impairment may play a major role. The possibility of modulating intestinal bacteria using antibiotics, in particular, rifaximin, has been demonstrated to improve IBS symptoms in non-constipation subtypes of IBS.

Areas covered: We reviewed the use of rifaximin in diarrhoea-predominant IBS, focusing on its pharmacokinetic characteristics, its absorption in GI disease, its lack of interaction with other drugs and its new extended release formulation.

Expert opinion: Rifaximin, with its low systemic absorption and no clinically significant interactions with other drugs, may represent a treatment of choice for IBS, mainly due to its ability to act on IBS pathogenesis, through the modulation of gut microbiota. Further studies to analyse the effect of rifaximin treatment on the composition of faecal microbiota are warranted. In particular, they need to evaluate whether resistant bacterial strains are selected and whether they are still present in the faecal sample even a long time after therapy.     

Mesalazine (5-aminosalicylic acid) alters faecal bacterial profiles, but not mucosal proteolytic activity in diarrhoea-predominant irritable bowel syndrome

Aliment Pharmacol Ther 2011; 34: 374–383

Summary

Background Imbalances in gut luminal bacteria may contribute to the pathogenesis of irritable bowel syndrome (IBS). Aim To explore select bacteriological and anti‐inflammatory effects of mesalazine (mesalamine; 5‐aminosalicylic acid or 5ASA) and their relation to potential therapeutic effects in IBS. Methods Prospective pilot study of 12 women with diarrhoea‐predominant IBS. Patients received oral mesalazine (1.5 g b.d.) for 4 weeks followed by a 4‐week washout phase. Molecular profiling of stool bacterial communities and IBS symptoms were assessed before, during and after mesalazine treatment. Colonic mucosal biopsies were assessed for proteolytic activity. Qualitative and quantitative effects of mesalazine on stool microbiota, mucosal proteolytic activity and IBS symptoms were assessed. Results Faecal bacteria decreased by 46% on mesalazine treatment (P = 0.014), but returned to baseline during washout. Firmicutes and Bacteroidetes represented 95% of identified phylotypes, with a trend towards an increase in the proportion of Firmicutes at week 4 in symptomatic responders [median (IQR) 14% (49) increase] compared with nonresponders [median 5% (11) decrease, P = 0.088]. Rectosigmoid mucosal proteolytic activity did not change between baseline and treatment [median 23.2 (17.9) vs. 19.5 (46.7) mU activity/mg tissue, P = 0.433]. Eight of 12 (67%) patients responded favourably to mesalazine based on a global relief questionnaire, with significant decreases in days with discomfort and increases in bowel movement satisfaction. Conclusions Mesalazine treatment is associated with a decrease in faecal bacteria abundance and rebalancing of the major constituents of the microbiota. Further study of the bacteriological and anti‐inflammatory properties of mesalazine in IBS is warranted.     

Review article: faecal transplantation therapy for gastrointestinal disease

Aliment Pharmacol Ther 2011; 34: 409–415

Summary

Background Evidence is emerging regarding the relationship between a dysbiosis of the human gut microbiota and a number of gastrointestinal diseases as well as diseases beyond the gut. Probiotics have been investigated in many gastrointestinal disease states, with variable and often modest outcomes. Faecal transplantation is an alternative approach to manipulate the gut microbiota. Aim To review the use of faecal transplantation therapy for the management of gastrointestinal disorders. Methods Available articles on faecal transplantation in the management of gastrointestinal disorders were identified using a Pubmed search and bibliographies of review articles on the subject were collated. Results A total of 239 patients who had undergone faecal transplantation were reported. Seventeen of 22 studies of faecal transplantation were in fulminant or refractory Clostridium difficile. Studies of faecal transplantation are heterogeneous regarding the patients, donors, screening, methods of administration and definition of response. Faecal transplantation for C. difficile has been demonstrated to be effective in 145/166 (87%) patients. Small numbers of patients are reported to have undergone successful faecal transplantation for irritable bowel syndrome and inflammatory bowel disease. Conclusions Faecal transplantation has been reported with good outcomes for fulminant and refractory C. difficile. No adverse effects of faecal transplantation have been reported. However, there are no level 1 data of faecal transplantation and reports to date may suffer from reporting bias of positive outcomes and under‐reporting of adverse effects. This therapy holds great promise, where a dysbiosis of the gut microbiota is responsible for disease and further studies are necessary to explore this potential.     

肠道菌群与川崎病

川崎病(KD)是一种儿童急性发热性全身性中、小动脉炎,是儿童获得性心脏病最常见的原因,其主要特征为免疫紊乱和全身性血管炎.以婴幼儿多见,其病因及发病机制不明,与感染、遗传及环境因素相关.近年来研究表明,KD病人存在肠道菌群紊乱,导致了肠道屏障功能破坏和自身免疫激活.作者对KD的肠道菌群研究做一综述,探讨菌群干预作为KD...     

Irritable bowel syndrome: patients' attitudes, concerns and level of knowledge

BACKGROUND: Irritable bowel syndrome (IBS) is a common, chronic disorder that reduces patients' quality-of-life. Although highly prevalent, little is known about patients' understanding of this disorder. AIM: To evaluate the knowledge, fears and concerns of IBS patients. METHODS: Seven hundred thirty-six IBS patients (Rome II criteria) were eligible for inclusion in this prospective study. Each patient received a validated questionnaire to evaluate knowledge, attitudes and fears regarding IBS. RESULTS: A total of 261 of 664 potential respondents completed the questionnaire (39.3%). 83% of respondents were women, with a mean age of 53.7 years, and mean duration of symptoms of 14.2 years. Patients frequently believed that IBS develops because of anxiety (80.5%), dietary factors (75.1%) and depression (63.2%). Few respondents (28.7%) recognized that abdominal pain is the cardinal symptom of IBS, and 40.6% stated that colonoscopy can diagnose IBS. One in seven patients stated that IBS turns into cancer, and 29.9% noted that IBS increases the risk of inflammatory bowel disease. CONCLUSIONS: Many IBS patients have significant misconceptions regarding the nature of their disease and its prognosis. An overwhelming majority of IBS patients believe that anxiety, dietary factors and depression cause IBS. These findings are discordant with physicians' views and practices and highlight the need for patient-oriented educational programs.     

Atypical antipsychotics as a possible treatment option for irritable bowel syndrome

Introduction: Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder (FGID) that is characterised by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits. Although the pathophysiology of IBS is not fully understood, it is believed that psychiatric comorbidities are highly common in such patients. A variety of psychotropic medications are widely used in the treatment of IBS, particularly older antidepressants such as tricyclic antidepressants (TCAs).

Areas covered: With the advent of newer antidepressant classes with better safety and tolerability compared with TCAs, such as serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), clinicians now have more advanced treatment options for treating IBS. Additionally, some atypical antipsychotics (AAs) have recently received approval for treatment of major depressive disorder (MDD). Some AAs may have potentials based on their pharmacodynamic profile and proven benefit for mood symptoms, pain, anxiety and sleep disturbances. This article describes the potential rationale, clinical data and practical aspects involved in the use of AAs for patients with IBS.

Expert opinion: Atypical antipsychotics (AAs) may have a role in the treatment of irritable bowel syndrome (IBS) based on the currently available findings, although there is no clear evidence, and a number of clinical issues to be addressed in the use of AAs for the treatment of IBS.