Irritable Bowel Syndrome in People
Irritable bowel syndrome (IBS) is a chronic functional disorder of the human gastrointestinal (GI) system. The prevalence of IBS reaches 7–10% worldwide and is associated with a significant reduction in health-related quality of life. Estimates of annual direct and indirect costs associated with IBS exceed 41 billion dollars in major industrial countries. Patients experience abdominal pain and altered bowel habit, with either predominantly diarrhoea (IBS-D), constipation (IBS-C), or both (IBS-M).1-3 The earliest reports describing IBS are from the turn of the 19th and 20th century, when diagnosis was made by exclusion of malignant, inflammatory, or infectious disease after full investigation and extensive unsuccessful surgeries. IBS remained frequently misdiagnosed and poorly understood as late as the 1970s, with the problem of unnecessary surgery continuing.1 In an attempt to improve IBS diagnosis and reduce unnecessary surgery, Manning created the first set of formal criteria that allowed IBS to be positively diagnosed rather than by rule-out. These criteria were reviewed and through expert consensus the Rome criteria were developed for diagnosis of IBS (www.romecriteria.org).
Current theories on IBS pathophysiology involve multiple factors: gut motility, inflammation, intestinal bacteria, diet, and psychosocial factors. GI dysmotility is recognized as the major pathophysiological mechanism, but it does not fully correlate with symptomatic bowel disturbances. Colonic transit is generally accelerated in IBS-D and delayed in IBS-C according to several studies.4
Pain is a major problem in IBS, and in the absence of inflammation is reported to be due to visceral hypersensitivity, a poorly understood concept but a conglomeration of peripheral and central processes; e.g., stress, psychological factors, diet. Bloating, gas and distention can also contribute to pain and hyperaesthesia. Alterations in the brain-gut axis are a new concept in IBS pathophysiology, and have been shown to affect intestinal sensory perception, motility, and visceral perception (pain).1-4
Recent evidence also supports a role for mucosal inflammation in IBS. Colonoscopic biopsy from patients meeting the Rome III criteria for noninvasive diagnosis showed an increased number of T-lymphocytes, neutrophils, and mast cells in the intestinal mucosa. Pathology is inconsistent with Crohn's disease and ulcerative colitis, but could be a predisposing factor. Possible causes of pain in IBS include bacterial imbalance, brain-gut neuroendocrine interactions, (e.g., steroid, cytokine and chemokine release), as well as delayed intestinal transit and increased mucosal contact with faeces, bacteria and toxins.
Another more recently recognised etiological factor in IBS pathogenesis is intestinal dysbiosis. This includes alterations in the intestinal commensal bacteria and the presence of small intestinal bacterial overgrowth (SIBO). Over 60 candidate genes have also been reported as positively associated with IBS.
There is no means of definitive diagnosis, as no biomarker for IBS has been found, hence it is diagnosed clinically, using symptom-based criteria, rather than by exclusion of other disorders. According to the Rome III Diagnostic Criteria, IBS is a syndrome with recurrent abdominal pain occurring at least 3 days per month over a 3 month span. It is associated with two or more of the following characteristics: (1) improvement with defecation; (2) change in stool frequency with onset; and (3) change in stool form with onset.
Because the cause of IBS remains unknown, management has focused on amelioration of symptoms, rather than disease modification or cure. Traditional first-line strategies include increasing fibre intake to regulate defaecation, control of spasm with hyoscine and peppermint oil, antidepressants, including tricyclic antidepressants and selective serotonin reuptake inhibitors, 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, 5-HT4 agonists, antibiotics, probiotics, and melatonin. Despite numerous studies, there is still no universally accepted satisfactory treatment. Patients with IBS also frequently find benefit in alternative therapies such as ayurvedic cures (e.g., triphala), yoga, herbs (peppermint), cognitive behavioural therapy, acupuncture, and spiritual healing - e.g., crystal and shaman healers.
Antispasmodics
Peppermint oil is known to reduce smooth muscle contraction in the gut and alleviate abdominal pain, hence its use in IBS. Its efficacy in IBS was assessed in a systematic review and meta-analysis of four placebo-controlled trials containing 392 patients. Only 26% of IBS patients given peppermint oil had persistent symptoms compared with 65% receiving placebo. Adverse events were very rare. It appears, therefore, that peppermint oil is highly effective in the treatment of IBS, although with only four randomized controlled trials, further data are required. The best evidence for antispasmodic drug efficacy exists for hyoscine.
Fiber
In a systematic review, data from 12 placebo-controlled trials of fiber were pooled. Persistent symptoms occurred in 52% of those randomized to fiber compared with 57% of placebo patients, but only with the soluble fiber, ispaghula. Insoluble fibers, such as wheat bran, showed no significant benefit, and these may exacerbate symptoms in some patients with IBS.
Probiotics, Antibiotics
Probiotics to modulate gut bacteria as a therapeutic intervention for IBS have been explored. Data from eighteen papers were pooled in a meta-analysis (evaluating individual probiotic species and combinations of these. Collectively, probiotics significantly reduced global symptoms in IBS. When individual IBS symptoms were studied, there was a significant reduction in abdominal pain scores with probiotics. Because of the variety of strains and doses of probiotics used across the studies it is difficult to know whether one strain, or combination of strains, is more effective than another. Rifaximin is a minimally absorbed antibiotic used in treatment of traveller's diarrhoea and SIBO. Two large randomized controlled trials showed relief of symptoms in those randomized to rifaximin for 2 weeks compared with placebo (41% versus 32%), and relief of bloating occurred in significantly more patients taking rifaximin (40% versus 30%). Patients were followed-up for 10 weeks, after which time the beneficial effect of rifaximin was still evident.
Antidepressants
There is a higher incidence of depression in IBS sufferers compared with the general population. Antidepressant drugs can modulate pain perception and stimulate gastrointestinal motility (SSRIs). Selective serotonin reuptake inhibitors (SSRI), have been assessed, and data from five trials were pooled. IBS symptoms persisted in significantly fewer patients compared with placebo (44% vs. 71%), but results are inconsistent. Tricyclic antidepressant drugs are also effective for treating chronic pain and their anticholinergic side effects may lead to constipation thus effective for diarrhea-predominant IBS. Tricyclic antidepressants were more efficacious than placebo for the treatment of IBS in a recent systematic review. The use of antidepressants for IBS treatment is very controversial.
Other Drugs
The 5-hydroxytryptamine receptors are involved in sensory and motor function of the gut. Tegaserod is a drug that stimulates the 5-HT-4 receptor, leading to a reduction in intestinal transit time. Lubiprostone acts on chloride channels in cells lining the intestine, stimulates intestinal fluid secretion, and accelerates transit in the gut and softening stools. Lubiprostone has demonstrated efficacy in patients with chronic idiopathic constipation but side effects, including headache and nausea, are common.
Irritable Bowel Syndrome in Dogs and Cats
In approximately 10%–20% of dogs and cats presented with gastrointestinal signs including diarrhoea, constipation, pain, bloating, lethargy, inappetence, no pathologic lesion can be found on investigation. It is probable that these animals have a functional diarrhoea, and are thought to have IBS. In dogs and cats, this is still very much a diagnosis of exclusion and a considerable therapeutic challenge. We have no biomarker available for these patients and, unfortunately, extensive investigation is required including sometimes exploratory abdominal surgery and intestinal biopsy to completely exclude inflammation and neoplasia.
If, having excluding all other causes of gastrointestinal signs, we consider the ROME III criteria, it is possible to diagnose IBS, but using only criterion (2) and (3) since we have means of showing improvement after defaecation.
Recurrent abdominal pain or discomfort** at least 3 days/month in the last 3 months associated with two or more of the following:
1. Improvement with defecation
2. Onset associated with a change in frequency of stool
3. Onset associated with a change in form (appearance) of stool.
Criterion fulfilled for the last 3 months with symptom onset 2 months prior to diagnosis
** "Discomfort" means an uncomfortable sensation not described as pain.
The main reason to extrapolate to the human criterion is in attempt to inform treatment. IBS is a underrecognised syndrome in dogs and cats, given our poor ability to detect mild to moderate pain in animals, especially intestinal pain. Many dog breeds are very stoic and like people may experience pain in varying degrees associated with IBS. There is no universal drug or dietary regimen available, but attention to quality of life, environment and diet and optimizing these are very important. Ideally, any underlying stress factor should be identified and removed. If this is not possible, treatment must be tailored to the individual and usually involves a combination of drug and dietary management. Hypoallergenic diets, containing hydrolyzed proteins may be helpful, but consider that we feed dogs the same dried kibble day in day out, and it would not be surprising that this unnatural existence compared to canine species existing in the wild may cause bowel dysfunction. A home-cooked varied diet of pasta, rice, fish, green vegetables, and a protein source of white fish, tofu or soy, plus omega-3 fatty acids is well worth trying. The choice of drugs to be used in the treatment of IBS depends on whether chronic diarrhoea or spastic colon and constipation are present. Motility-modifying drugs such as loperamide, diphenoxylate, mebeverine and hyoscine have been used but there are no clinical trials. Dietary management usually involves the feeding of a low residue hypoallergenic diet with added insoluble (nonfermentable) fiber. Trials with peppermint have not been conducted but would appear to be very worthwhile. Tegaserod has proven safe in toxicity studies in dogs, and stimulated the peristaltic reflex in vitro, causing increased canine intestinal and colonic motility and transit, reduced visceral afferent firing or sensation in response to distension. In people, it is known to accelerate gastric, small bowel and colonic transit in healthy patients, and small bowel transit in patients with constipation-predominant irritable bowel syndrome. Three large, phase III randomized, double-blinded, and placebo-controlled trials were performed predominantly in females (approximately 85%) with constipation-predominant irritable bowel syndrome. Overall, phase III results support efficacy as assessed by the subject's global assessment of relief with significant improvement in secondary endpoints such as abdominal pain, bowel frequency and consistency. Tegaserod was well tolerated; the most frequent adverse event was transient diarrhoea. Antibiotics such as metronidazole have been used to treat IBD and rifaximin.
References
1. Canavan C, West J, Card T. The epidemiology of irritable bowel syndrome. Clin Epidemiol. 2014;6:71–80. Available from: www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3921083&tool=pmc%20entrez&rendertype=abstract.
2. Chaudhary NA, Truelove SC. The irritable colon syndrome. A study of the clinical features, predisposing causes, and prognosis in 130 cases. Q J Med. 1962;31:307–322. Available from: http://www.ncbi.nlm.nih.gov/pubmed/13878459.
3. Kruse FH. Functional disorders of the colon: The spastic colon, the irritable colon, and mucous colitis. Cal West Med. 1933;39(2):97–103. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1658751.
4. Lee YJ, Park KS. Irritable bowel syndrome: emerging paradigm in pathophysiology. World J Gastroenterol. 2014;20(10):2456–2469. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949256.