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Irritable Bowel Syndrome, Fat-Soluble Nutrients, Metabolic Syndrome, and Oral Anticoagulants

July 2015

By Life Extension

Irritable Bowel Syndrome

Irritable bowel syndrome: a microbiome-gut-brain axis disorder?

Irritable bowel syndrome (IBS) is an extremely prevalent but poorly understood gastrointestinal disorder. Consequently, there are no clear diagnostic markers to help diagnose the disorder and treatment options are limited to management of the symptoms. The concept of a dysregulated gut-brain axis has been adopted as a suitable model for the disorder. The gut microbiome may play an important role in the onset and exacerbation of symptoms in the disorder and has been extensively studied in this context. Although a causal role cannot yet be inferred from the clinical studies which have attempted to characterise the gut microbiota in IBS, they do confirm alterations in both community stability and diversity. Moreover, it has been reliably demonstrated that manipulation of the microbiota can influence the key symptoms, including abdominal pain and bowel habit, and other prominent features of IBS. A variety of strategies have been taken to study these interactions, including probiotics, antibiotics, faecal transplantations and the use of germ-free animals. There are clear mechanisms through which the microbiota can produce these effects, both humoral and neural. Taken together, these findings firmly establish the microbiota as a critical node in the gut-brain axis and one which is amenable to therapeutic interventions.

World J Gastroenterol. 2014 Oct 21;20(39): 14105-25

Brain and gut interactions in irritable bowel syndrome: new paradigms and new understandings.

Irritable bowel syndrome (IBS) is characterized by abdominal pain and altered bowel habits. Visceral hypersensitivity is believed to be a key underlying mechanism that causes pain. There is evidence that interactions within the brain and gut axis (BGA), that involves both the afferent-ascending and the efferent-descending pathways, as well as the somatosensory cortex, insula, amygdala, anterior cingulate cortex, and hippocampus, are deranged in IBS showing both the activation and inactivation. Clinical manifestations of IBS such as pain, altered gut motility, and psychological dysfunction may each be explained, in part, through the changes in the BGA, but there is conflicting information, and its precise role is not fully understood. A better understanding of the BGA may shed more knowledge regarding the pathophysiology of IBS that in turn may lead to the discovery of novel therapies for this common disorder.

Curr Gastroenterol Rep. 2014 Apr;16(4):379

Brain-Gut Interactions in IBS.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder with an estimated prevalence of 10-20%. Current understanding of the pathophysiology of IBS is incomplete due to the lack of a clearly identified pathological abnormality and due to the lack of reliable biomarkers. Possible mechanisms believed to contribute to IBS development and IBS like symptoms include physical stressors, such as infection or inflammation, psychological, and environmental factors, like anxiety, depression, and significant negative life events. Some of these mechanisms may involve the brain-gut axis (BGA). In this article we review the current knowledge on the possible involvement of the BGA in IBS and discuss new directions for potential future therapies of IBS.

Front Pharmacol. 2012 Jul 5;3:127

The hypersensitivity to colonic distension of IBS patients can be transferred to rats through their fecal microbiota.

BACKGROUND: Alterations of intestinal microbiota and hypersensitivity to colonic distension are two features of the irritable bowel syndrome (IBS). However, the role of intestinal microbiota in visceral hypersensitivity of IBS patients is far to be established. The aim of our study was to determine whether the intestinal microbiota is involved in the visceral hypersensitivity in IBS. METHODS: The painful response to colorectal distension and colonic mucosal parameters were assessed in gnotobiotic rats. Germfree (GF) rats were inoculated with the fecal microbiota from IBS patients characterized by hypersensitivity to colorectal distension (IBS HMA rats) or from non-hypersensitive healthy volunteers (Healthy HMA rats). Conventional rats were studied as normosensitivity control. Fecal microbial analyses were carried out in human and HMA rats fecal samples using cultural and molecular approaches. KEY RESULTS: The microbial dysbiosis of the IBS gut microbiota (more sulfate-reducing bacteria and Enterobacteriaceae and less bifidobacteria) could be maintained in gnotobiotic rats. The number of abdominal contractions in response to colorectal distensions was significantly higher in IBS HMA rats than in healthy HMA rats. No difference was observed between healthy HMA and conventional rats. Colorectal compliance, epithelial paracellular permeability, and density of colonic mucosal mast cells were similar in the three groups of rats. CONCLUSIONS & INFERENCES: We herein showed that sensitivity to colonic distension of IBS patients can be transferred to rats by the fecal microbiota. Mucosal alterations associated with microbiota transfer are not involved in this hypersensitivity. The altered IBS microbiota may have important role in the hypersensitivity characterizing IBS patients through specific bacterial metabolites.

Neurogastroenterol Motil. 2013 Apr;25(4):e272-82

Early-life stress induces visceral hypersensitivity in mice.

Early-life stress is a risk factor for irritable bowel syndrome (IBS), a common and debilitating functional gastrointestinal disorder that is often co-morbid with stress-related psychiatric disorders. In the rat, maternal separation (MS) stress has been shown to induce visceral hypersensitivity in adulthood and thus has become a useful model of IBS. However, development of mouse models of maternal separation has been difficult. Given the advent of transgenic mouse technology, such models would be useful to further our understanding of the pathophysiology of IBS and to develop new pharmacological treatments. Thus, the present study aimed to develop a mouse model of MS stress-induced visceral hyperalgesia as measured using manometric recordings of colorectal distension (CRD). Moreover, since the GABA(B) receptor has been reported to play a role in pain processes, we also assessed its role in visceral nociception using novel GABA(B(1b)) receptor subunit knockout mice. CRD was performed in adult male wildtype and GABA(B(1b)) receptor knockout mice that had undergone unpredictable MS combined with unpredictable maternal stress (MSUS) from postnatal day 1 through 14 (PND 1-14). MSUS induced visceral hypersensitivity in both wildtype and GABA(B(1b)) receptor knockout mice when compared with non-stressed mice. Wildtype and GABA(B(1b)) receptor knockout mice did not differ in baseline or stress-induced visceral sensitivity. To the best of our knowledge, this is the first study to show that early-life stress induces visceral hypersensitivity in a mouse model. These findings may provide a novel mouse model of visceral hypersensitivity which may aid our understanding of its underlying mechanisms in future studies.

Neurosci Lett. 2012 Mar 23;512(2):99-102

Colonic mucosal mediators from patients with irritable bowel syndrome excite enteric cholinergic motor neurons.

BACKGROUND: Mediators released in the mucosal milieu have been suggested to be involved in visceral hypersensitivity and abdominal pain in patients with irritable bowel syndrome (IBS). However, their impact on myenteric neurons remains unsettled. METHODS: Mucosal biopsies were obtained from the descending colon of patients with IBS and controls. Mucosal mast cells were identified immunohistochemically. The impact of spontaneously released mucosal mediators on guinea pig electrically stimulated longitudinal muscle myenteric plexus (LMMP) preparations was assessed in vitro by means of selective receptor antagonists and inhibitors. KEY RESULTS: Patients with IBS showed an increased mast cell count compared with controls. Application of mucosal mediators of IBS to LMMPs potentiated cholinergic twitch contractions, an effect directly correlated with mast cell counts. Enhanced contractions were inhibited by 50.3% with the prostaglandin D2 antagonist BW A868C, by 31.3% and 39% with the TRPV1 antagonists capsazepine and HC-030031, respectively, and by 60.5% with purinergic P2X antagonist pyridoxalphosphate-6-azophenyl-2’,4’-disulfonic acid. Conversely, the serotonin1-4, histamine1-3, tachykinin1-3 receptor blockade, and serine protease inhibition had no significant effect. CONCLUSIONS & INFERENCES: Colonic mucosal mediators from patients with IBS excite myenteric cholinergic motor neurons. These effects were correlated with mast cell counts and mediated by activation of prostanoid receptors, TRPV1, and P2X receptors. These results support the role of mucosal inflammatory mediators and mast cell activation in altered motor function of IBS.

Neurogastroenterol Motil. 2012 Dec;24(12): 1118-e570

Low-FODMAP Diet for Treatment of Irritable Bowel Syndrome.

Functional bowel disorders, including irritable bowel syndrome (IBS), are common disorders that have a significant impact on patients’ quality of life. These disorders present major challenges to healthcare providers, as few effective medical therapies are currently available. Recently, there has been increasing interest in dietary therapies for IBS, particularly a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs). Since ingestion of FODMAPs increases the delivery of readily fermentable substrates and water to the distal small intestine and colon-which results in luminal distention and gas-the reduction of FODMAPs in a patient’s diet may improve functional gastrointestinal symptoms. This paper will review the pathophysiology of IBS and the role of FODMAPs for the treatment of this condition.

Gastroenterol Hepatol (N Y). 2012 Nov;8(11): 739-45

The treatment of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a highly prevalent functional bowel disorder routinely encountered by healthcare providers. Although not life-threatening, this chronic disorder reduces patients’ quality of life and imposes a significant economic burden to the health care system. IBS is no longer considered a diagnosis of exclusion that can only be made after performing a battery of expensive diagnostic tests. Rather, IBS should be confidently diagnosed in the clinic at the time of the first visit using the Rome III criteria and a careful history and physical examination. Treatment options for IBS have increased in number in the past decade and clinicians should not be limited to using only fiber supplements and smooth muscle relaxants. Although all patients with IBS have symptoms of abdominal pain and disordered defecation, treatment needs to be individualized and should focus on the predominant symptom. This paper will review therapeutic options for the treatment of IBS using a tailored approach based on the predominant symptom. Abdominal pain, bloating, constipation and diarrhea are the four main symptoms that can be addressed using a combination of dietary interventions and medications. Treatment options include probiotics, antibiotics, tricyclic antidepressants, selective serotonin reuptake inhibitors and agents that modulate chloride channels and serotonin. Each class of agent will be reviewed using the latest data from the literature.

Therap Adv Gastroenterol. 2009 Jul;2(4):221-38

Importance of diarrhea in evaluating constipation in irritable bowel syndrome clinical studies.

BACKGROUND: Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by alterations in bowel function, abdominal discomfort, and bloating. The symptoms of IBS vary widely between constipation and diarrhea predominance. In this study, we examine “constipation minus diarrhea” score (C-D) to account for the contribution of diarrhea and to create a reliable method for predicting constipation predominance in IBS. METHODS: A nested study was conducted in participants with IBS by Rome I criteria. After consent, they completed a daily stool diary for 1 week. This included recording frequency of bowel movements and describing consistency of stool using the Bristol stool scale. After submitting their diaries, participants rated their bowel symptoms using a visual analog score (VAS) scale from 0 to 100 mm, with 100 mm representing maximum severity. VAS scores for C, D, and C-D were subsequently compared with the true stool events of the previous week by stool diary to validate the potential usefulness of the simple C-D method. RESULTS: Eighty-four participants with IBS completed stool diaries and VAS surveys for bowel symptoms, from which C-D scores were compiled. By correcting for the predominance of constipation compared with diarrhea, C-D scores predicted constipation based on the frequency of bowel movements and Bristol stool score. Furthermore, a second method was used to validate the C-D technique by comparing the mean C-D score in participants with constipation (≤3 d with bowel movement in previous week). In this case, the mean C-D score was 74.1 ± 3.8 compared with -3.0 ± 5.9 for patients with >3 days with bowel movement in that week (P<0.001). Although the constipation severity alone also distinguished these 2 groups, the difference was less impressive (P<0.01). In participants with mean Bristol stool scores of ≤2 in the preceding week, the C-D mean score was 25.4 ± 6.1 compared with participants having mean Bristol stool score of >2 where the C-D was -11.1 ± 5.9 (P<0.01). Using constipation severity by VAS alone, there was no significant difference between these same 2 Bristol stool categories (P=0.29). CONCLUSIONS: IBS patients’ self-assessment of constipation and diarrhea severity using the C-D score is an effective predictor of C-IBS and constipation severity. The C-D score may be a useful tool in future IBS constipation trials, as it seems to predict constipation and it correlates well with stool diaries.

J Clin Gastroenterol. 2011 Oct;45(9):790-3

Treatment options in irritable bowel syndrome.

The irritable bowel syndrome (IBS) is part of the spectrum of functional bowel disorders characterised by a diverse consortium of abdominal symptoms including abdominal pain, altered bowel function (bowel frequency and/or constipation), bloating, abdominal distension, the sensation of incomplete evacuation and the increased passage of mucus. It is not surprising therefore that no single, unifying mechanism has as yet been put forward to explain symptom production in IBS. The currently favoured model includes both central and end-organ components which may be combined to create an integrated hypothesis incorporating psychological factors (stress, distress, affective disorder) with end-organ dysfunction (motility disorder, visceral hypersensitivity) possibly aggravated by sub-clinical inflammation as a residuum of an intestinal infection. There is currently no universally effective therapy for IBS. Standard therapy generally involves a symptom-directed approach; anti-diarrhoeal agents for bowel frequency, soluble fibre or laxatives for constipation and smooth muscle relaxants and anti-spasmodics for pain. New drug development has focused predominantly on agents that modify the effects of 5-hydroxytryptamine (5-HT) in the gut, principally the 5-HT(3) receptor antagonists for painful diarrhoea predominant IBS and 5-HT(4) agonists for constipation predominant IBS. More speculative new therapeutic approaches include anti-inflammatory agents, antibiotics, probiotics, antagonists of CCK1 receptors, tachykinins and other novel neuronal receptors.

Best Pract Res Clin Gastroenterol. 2004 Aug;18(4):773-86

Management of irritable bowel syndrome: novel approaches to the pharmacology of gut motility.

Although it is unclear to what extent irritable bowel syndrome (IBS) symptoms represent a normal perception of abnormal function or an abnormal perception of normal function, many believe that IBS constitutes the clinical expression of an underlying motility disorder, affecting primarily the mid- and lower gut. Indeed, transit and contractile abnormalities have been demonstrated with sophisticated techniques in a subset of patients with IBS. As a consequence, drugs affecting gastrointestinal (GI) motility have been widely employed with the aim of correcting the major IBS manifestations, ie, pain and altered bowel function. Unfortunately, no single drug has proven to be effective in treating IBS symptom complex. In addition, the use of some medications has often been associated with unpleasant side effects. Therefore, the search for a truly effective and safe drug to control motility disturbances in IBS continues. Several classes of drugs look promising and are under evaluation. Among the motor-inhibiting drugs, gut selective muscarinic antagonists (such as zamifenacin and darifenacin), neurokinin2 antagonists (such as MEN-10627 and MEN-11420), beta3-adrenoreceptor agonists (eg, SR-58611A) and GI-selective calcium channel blockers (eg, pinaverium bromide and octylonium) are able to decrease painful contractile activity in the gut (antispasmodic effect), without significantly affecting other body functions. Novel mechanisms to stimulate GI motility and transit include blockade of cholecystokinin (CCK)A receptors and stimulation of motilin receptors. Loxiglumide (and its dextroisomer, dexloxiglumide) is the only CCKA receptor antagonist that is being evaluated clinically. This drug accelerates gastric emptying and colonic transit, thereby increasing the number of bowel movements in patients with chronic constipation. It is also able to reduce visceral perception. Erythromycin and related 14-member macrolide compounds inhibit the binding of motilin to its receptors on GI smooth muscle and, therefore, act as motilin agonists. This antibiotic accelerates gastric emptying and shortens orocecal transit time. In the large bowel a significant decrease in transit is observed only in the right colon, which suggests a shift in fecal distribution. Several ‘motilinomimetics’ have been synthesized. Their development depends on the lack of antimicrobial activity and the absence of fading of the prokinetic effect during prolonged administration. 5-hydroxytryptamine (5-HT)4 agonists with significant pharmacological effects on the mid- and distal gut (such as prucalopride and tegaserod) are available for human use. These ‘enterokinetic’ compounds are useful for treating constipation-predominant IBS patients. 5-HT3 receptor antagonists also possess a number of interesting pharmacological properties that may make them suitable for treatment of IBS. Besides decreasing colonic sensitivity to distension, these drugs prolong intestinal transit and may be particularly useful in diarrhea-predominant IBS. Finally, when administered in small pulsed doses, octreotide, besides reducing the perception of rectal distension, accelerates intestinal transit, although other evidence disputes such an effect.

Can J Gastroenterol. 1999 Mar;13 Suppl A:50A-65A

Perilla extract improves gastrointestinal discomfort in a randomized placebo controlled double blind human pilot study.

BACKGROUND: Gastrointestinal (GI) discomfort, e.g. bloating or rumbling, is a common symptom in otherwise healthy adults. Approximately 20% of the population, particularly women suffer from gastrointestinal discomfort and this affects quality of life. Recent studies discovered a link between the body and mind, called the gut-brain axis. Psychosocial factors, such as e.g. daily stress may cause altered gut physiology leading to ileum contractions and consequently gastrointestinal symptoms. In vitro and ex vivo studies clearly showed that a Perilla frutescens extract combines prokinetic, antispasmodic and anti-inflammatory effects. The aim of the intervention was to investigate the effects of the proprietary Perilla extract on GI discomfort in healthy subjects with gastrointestinal discomfort and reduced bowel movements in comparison to a placebo product. METHODS: The pilot study was performed according to a double-blind, randomized, placebo-controlled parallel design. Fifty healthy subjects with gastrointestinal discomfort and reduced bowel movements, 30-70 years, documented their GI symptoms, stool frequency and consistency daily during a 2-week run-in phase and a 4-week intervention phase with Perilla frutescens extract or placebo. GI symptoms were assessed on a 5-point scale daily and average scores over 14 days intervals were calculated. RESULTS: All GI symptoms were significantly improved over time by Perilla frutescens extract during the intervention phase (bloating: -0.44±0.56, p=0.0003; passage of gas: -0.30±0.66, p=0.0264; GI rumbling: -0.55±0.87, p=0.0014; feeling of fullness: -0.36±0.72, p=0.0152; abdominal discomfort: -0.54±0.75, p=0.004), whereas in the placebo group only abdominal discomfort was significantly improved (-0.31±0.55, p=0.0345). In the subgroup of women results were strengthened and a subscore out of bloating and abdominal discomfort was significantly improved against placebo (95%CI 0.003 to 0.77; p=0.048). CONCLUSION: The demonstrated effects of Perilla frutescens extract to improve GI complaints offer very promising results, taking into consideration the challenging set up of a nutritional human study with healthy subjects and in the area of digestive health, which is known for high placebo effects.

BMC Complement Altern Med . 2014 May 27;14:173

Antiepileptogenic, antioxidant and genotoxic evaluation of rosmarinic acid and its metabolite caffeic acid in mice.

AIMS: Antioxidant compounds have been extensively investigated as a pharmacological alternatives to prevent epileptogenesis. Rosmarinic acid (RA) and caffeic acid (CA) are compounds with antioxidant properties, and RA has been shown to inhibit GABA transaminase activity (in vitro). Our aim was to evaluate the effect of RA and CA on seizures induced by pentylenotetrazole (PTZ) using the kindling model in mice. MAIN METHODS: Male CF-1 mice were treated once every three days during 16 days with RA (1, 2 or 4mg/kg; i.p.), or CA (1, 4 or 8mg/kg; i.p.), or positive controls diazepam (1mg/kg; i.p.) or vigabatrin (600mg/kg; p.o.), 30 min before PTZ administration (50mg/kg; s.c.). After the last treatment, animals were sacrificed and the cortex was collected to evaluate free radicals (determined by 2’,7’-dichlorofluorescein diacetate probe), superoxide dismutase (SOD) and genotoxic activity (Alkaline Comet Assay). KEY FINDINGS: Rosmarinic acid 2mg/kg increased latency and decreased percentage of seizures, only on the 4th day of observation. The other tested doses of RA and CA did not show any effect. Rosmarinic acid 1mg/kg, CA 4mg/kg and CA 8mg/kg decreased free radicals, but no dose altered the levels of enzyme SOD. In the comet assay, RA 4mg/kg and CA 4mg/kg reduced the DNA damage index. SIGNIFICANCE: Some doses of rosmarinic acid and CA tested showed neuroprotective action against oxidative and DNA damage produced in the kindling epilepsy model, although they did not produce antiepileptogenic effect in vivo.

Life Sci. 2015 Feb 1;122:65-71