The probiotic Bifidobacterium infantis 35624 displays visceral antinociceptive effects in the rat

Background Irritable bowel syndrome (IBS) is characterized by recurrent abdominal pain and altering bowel habit with a high percentage of patients displaying comorbid anxiety. Growing clinical and preclinical evidence suggests that probiotic agents may restore the altered brain–gut communication in IBS. In this study, we evaluated the efficacy of repeated treatment with three different probiotics in reducing visceral pain in visceral normosensitive (Sprague–Dawley [SD]) and visceral hypersensitive (Wistar–Kyoto [WKY]) rat strains. Methods Following 14 days oral gavage of Lactobacillus salivarius UCC118, Bifidobacterium infantis 35624, or Bifidobacterium breve UCC2003 both SD and WKY rats were exposed to a novel stress, the open field arena and their behavior was recorded. Subsequently, the effects of probiotics on visceral nociceptive responses were analyzed by recording pain behaviors during colorectal distension (CRD). Key Results It was found that there was a difference in the open field behavior between strains but none of the probiotic treatment altered behavior within each strain. Interestingly, the probiotic B. infantis 35624 but not others tested significantly reduced CRD‐induced visceral pain behaviors in both rat strains. It significantly increased the threshold pressure of the first pain behavior and also reduced the total number pain behaviors during CRD. Conclusions & Inferences These data confirm that probiotics such as B. infantis 35624 are effective in reducing visceral pain and may be effective in treating certain symptoms of IBS.     

Microbiote et dépression : une piste thérapeutique prometteuse

There is increasing evidence towards an interaction between the intestinal microbiota, gut, and central nervous system. Based on this compelling body of evidence, there is growing enthusiasm for research focused on translating this emerging association into novel therapies for psychiatric illnesses. The links between gut microbiota disturbances and brain dysfunction have clearly been demonstrated in rodents. Researchers have proven that gut microbiota plays a major role in the central nervous system development, and that germ-free mice (mice born by c-section and without microbiota) do develop severe behavioral disorders mimicking MD with social withdrawal, self-neglect, eating and sleep disorders, anxiety, as well as hopelessness. A recent study has demonstrated that this major depression phenotype could be transferable from one mouse to another through microbiota transplantation. Moreover, microbiota dysfunctions have been associated with peripheral immune inflammation as well as neuro-inflammation (also called microglia activation). Subjects with irritable bowel syndrome (IBS) display higher rates of comorbid MD. The gut microbiota of patients with Major Depression (MD) to be similar to that of patients with IBS-diarrhea subtype (IBS-D) in that sense that their gut microbiota was less diverse than that from healthy control samples, with similar abundances of alterations (high proportions of Bacteroides and Prevotella). IBS is currently considered to be the paradigmatic microbiota-related disorder. Another study found the MD groups exhibited increased levels of Enterobacteriaceae and Alistipes (nocive bacteria), though reduced levels of Faecalibacterium (healthy bacteria). In this study, a negative correlation was likewise observed between Faecalibacterium and severity of depressive symptoms. Alpha gut microbiota diversity within samples was associated with depressive severity in two studies. Another study found altered microbiota signatures in the gut microbiota of MD patients, including Bacteroidetes, Proteobacteria, Firmicutes, and Actinobacteria phyla and, more specifically, 16 bacterial families. Probiotics are microorganisms that, when consumed, contribute to the host gut microbial flora, thereby producing beneficial effects on health. Among several possibilities for MD treatment that have garnered substantial interest in recent times, probiotics hold particular appeal. The effectiveness of probiotic administration in MD constitutes a strong evidence for developing microbiota-orientated treatments in this indication. Probiotics have yielded medium-to-large significant effects in the setting of depression (d = −.73 [95% CI = −1.02; −.44]). Whereas the first study evaluating the therapeutic efficacy of prebiotics or probiotics on depression or anxiety was conducted over a decade ago, approximately half of all existing studies were published over the past two years, reflecting the rapidly growing interest in this area. Duration of probiotic administration across trials ranged from 8 days to 45 weeks, whereas it is still unclear if the effect is maintained following probiotic discontinuation.     

Tianeptine vs amitriptyline for the treatment of irritable bowel syndrome with diarrhea: a multicenter, open-label, non-inferiority, randomized controlled study

Background Tricyclic antidepressants have good efficacy in irritable bowel syndrome with diarrhea (IBS‐D), but their clinical use is limited by considerations of tolerability. Tianeptine, another antidepressant, acts as a selective serotonin reuptake enhancer. We compared tianeptine with amitriptyline for the treatment of patients with IBS‐D. Methods We undertook a multicenter, randomized, open‐label, non‐inferiority clinical study that compared tianeptine with amitriptyline, each in combination with probiotics, for the treatment of IBS‐D. Subjects were randomized to receive tianeptine (37.5 mg)/probiotics (Bacillus subtilis + Streptococcus faecium) or amitriptyline (10 mg)/probiotics (Bacillus subtilis + Streptococcus faecium) for 4 weeks. A total of 228 patients were analyzed by the intention‐to‐treat approach. The primary efficacy endpoint was the proportion of patients who had global relief of IBS symptoms at week 4. The secondary efficacy endpoints were intensity of abdominal pain/discomfort, stool frequency/consistency, quality of life, and overall satisfaction with treatment. Key Results At week 4, non‐inferiority of the tianeptine group to the amitriptyline group (treatment difference ?15.1%; 95% CI ?26.6% to ?3.8%) was shown, with 81.1% (99 of 122 patients) of the patients in the tianeptine group and 66.0% (70 of 106 patients) in the amitriptyline group reporting global relief of IBS symptoms. The secondary endpoints also demonstrated non‐inferiority of the tianeptine group to the amitriptyline group. Adverse events such as dry mouth and constipation were significantly lower in the tianeptine group than the amitriptyline group (P < 0.05). Conclusions & Inferences Tianeptine is not inferior to amitriptyline for treating IBS‐D in terms of both efficacy and tolerability.     

Pain in irritable bowel syndrome: Does anything really help?

Pain relief remains a significant challenge in the management of irritable bowel syndrome (IBS): “Does anything really help relieve the pain in patients with IBS?”. Interventions aimed at pain relief in patients with IBS include diet, probiotics or antibiotics, antidepressants, antispasmodics, and drugs targeting specific gastrointestinal receptors such as opioid or histamine receptors. In the systematic review and meta-analysis published in this journal, Lambarth et al. examined the literature on the role of oral and parenteral anti-neuropathic agents in the management of pain in patients with IBS. This review article appraises their assessment of the efficacy of the anti-neuropathic agents amitriptyline, pregabalin, gabapentin, and duloxetine in the relief of abdominal pain or discomfort, and impact on overall IBS severity and quality of life. This commentary provides an update of current evidence on the efficacy of the dietary and pharmacological treatments that are available or in development, as well psychological and cognitive behavioral therapy for pain in IBS. Advances in recent years augur well for efficacious treatments that may expand the therapeutic arsenal for pain in IBS.     

Food supplements and diet as treatment options in irritable bowel syndrome

Irritable bowel syndrome (IBS) is a chronic functional bowel disorder affecting 5.7% of the general population. Most patients relate their symptoms of IBS to foods they consume with diet being the most frequently reported factor impacting their life. However, although some foods may trigger symptoms, others may provide symptom relief. Indeed, several foods and diets have been investigated for their effectiveness in relieving IBS symptoms. In this issue of Neurogastroenterology and Motility, a double‐blind randomized placebo‐controlled trial in 160 patients with IBS demonstrated Aloe vera not to be effective in improving IBS symptoms. The aim of this review is to discuss the evidence on the effect of food supplements and diets in the management of IBS. Specifically, this review examines the evidence for aloe vera, peppermint oil, probiotics, fiber and prebiotics, healthy eating, the low FODMAP diet, and the gluten‐free diet.     

Is there a role of food allergy in irritable bowel syndrome and functional dyspepsia? A systematic review

A significant proportion of adults believe they suffer from food allergy, and 20-65% of patients with irritable bowel syndrome (IBS) attribute their symptoms to something in food that activates an abnormal response. This systematic review evaluates the role of food allergy in aetiology and management of these disorders. Activation of gastrointestinal mucosal immune system may be one of the causative factors in the pathogenesis of functional dyspepsia and IBS. This activation may result from effects of bacterial infection or other luminal factors including commensal microbial flora and food antigens. Some studies have reported on the role of food allergy in IBS; only one epidemiological study on functional dyspepsia and food allergy has been published. The mechanism by which food activates mucosal immune system is uncertain, but food specific IgE and IgG4 appeared to mediate the hypersensitivity reaction in a subgroup of IBS patients. Exclusion diets based on skin prick test, RAST for IgE or IgG4, hypoallergic diet and clinical trials with oral disodium cromoglycate have been conducted, and some success has been reported in a subset of IBS patients. Further well-controlled studies are needed to establish whether food allergy plays a role in the pathophysiology of functional dyspepsia and IBS.     

Effect of probiotic interventions on depressive symptoms: A narrative review evaluating systematic reviews

Depression is one of the most prevalent mental illnesses and is often associated with various other medical disorders. Since the 1980s, the primary pharmacological treatment has been antidepressants, but due to the recent discovery of the association between the gut microbiome and mental health, probiotics have been proposed as an adjunctive or alternate treatment. In this narrative review, we aim to provide a holistic perspective by synthesizing and evaluating existing evidence, discussing key biological mechanisms, exploring the history of probiotic use, and appreciating the influence of modern diet on mental health. Five online databases were searched for relevant studies up to December 2017. Systematic reviews that included randomized controlled trials assessing the efficacy of probiotics in the treatment of depressive symptoms were included. Seven systematic reviews met the inclusion criteria. Three of these reviews conducted meta‐analyses, out of which, two concluded that probiotics improved depressive symptoms in the sample population. Out of the four reviews that conducted qualitative analysis, three reviews concluded that probiotics have the potential to be used as a treatment. Due to the differences in clinical trials, a definitive effect of probiotics on depressive symptoms cannot be concluded. Nonetheless, probiotics seem to potentially produce a significant therapeutic effect for subjects with pre‐existing depressive symptoms. Further studies are warranted for definitive conclusions.     

The Association of Irritable Bowel Syndrome and Somatization Disorder

Background and objective: Irritable bowel syndrome (IBS) and somatization disorder (SD) are defined by nonobjective symptoms that overlap considerably. Psychiatric symptoms associated with IBS may originate from SD in IBS patients. Previous studies of IBS have not considered SD separately from IBS. Methods: This study explored psychiatric symptoms and illness behavior in IBS in relation to SD. A total of 50 outpatients with IBS or ulcerative colitis (UC) were evaluated with the Diagnostic Interview Schedule and Illness Behavior Questionnaire. Results: Definite or probable SD was diagnosed in no UC patients and in 42% of IBS patients (confirmed in 25% and lacking one symptom in another 17%). IBS patients with probable or definite SD, but not those without SD, reported more psychiatric symptoms and abnormal illness behaviors than did UC patients. SD accounted for the association of psychiatric symptoms with IBS. Conclusions: In this university-based office setting, the association of psychiatric features with IBS appears heterogeneous predicated on whether SD is present. Future studies of functional bowel diseases should distinguish between patients with and without SD to clarify its relationship to these disorders. Clinicians should consider whether patients with functional disorders have SD, a diagnosis that indicates specific clinical management strategies.     

Mental imagery,emotion and psychopathology across child and adolescent development

Mental imagery-based interventions are receiving increasing interest for the treatment of psychological disorders in adults. This is based on evidence that mental imagery potently influences the experience of emotion in non-clinical samples, and that a number of psychological disorders are marked by syndrome-specific, distressing abnormalities in mental imagery.During childhood and adolescence, neurocognitive development impacting mental imagery processes may moderate its relationship with clinically-relevant emotional symptoms at a number of potential loci. Crucially, these changes could impact vulnerability to distressing mental imagery and the efficacy of mental imagery-based clinical interventions. This review synthesises evidence pertaining to developmental changes in the role and content of mental imagery, and in the cognitive sub-processes required to generate and sustain mental images. Subsequently, we discuss implications for understanding the developmental relationship between mental imagery, emotion and psychopathology.Translational cognitive neuroscience research investigating the content, emotional impact and neurocognitive substrates of mental imagery across development may reveal insights into trajectories of vulnerability to symptoms of a number of psychological disorders. If proper consideration is given to developmental factors, techniques based on mental imagery may be valuable as part of a treatment armoury for child and adolescent clinical populations and those at risk of emotional disorders.     

Gut memories: towards a cognitive neurobiology of irritable bowel syndrome

The brain and the gut are engaged in continual crosstalk along a number of pathways collectively termed the ‘brain-gut axis’. Over recent years it has become increasingly clear that dysregulation of the axis at a number of levels can result in disorders such as irritable bowel syndrome (IBS). With recent advances in neuroimaging technologies, insights into the neurobiology of IBS are beginning to emerge. However the cognitive neurobiology of IBS has remained relatively unexplored to date. In this review we summarise the available data on cognitive function in IBS. Moreover, we specifically address three key pathophysiological factors, namely; stress, immune activation and chronic pain, together with other factors involved in the manifestation of IBS, and explore how each of these components may impact centrally, what neurobiological mechanisms might be involved, and consider the implications for cognitive functioning in IBS. We conclude that each factor addressed could significantly impinge on central nervous system function, supporting the view that future research efforts must be directed towards a detailed assessment of cognitive function in IBS.     

Platelets as immune mediators: their role in host defense responses and sepsis

Platelets occupy a central role at the interface between thrombosis and inflammation. At sites of vascular damage, adherent platelets physically and functionally interact with circulating leukocytes. Activated platelets release soluble factors into circulation that may have local and systemic effects on blood and vascular cells. Platelets can also interact with a wide variety of microbial pathogens. Emerging evidence from animal models suggests that platelets may participate in a wide variety of processes involving tissue injury, immune responses and repair that underlie diverse diseases such as atherosclerosis, autoimmune disorders, inflammatory lung and bowel disorders, host-defense responses and sepsis. In this review, we summarize the general mechanisms by which platelets may contribute to immune function, and then discuss evidence for their role in host defense responses and sepsis from preclinical and clinical studies.     

How statins could be evaluated successfully in clinical trials for Alzheimer's disease?

Over the last decade, a large number of experimental observations have suggested a relationship between alterations in cholesterol homeostasis and Alzheimer's disease (AD). Moreover, epidemiological studies have pointed an association between statin treatment and a decrease in the risk of having AD. For these reasons, a large number of clinical trials have been carried out to determine whether the statins can prevent the progression of AD. However, these studies did not provide clear evidence for the therapeutic efficacy in AD. We consider that there are a number of explanations for this failure that may provide guidance for selecting and clinically developing statins with therapeutic efficacy in AD.     

Respiratory dysregulation in anxiety, functional cardiac, and pain disorders. Assessment, phenomenology, and treatment

Respiration is a complex physiological system affecting a variety of physical processes that can act as a critical link between mind and body. This review discusses the evidence for dysregulated breathing playing a role in three clinical syndromes: panic disorder, functional cardiac disorder, and chronic pain. Recent technological advances allowing the ambulatory assessment of endtidal partial pressure of CO2 (PCO2) and respiratory patterns have opened up new avenues for investigation and treatment of these disorders. The latest evidence from laboratories indicates that subtle disturbances of breathing, such as tidal volume instability and sighing, contribute to the chronic hypocapnia often found in panic patients. Hypocapnia is also common in functional cardiac and chronic pain disorders, and studies indicate that it mediates some of their symptomatology. Consistent with the role of respiratory dysregulation in these disorders, initial evidence indicates efficacy of respiration-focused treatment.     

Development of drugs for gastrointestinal motor disorders: translating science to clinical need.

Only a small number of new drugs have recently become available for gastrointestinal (GI) disorders. This is partly because we await outcomes of research into functional bowel disorder aetiology (e.g., role of microbiota) and of trials to control stress- related or painful GI symptoms (e.g., via CRF(1) receptors or beta(3) adrenoceptors). Nevertheless, only the ClC-2 channel activator lubiprostone has recently reached the clinic, joining the 5-HT(3) antagonist alosetron and the long-established 5-HT(4) agonist and D(2) antagonist metoclopramide; tegaserod, a non-selective ligand, was withdrawn. Interestingly, each has shortcomings, providing opportunities for molecules with 5-HT(4) or motilin receptor selectivity, and for new biology via guanylate cyclase C or ghrelin receptor activation. For translation into new drugs, the molecule must have appropriate efficacy, selectivity and pharmacodynamic properties. It is argued that the compound must then be evaluated in conditions where changes in motility are known to exist, before considering more difficult symptomatic conditions such as irritable bowel syndrome (IBS) or functional dyspepsia (FD), where relationships with disordered motility are unclear. Thus, it may be better to begin studying a gastric prokinetic in diabetics requiring improved glucose control, rather than in FD. Notably, new 5-HT(4) receptor agonists are being evaluated firstly as treatments of constipation, not IBS. New antidiarrhoeal agents should be developed similarly. Thus, progression of new drugs may require initial studies in smaller patient populations where clinical outcome is better defined. Only then can disease-related ideas be properly tested and drugs brought forward for these disorders (with high clinical need) and then, if successful for IBS and FD.     

Transcranial Magnetic Stimulation in Neurology: What We Have Learned From Randomized Controlled Studies

Background. Initially developed to excite peripheral nerves, magnetic stimulation was quickly recognized as a valuable tool to noninvasively activate the cerebral cortex. The subsequent discovery that repetitive transcranial magnetic stimulation (rTMS) could have long‐lasting effects on cortical excitability spawned a broad interest in the use of this technique as a new therapeutic method in a variety of neuropsychiatric disorders. Although the current outcomes from initial trials include some conflicting results, initial evidence supports that rTMS might have a therapeutic value in different neurologic conditions. Methods. We reviewed the results of clinical trials of rTMS on four different disorders: stroke, Parkinson's disease, chronic refractory pain, and epilepsy. We reviewed randomized, controlled studies only in order to obtain the strongest evidence for the clinical effects of rTMS. Results. An extensive literature review revealed 32 articles that met our criteria. From these studies, we found evidence for the therapeutic efficacy of rTMS, particularly in the relief of chronic pain and motor neurorehabilitation in single hemisphere stroke patients. Repetitive TMS also seems to have a therapeutic effect on motor function in Parkinson's disease, but the evidence is somewhat confounded by the uncontrolled variability of multiple factors. Lastly, only two randomized, sham‐controlled studies have been performed for epilepsy; although evidence indicates rTMS may reduce seizure frequency in patients with neocortical foci, more research is needed to confirm these initial findings. Conclusions. There is mounting evidence for the efficacy of rTMS in the short‐term treatment of certain neurologic conditions. More long‐term research is needed in order to properly evaluate the effects of this method in a clinical setting.     

Hypnosis and irritable bowel syndrome: a review of efficacy and mechanism of action

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain, distension, and an altered bowel habit for which no cause can be found. Despite its prevalence, there remains a significant lack of efficacious medical treatments for IBS to date. In this paper we reviewed a total of 14 published studies (N=644) on the efficacy of hypnosis in treating IBS (8 with no control group and 6 with a control group). We concluded that hypnosis consistently produces significant results and improves the cardinal symptoms of IBS in the majority of patients, as well as positively affecting non-colonic symptoms. When evaluated according to the efficacy guidelines of the Clinical Psychology Division of American Psychological Association, the use of hypnosis with IBS qualifies for the highest level of acceptance as being both efficacious and specific. In reviewing the research on the mechanism of action as to how hypnosis works to reduce symptoms of IBS, some evidence was found to support both physiological and psychological mechanisms of action.     

The role of microbiome in central nervous system disorders

Mammals live in a co-evolutionary association with the plethora of microorganisms that reside at a variety of tissue microenvironments. The microbiome represents the collective genomes of these co-existing microorganisms, which is shaped by host factors such as genetics and nutrients but in turn is able to influence host biology in health and disease. Niche-specific microbiome, prominently the gut microbiome, has the capacity to effect both local and distal sites within the host. The gut microbiome has played a crucial role in the bidirectional gut–brain axis that integrates the gut and central nervous system (CNS) activities, and thus the concept of microbiome–gut–brain axis is emerging. Studies are revealing how diverse forms of neuro-immune and neuro-psychiatric disorders are correlated with or modulated by variations of microbiome, microbiota-derived products and exogenous antibiotics and probiotics. The microbiome poises the peripheral immune homeostasis and predisposes host susceptibility to CNS autoimmune diseases such as multiple sclerosis. Neural, endocrine and metabolic mechanisms are also critical mediators of the microbiome–CNS signaling, which are more involved in neuro-psychiatric disorders such as autism, depression, anxiety, stress. Research on the role of microbiome in CNS disorders deepens our academic knowledge about host-microbiome commensalism in central regulation and in practicality, holds conceivable promise for developing novel prognostic and therapeutic avenues for CNS disorders.     

Intestinal barrier function in health and gastrointestinal disease

Defects in intestinal barrier function are associated with diseases of the gastrointestinal (GI) tract. There is growing evidence that increases in intestinal permeability plays a pathogenic role in diseases, such as inflammatory bowel disease (IBD) and celiac disease, and functional bowel disorders, such as irritable bowel syndrome (IBS). This review takes a unique translational approach to discuss the physiological and pathophysiological mechanisms involved in the regulation of intestinal barrier function in IBS. The review summarizes the components of the intestinal barrier including the tight junction complex within the epithelium, and the methods used to assess gut permeability both in vitro and in vivo. Throughout the review, the authors have attempted to critically review the latest research from both experimental animal models and human studies to appraise whether intestinal barrier dysfunction is a primary cause of functional GI disorders, such as IBS.…     

Melancholic microbes: a link between gut microbiota and depression?

There is a growing awareness of the potential for microbiota to influence gut‐brain communication in health and disease. A variety of strategies have been used to study the impact of the microbiota on brain function and these include antibiotic use, probiotic treatments, fecal microbiota transplantation, gastrointestinal infection studies, and germ‐free studies. All of these approaches provide evidence to support the view that the microbiota can influence brain chemistry and consequently behavior. Efforts are now turning to investigate the role of microbiota in animal models of psychopathology. Animal models of depression are thus essential in studying the complex interplay between the microbiota and brain. Recent studies published in this Journal and elsewhere demonstrate that there is a distinct perturbation of the composition of gut microbiota in animal models of depression and chronic stress. This has direct implications for the development of psychobiotic‐based therapeutic strategies for psychiatric disorders. Moreover, given that affective co‐morbidities, such as major depression and anxiety states, are common in patients presenting with irritable bowel syndrome (IBS), it may have implications for functional bowel disorders also. Further studies require appropriately phenotyped patients with depression and/or IBS using a judicious use of techniques including functional imaging and in depth microbial pyrosequencing.     

When the microbiome helps the brain-current evidence

The gut microbiota-brain axis has been recognized as a network of connections that provides communication between the gut microflora and both central and autonomic nervous system. The gut microbiota alteration has been targeted for therapy in various neurodegenerative and psychiatric disbalances. Psychobiotics are probiotics that contribute beneficially to the brain function and the host mental health as a result of an interaction with the commensal gut bacteria, although their mechanism of action has not been completely revealed. In this state-of-art review, the findings about the potential therapeutic effects of the psychobiotics alone or in combination with conventional medicine in the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, as well as in some psychiatric diseases like depression, schizophrenia, and bipolar disorder, have been summarized. The evidence of the psychobiotics therapeutic outcomes obtained in preclinical and clinical trials have been given respectively for the observed neurodegenerative and psychiatric disorders.