Irritable bowel syndrome and bloating

Best Practice & Research Clinical Gastroenterology Vol. 21, No. 4, pp. 689–707, 2007 doi:10.1016/j.bpg.2007.03.007 available online at http://www.sciencedirect.com

9 Irritable bowel syndrome and bloating William L. Hasler *

MD

Associate Professor of Internal Medicine Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, MI, USA

Gaseous symptoms in irritable bowel syndrome (IBS) including eructation, flatulence, and bloating occur as a consequence of excess gas production, altered gas transit, abnormal perception of normal amounts of gas within the gastrointestinal tract, or dysfunctional somatic muscle activity in the abdominal wall. Because of the prominence of gaseous complaints in IBS, recent investigations have focussed on new insights into pathogenesis and novel therapies of bloating. The evaluation of the IBS patient with unexplained gas and bloating relies on careful exclusion of organic disease with further characterisation of the underlying condition with directed functional testing. Treatment of gaseous symptomatology in IBS should be targeted to pathophysiologic defects whenever possible. Available therapies include lifestyle alterations, dietary modifications, enzyme preparations, adsorbents and agents which reduce surface tension, treatments that alter gut flora, and drugs that modulate gut transit. Key words: gas and bloating; gastrointestinal transit; bacterial overgrowth; breath tests; probiotics.

NORMAL PHYSIOLOGY Gas production The gastrointestinal tract contains <200 ml of gas, while daily gas expulsion averages 600–700 ml after consuming a standard diet plus 200 g of baked beans.1 On average, men pass flatus 14 times per day, especially after meals. Daily flatus numbers up to 25 are normal. Ingesting a nonabsorbable carbohydrate such as lactulose doubles flatus frequency. The major gases in flatus are nitrogen, oxygen, carbon dioxide, hydrogen, and methane (Figure 1).2 Gases produced by colonic bacterial fermentation of ingested nutrients and endogenous glycoproteins (hydrogen, methane, and carbon dioxide) * 3912 Taubman Center, Box 0362, Ann Arbor, MI 48170, USA. Tel.: þ1 734 936 8644; Fax: þ1 734 936 7392. E-mail address: [email protected] 1521-6918/$ - see front matter ª 2007 Published by Elsevier Ltd.

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Figure 1. The volume of each gas passed from the rectum over a 4-h period is shown for 16 healthy volunteers. The major gases (A) are hydrogen (H2), carbon dioxide (CO2), methane (CH4), oxygen (O2), and nitrogen (N2). Sulphur-containing gases (B) are passed in much smaller quantities and include hydrogen sulphide (H2S), methanethiol (MES), and dimethylsulphide (DMS). From Ref. 2.

represent 74% of flatus. Flatus odour correlates with hydrogen sulphide concentrations; other sulphur-containing gases in flatus include methanethiol and dimethyl sulphide.3 Men produce more aromatic flatus than women. Gas transit Insight into gas transit is provided by experiments in which physiologic gas mixtures of nitrogen, oxygen, and carbon dioxide are perfused in the jejunum. In healthy humans, gas perfusion produces steady state flow with little distention and few symptoms.4 Gas collected from the rectum in such studies is expelled in pulsatile fashion indicating flow is regulated by intrinsic motor patterns in the distal gut (Figure 2).5 Gas transit is accelerated by caloric liquid or solid meals whereas non-caloric liquids have no stimulatory effects, providing an experimental correlate to the observation that gas passage and gaseous symptoms increase postprandially.6 Conversely, intestinal lipid perfusion retards propulsion of gas perfused into the jejunum, demonstrating nutrient-induced reflex modulation of gas transit.7 Retardation of gas flow by lipid is more pronounced with ileal perfusion than with duodenal perfusion indicative of

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Figure 2. A sample rectal gas evacuation profile from a healthy volunteer during jejunal perfusion of a physiologic gas mixture is shown. Prior to gas perfusion, the barostat cylinder was emptied (starting volume ¼ 1170 ml). After initiation of gas perfusion, there was a lag period of approximately 1900 s during which no gas was evacuated at the level of the rectum. Thereafter, gas evacuation into the barostat cylinder was pulsatile with passage of discrete boluses (arrows) with a total expulsion of approximately 900 ml over a 2-h period. From Ref. 5.

region-specific activation of this reflex.8 Other factors regulate physiologic gas flow. Assuming an upright posture expedites gas flow compared to studies performed when supine.9 Likewise, mild physical activity accelerates gas transit and reduces gas retention in healthy individuals.10 Some of the motor events which regulate gas flow have been defined. Using combined colonic manometry with jejunal gas perfusion and rectal gas collection, one group has shown increases in propagative distal colonic pressure waves which temporally correlate with pulsatile gas expulsions.11 Furthermore, there is some correlation between fasting duodenojejunal motility and gas expulsion, indicating participation of phasic motor activity throughout the gut in the transit of luminal gas. Additionally employing barostat methods, increases in duodenal tone with reductions in gut capacitance are observed during jejunal gas perfusion.12 Disruption of gas transit by different stimuli produces variable perception of bloating, indicating stimulus-specific activation of gut sensory pathways. Retarding gas flow with glucagon evokes significant distention but little symptomatic bloating, whereas similar degrees of distention occurring with voluntary anal contraction cause significant gaseous symptomatology.13 Jejunal and rectal gas perfusion produce similar degrees of gas retention in healthy volunteers; however, significant symptoms are elicited only with jejunal gas loading.14 Retardation of gas flow by intestinal lipid perfusion is prevented by concurrent rectal or duodenal distention; however, symptomatic bloating is reported only during duodenal distention.15 EPIDEMIOLOGY OF BLOATING IN IBS Several symptoms pertain to gas within the gut lumen. Eructation, or belching, is retrograde gas expulsion from the mouth. The Magenblase syndrome is fullness and bloating relieved by belching. Manometric studies of eructation show decreased lower oesophageal sphincter tone followed by upper oesophageal sphincter relaxation. Flatulence is the volitional or involuntary release of gas from the anus. Manometry during

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flatulence demonstrates propagated colon contractions with increased rectal pressure and anal relaxation.16 Bloating, the perception of retained gas, is experienced monthly by 15.9% of the population.17 Bloating was more common in women (19.2%) than men (10.5%) in one study, but was reported less often by women in another survey.17,18 Other symptoms experienced by patients with gaseous complaints include pain, halitosis, anorexia, early satiety, nausea, loud borborygmi, and bowel dysfunction. In otherwise healthy individuals, bloating has significant impact limiting the ability to perform normal daily activities in 54% and requiring medication use in 43%.17 Gaseous symptoms are prevalent in irritable bowel syndrome (IBS). In one investigation, bloating was rated the most bothersome symptom by 60% of IBS patients whereas 29% considered pain to be most intrusive.19 Bloating was experienced on 28% of days in another study, while pain was reported on 33% of days.20 Abdominal distention and bloating are more often noted by women with IBS than men, with symptoms increasing in relation to menses.21 In premenopausal women with IBS, bloating is strongly associated with uterine cramping and breast tenderness suggesting that gastrointestinal complaints may be confounded by menses-associated symptoms.22 Bloating in IBS may be worsened by stress and relieved by relaxation.23 Most studies show more prominent bloating with constipation-predominant IBS than those with diarrhoea, although some investigations report no relation of bloating to a particular defecation profile.24,25 Recent investigations distinguish the sensation of bloating from objective measures of abdominal distention. In one study, constipated patients reported bloating and exhibited abdominal distention whereas those with diarrhoea noted bloating without distention.23 Objective distention shows diurnal variability in IBS patients, being higher later in the day. PATHOGENESIS OF BLOATING IN IBS Symptoms of gas and bloating in IBS are postulated to result from excess gas production, altered gas transit, heightened perception of normal amounts of gas within the gut, or abnormal somatic muscular activity in the abdominal wall. The relative roles of each of these factors in the IBS population as a whole have not been firmly delineated. Indeed, five published studies in IBS report increases in abdominal distention while two report no change.26 Likewise, two studies report increased gas production while two do not and three investigations observe more gas within the gut lumen whereas four reports show no change.26 It is likely that only some of these pathogenic factors contribute to symptoms in any given IBS patient. Carbohydrate maldigestion Maldigestion and malabsorption of carbohydrates commonly are associated with gas and bloating in the population and in disorders such as IBS. Unabsorbed carbohydrates are propelled to the colon and serve as nutrient substrates for enteric bacteria, liberating hydrogen and short-chain fatty acids, both of which may induce symptoms. The most common carbohydrate maldigestion syndrome, lactose intolerance, results from insufficient enterocyte lactase which hydrolyzes lactose into glucose and galactose. Lactase deficiency occurs in 21% of Caucasians but is more prevalent in those of African (75%), Hispanic (51%), and Native American (79%) descent.27 However, many of those who consider themselves to be severely lactose intolerant inappropriately attribute their gastrointestinal symptoms to inability to digest milk sugar.28 Lactose intolerance is common in IBS. However, responses of IBS patients to lactose

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restriction or lactase supplementation are inconsistent questioning the relevance of lactase deficiency in symptom pathogenesis.29 Impaired assimilation of other simple sugars produces gaseous symptoms as well. Forty percent of fructose is not intestinally absorbed. Increased gas production occurs after consuming fructose-containing fruits, juices, and soft drinks with a threshold of 37.5 g of fructose.30 Patients with fructose intolerance pass more flatus and produce excess hydrogen than controls for given amounts of fructose. Sorbitol, a natural substance in fruits and an artificial sweetener, is malabsorbed at doses as low as 5 g.31 Other malabsorbed carbohydrates include isomalt, xylitol, and (rarely) sucrose. Most studies show no increase in fructose or sorbitol intolerance in IBS, although some report response to dietary restriction of these sugars.32 Complex carbohydrates also may be incompletely assimilated. Twenty percent of carbohydrates in baked beans, and lower amounts in wheat, oats, potatoes, corn, and rice are malabsorbed.33 Reduced faecal pH and increased fatty acids show that most unabsorbed starch is metabolised in the colon. Undigestible oligosaccharides (stachyose, raffinose, verbascose) are abundant in legumes. Soybeans low in these compounds produce less gas than standard beans.34 Restricting dietary fibre can reduce daily gas expulsion from 700 to 200 ml.1 However, incubating faeces with bran produces 10% as much gas as with lactulose suggesting that bloating with fibre stems from factors other than increased gas production.35 In healthy humans, 30 g of psyllium daily retards transit of jejunally perfused gas mixtures providing a mechanism for increased gas symptoms after fibre.5 In IBS, several studies report increased bloating with bran.36 Conversely, dietary fibre restriction reduces symptoms in some individuals.37 Abnormal gut flora The human colon contains up to 1014 bacteria which serve several roles including fermentation of food residue, modulation of gut immunity, and synthesis of vitamins.38,39 Investigations suggest that altered gut flora may relate to symptom genesis in IBS. Cumulative breath hydrogen excretion after lactulose in increased in IBS suggesting enhanced colonic fermentation, although others report no increase in hydrogen production.40,41 In an older study, IBS patients exhibited fewer faecal coliforms, lactobacilli, and bifidobacteria versus controls.42 Recently, Bifidobacterium and Lactobacillus species were reportedly reduced in patients with constipation and potentially pathogenic bacteria and fungi were higher.43 Immune alterations observed in these individuals included increases in CD3þ, CD4þ, and CD25þ lymphocytes, reduced CD72þ B lymphocytes, diminished neutrophil and monocyte phagocytosis, and elevated antibodies to Escherichia coli and Staphylococcus aureus.43 Studies employing polymerase chain reactions characterise differences in gut flora in different IBS subtypes including decreases in Lactobacilli and trends to reduced Desulfovibrio and Bifidobacteria in diarrhoea-predominant patients and higher Veillonella counts in constipated patients.44 Small intestinal bacterial overgrowth is promoted as a cause of IBS symptoms which are postulated to result from microbial metabolism of consumed and endogenous carbohydrates. Bacterial overgrowth is defined as >105 CFU/ml in proximal intestinal fluid. Organisms cultured include Streptococcus, E. coli, Lactobacillus, and Bacteroides species. Organic causes of bacterial overgrowth include small intestinal obstruction, diverticula, fistula, and stasis. Vagotomy and proton pump inhibitors increase intestinal colonization because of decreased gastric acid production. Common variable immunodeficiency syndrome presents with bacterial overgrowth from reduced luminal

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immunity. Many diabetics with diarrhoea acquire bacterial overgrowth due to altered motor function as do patients with intestinal pseudoobstruction. Bacterial overgrowth is a cause of gaseous symptoms in the elderly and is likely due to altered motility, acid production, and immune function. Recent studies report positive lactulose breath tests in many IBS patients (78%), which are attributed to bacterial overgrowth and have been associated with impaired small intestinal motility.45,46 Patients with diarrhoea commonly produce increased breath hydrogen after lactulose or glucose, whereas those with constipation generate excess methane (Figure 3).47,48 This differential gas production may have pathogenic relevance. Constipated IBS patients with excess methane exhibit reduced blood serotonin release after glucose versus hydrogen-producers.49 In dogs, small intestinal methane perfusion delays transit while in isolated guinea pig ileum, methane augments contractile responses to mechanical stimuli.48 However, other groups using other diagnostic methods report much lower rates of overgrowth (10–31%) in IBS and show no response to antibiotics.50 This is an area of active investigation. Altered gas transit/perception The pathogenesis of bloating in IBS not secondary to luminal factors is likely multifactorial with contributions from abnormal gut motor and sensory functions.26 Early

Figure 3. The mean diarrhoea and constipation severity scores are shown for patients with purported small intestinal bacterial overgrowth as a function of the gas pattern (hydrogen [H2], methane [CH4], or both [CH4 þ H2]) on lactulose breath testing. Constipation scores were significantly greater for individuals with methane production. From Ref. 47.

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studies referred to a splenic flexure syndrome with localised air-trapping, suggestive of altered transit of luminal gas. In an argon washout study, patients with functional abdominal pain retained normal amounts of infused gas.51 However, half of patients exhibited prolonged gas transit and many showed abnormal retrograde gas reflux into the stomach. In jejunal gas perfusion investigations, many IBS patients exhibit abnormal gas retention which correlates with increased distention and symptoms of bloating.52 In a recent study combining gas perfusion with radiolabelled xenon gas transit, patients with bloating exhibited selective retardation of gas flow in the small intestine suggesting this region is responsible for generation of abdominal distention (Figure 4).53 In these subjects, gas retention was observed only when gas was perfused into the jejunum whereas transit of gas perfused into the ileum or colon was normal. Lipid perfusion of the duodenum and jejunum but not ileum retards transit of jejunally perfused gas with associated increases in bloating and abdominal distention in patients with IBS.54 Indeed, the changes in gas retention observed during proximal intestinal lipid perfusion distinguish IBS patients from healthy controls with >90% sensitivity and specificity.54 Furthermore, reflex inhibition of nutrient-modulated gas flow is impaired in IBS. Rectal distention prevents retardation of gas flow during duodenal lipid perfusion in healthy subjects but has no effect in IBS, leading to gas retention in affected patients.55 Others report no alterations in retention and postulate that bloating results from visceral hypersensitivity. In one study, IBS patients reported more pain with duodenal nitrogen perfusion and with sham gas perfusion compared to healthy volunteers.56 Duodenojejunal motility indices were unaffected by true or sham gas perfusion in either subject group, suggesting that gaseous symptoms result from heightened perception

Figure 4. Responses to proximal versus distal gas perfusion are shown for IBS patients and healthy volunteers. Compared to healthy subjects, IBS patients developed significant gas retention with jejunal but not ileal or caecal gas perfusion. From Ref. 53.

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rather than alterations in gut transit. Recent studies suggest that perceptual hypersensitivity may be greater in those who complain of bloating without distention than in those with bloating and associated distention.57 Dysfunctional abdominal wall muscular activity In addition to gut neuromuscular factors, some cases of bloating may stem from dysfunctional somatic muscular activity in the abdominal wall.26 Older studies postulated roles for weak abdominal muscles, a low diaphragm, or exaggerated lumbar lordosis. Computed tomography (CT) scans of IBS patients show increased lateral abdominal profiles, which may relate to changes in gut or abdominal wall muscle tone.58 Recently in a CT study in patients with bloating, severe distention episodes were associated with exaggerated diaphragmatic descent.59 Measurements of abdominal girth in healthy humans with inductance plethysmography show increases while sitting or standing compared to lying supine.60 Likewise, girth increases after meals and decreases during sleep.60 Using this method, bloated IBS patients with constipation exhibited significantly greater distention compared to bloated IBS patients with diarrhoea.61 However, in some studies using other methods, abdominal wall activity was similar in IBS patients and healthy controls. More recently, rectal gas perfusion studies reported increases in perception in IBS and functional bloating which were associated with changes in external and internal oblique muscle contraction indicating an interaction of visceral and somatic musculature in production of gaseous symptomatology.62 Other causes Most upper gut air in healthy individuals results from aerophagia, but the prevalence of aerophagia as a cause of gaseous symptoms in IBS is unknown. Aerophagia occurs when intrathoracic pressure is negative and is worsened by gum chewing, smoking, or oral irritation. Coeliac disease produces gaseous symptoms that may overlap with symptoms of IBS. Population-based studies observe increases in the prevalence of coeliac disease in patients with presumed IBS compared to healthy controls.63 Furthermore, many coeliac disease patients satisfy diagnostic criteria for IBS. Finally, some patients with IBS symptoms and evidence of coeliac disease exhibit symptom responses to dietary gluten exclusion.64 Food allergy has been proposed to contribute to bloating in IBS, however, its importance remains to be defined. Selected IgG4 antibodies to food antigens are reportedly elevated in some IBS patients with bloating.65 Medications (anticholinergics, opiates, calcium blockers, antidepressants) produce gas by effects on gut motility. Psychological factors may play a role in the genesis of bloating in some IBS patients. One third of patients relate symptoms of bloating to stress or anxiety.23 However, other studies observe no relation of bloating severity with degree of anxiety. EVALUATION OF BLOATING IN IBS The diagnostic approach to the patient with unexplained gas and bloating secondary to presumed IBS relies on a careful history and physical examination complemented by directed structural and functional testing.

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History and physical examination Several historical points must be elicited by the clinician. Relief of symptoms with defecation or flatus is consistent with IBS. Anxiety or psychiatric disease associate with aerophagia or IBS. Conversely, vomiting, fever, weight loss, nocturnal diarrhoea, rectal bleeding, or steatorrhoea indicates probable organic disease. One’s ethnicity and family history increase risks of lactase deficiency or coeliac disease. Risks for bacterial overgrowth should be assessed. A diet history should quantify legumes, unrefined starches, and lactose-, fructose-, or sorbitol-containing foods. The physical examination usually is normal in IBS patients with gas and bloating. Occult faecal blood, cutaneous findings (sclerodactyly with scleroderma, dermatitis herpetiformis in coeliac disease), peripheral or autonomic neuropathy, cachexia, jaundice, or palpable masses suggest underlying organic disease which warrants aggressive evaluation. Satisfaction of the Rome criteria for IBS without evidence of alarm features may be adequate for diagnosis and obviate the need for extensive further testing in many individuals. Laboratory and structural testing Laboratory tests facilitate exclusion of organic disease. In addition to standard haematology and chemistry determinations to screen for inflammatory or mucosal processes, thyroid chemistries or fasting cortisol levels are indicated in some individuals. Serologic testing for coeliac disease (tissue transglutaminase or endomysial antibodies) is performed in patients of appropriate ethnic backgrounds with IBS-like symptoms due to the increased prevalence of coeliac sprue in these populations.66 Other serologies of value in rare cases include antinuclear antibodies and scleroderma antibodies to evaluate for collagen vascular disease and antinuclear neuronal antibodies to screen for paraneoplastic visceral neuropathy. Stool analysis for Giardia may be indicated in some patients with diarrhoea. Imaging tests may be performed in selected cases to distinguish mechanical obstruction from functional gas retention. Flat and upright abdominal radiographs may show diffuse distention with ileus, haziness in ascites, or air-fluid levels with obstruction. Contrast enema radiography detects distal obstruction, whereas small intestinal contrast studies or CT scanning can characterise partial proximal obstruction. Ultrasound or CT also can further delineate extraluminal processes contributing to objective distention. Functional testing When structural tests are negative, methods to assess carbohydrate absorption, quantify gut transit, or measure flatus production can provide insight into the cause of symptoms. Breath testing Hydrogen breath testing can be employed to confirm carbohydrate intolerance as a cause of gaseous symptoms. These methods quantify hydrogen produced by luminal bacteria during metabolism of ingested test substrates. Conversely, carbohydrate metabolism by human tissues does not elicit hydrogen production. Expired breath samples are obtained before and for 2 h after ingesting a solution of the sugar which

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is presumed to be maldigested or malabsorbed. Hydrogen raises >20 parts per million within 120 min of lactose ingestion distinguish biopsy-proven lactase deficiency from lactase-sufficiency with 90% sensitivity.67 Hydrogen breath testing also has been employed to detect fructose or sorbitol malabsorption, however, normal values for these tests are less well defined. Hydrogen measurement may be extended to 10 h to test for maldigestion of complex carbohydrates. Breath testing also is employed to test for small intestinal bacterial overgrowth. Elevated fasting hydrogen or early raises within 30 min of substrate ingestion suggest overgrowth. Breath testing after glucose provides sensitivities and specificities of 60– 90% for diagnosing bacterial overgrowth.68 Lactulose and rice have been used as substrates, but the sensitivities of these methods are <33% for detecting overgrowth. False negative results occur in patients without hydrogen-producing bacteria, while false positive tests occur with rapid small bowel transit. Thus, lactulose breath testing has not been universally accepted as a reliable test for bacterial overgrowth. Other centres rely on 14C- or 13C-labelled substrates, with measurement of breath 14CO2 or 13CO2, although special facilities are necessary for these analyses. If the diagnosis is uncertain, diagnosis of bacterial overgrowth is made by documentation of bacterial counts >105 CFU/ml on quantitative culture of duodenal or jejunal secretions.68 Finally, hydrogen breath testing with lactulose is used to quantify orocaecal transit in suspected intestinal pseudoobstruction. The transit time is measured from the time of ingestion until an increase in breath hydrogen is observed, reflecting colonic bacterial metabolism of the substrate. This method has significant limitations. Lactulose accelerates small intestinal transit.69 Furthermore, erroneous values are obtained with superimposed bacterial overgrowth. Tests of gut motor function Gastric emptying tests or gastrointestinal manometry are often performed for suspected gastrointestinal dysmotility as a cause of bloating. Scintigraphic measures of emptying of radiolabelled solid meals (99mTc-sulphur colloid in eggs) are employed to exclude gastroparesis or rapid emptying. Other methods of quantifying gastric emptying include isotopic breath tests (e.g. 13C-octanoate) and ingested capsule techniques. In some centres, scintigraphy is used to assess rates of small intestinal or colonic transit in suspected pseudoobstruction and constipation. More often, radioopaque marker techniques are ordered to diagnose slow transit constipation. In some cases, full thickness biopsy may be required to document degeneration of nerve or muscle layers. Flatus analysis In some research institutions, flatus analysis is performed to gain insight into the cause of excess flatulence.70 Flatus passages are counted and expelled gas is analysed. Excess release of nitrogen indicates probable aerophagia, whereas increases in carbon dioxide, hydrogen, and methane suggest increased colonic metabolism of ingested food residue. THERAPY OF BLOATING IN IBS Gaseous symptoms in IBS are treated with dietary measures, enzymes to facilitate digestion, adsorbents and agents to decrease surface tension, treatments to alter gut flora, or drugs to modify gut transit. Evidence favouring any therapy is limited as few controlled investigations have been performed.

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Dietary and non-medication therapy Diet changes may reduce gaseous symptoms in some IBS patients. Most lactasedeficient persons have residual enzyme and tolerate small amounts of lactose. When consumed in yogurt with active cultures, lactose may be tolerated because of bacterial b-galactosidase.71 Dairy products containing lactase-producing Lactobacillus acidophilus, Bifidobacterium species, and Lactobacillus bulgofilus reduce bloating in some with lactose intolerance.72 Only a fraction of IBS patients with documented lactase deficiency respond to lactose restriction. Similarly in an older study, <40% experience symptom improvement upon exclusing fructose and sorbitol.32 However, in a newer investigation of patients with functional bloating, two thirds of those with malabsorption of lactose, fructose plus sorbitol, or both reported symptom reductions with restriction of the malabsorbed sugars.73 In another study, fructose exclusion reduced symptoms in 85% of 62 IBS patients with fructose intolerance.74 Low gas diets that exclude many complex carbohydrates reduce flatus frequency by up to 50% (Table 1).75 Food can be modified to reduce gas production. Soaking cowpeas and yam beans for 12 h prior to cooking degrades malabsorbed raffinose and stachyose.76 IBS patients with coeliac disease may respond to dietary gluten exclusion.64 In patients with food allergy with elevated IgG4 antibodies to food antigens, exclusion diets are reportedly beneficial.65 Lifestyle changes are useful for selected patients. Aerophagia may be reduced by stopping gum chewing and smoking. Chronic belchers may improve after observing their swallowing mechanics in a mirror. Mild exercise can enhance clearance of jejunal gas loads in IBS.77 Gas-trapping undergarments are available for those with excess malodorous flatus.3 Enzymes, adsorbents, and agents to reduce surface tension Luminally active agents are available to treat gaseous symptoms. Exogenous enzymes help breakdown undigested food (Table 2). b-galactosidase (lactase) reduces hydrogen Table 1. Foods which promote significant gas production. Dairy products Vegetables Onions Beans Celery Carrots Brussels sprouts Fruits Raisins Bananas Apricots Prune juice Complex carbohydrates Pretzels Bagels Wheat germ Source: Adapted from Ref. 75.

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Table 2. Medication therapies of gas and bloating. Medication class Enzyme preparations

Examples

Comments

b-galactosidase (lactase)

For lactose intolerance; variable effectiveness in lactose intolerant IBS patients Effective for legume-rich meals in healthy volunteers Uncertain efficacy for gas and bloating of any cause

a-galactosidase Pancreatic enzymes Adsorbents and agents that reduce surface tension

Simethicone Activated charcoal Bismuth subsalicylate

Treatments to modify gut flora

Antibiotics Probiotics (Lactobacillus sp., Bifidobacterium sp.) Prebiotics

Prokinetic medications

Tegaserod Neostigmine

Possible benefits in functional dyspepsia and gas with diarrhoea; uncertain benefits in IBS Possible benefits in gas production and malodorous flatus; charcoal-lined undergarments are available Possible benefits in reducing malodorous flatus Useful for bacterial overgrowth secondary to organic disease; possible benefits in IBS Possible benefits in IBS Uncertain benefits in IBS Reduces bloating in IBS; removed from market Reduces luminal distention in acute colonic pseudoobstruction; uncertain benefits in bloating

excretion and symptoms with lactose intolerance. Bacterial a-galactosidase from Aspergillus niger (Beano) reportedly reduces flatulence in healthy volunteers who eat chili.78 However, most indigestible fibre does not contain galactose thus this agent is unlikely to produce benefit when foods not containing legumes are eaten. Pancreatic enzymes reduce bloating and fullness after high calorie, fatty meals in healthy individuals, but their use for unexplained gas and bloating is unexplored.79 Agents which reduce surface tension of gas bubbles and adsorbents often are employed for gas symptoms (Table 2). Simethicone promotes rupture of thick foam films, but its effects on hydrogen production are inconsistent. Benefits of simethicone are reported in functional dyspepsia and with diarrhoea-associated gas discomfort.80,81 Activated charcoal reduced flatulence and hydrogen production after carbohydrate-rich meals in two studies, but others observed no improvement.82,83 Reductions in flatus odour with charcoal are undocumented. In flatulent patients, bismuth subsalicylate reduces raffinose fermentation and may reduce flatus odour.84 The utility of these preparations in IBS with bloating is unexplored. Treatments to modify gut flora Antibiotics provide benefit to selected gaseous syndromes (Table 2). Proven bacterial overgrowth may responds to single prescriptions of oral antibiotics, but some individuals require multiple or rotating courses. Short-term benefits are reported with antibiotic treatment of IBS. In an uncontrolled study in IBS patients, hydrogen production was reduced by metronidazole.85 In 111 IBS patients, neomycin reduced IBS symptoms by 35% versus 11% with placebo.86 In constipation-predominant IBS patients, neomycin reportedly reduced symptoms more than placebo—especially in those who produced excess methane during lactulose breath testing.87 The nonabsorbable antibiotic rifaximin has been reported to reduce gas symptoms in patients with functional disorders in open label and placebo-controlled trials.88 In a more recent, double-blind

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placebo-controlled trial in 87 IBS patients, rifaximin reduced bloating, bowel disturbances, and abdominal discomfort for at least 10 weeks.89 Another means to modify gut flora is to replace pathogenic organisms with innocuous strains (Table 2). Such probiotics may enhance the epithelial barrier, decrease luminal pH, block bacterial adhesion, and release neuroactive mediators.90 Controlled trials of the probiotic VSL#3 in IBS show reductions in flatulence or bloating without improvement in pain or bowel disturbance.91 VSL#3 increases Lactobacillus, Streptococcus thermophilus, and Bifidobacteria populations and reduces faecal b-galactosidase and urease levels.92 A recent study with Bifidobacterium infantis reported decreased pain, bloating, distention, and defecatory difficulty in IBS associated with reversal of proinflammatory interleukin-10 to interleukin-12 ratios, suggesting modulation of gut immunity.93 In a multicenter trial, reductions in bloating scores and other IBS symptoms with B. infantis exceeded those with placebo by >20%.94 Other probiotics reportedly reduce symptoms in some individuals.95 Diet changes also may influence enteric microbial activities. In an IBS study, consuming an elemental diet reduced hydrogen excretion and symptoms.96 Another means of altering gut flora is by use of prebiotic nutrients such as inulin, lactulose, oligofructose, and galacto-oligosaccharides that selectively promote growth of beneficial bacteria.97,98 In healthy volunteers, short-chain fructo-oligosaccharides increase faecal bifidobacteria and total anaerobes but have no effect on Bacteroides, Lactobacillus, or enterobacterial counts.99 Bifidobacteria possess high b-fructosidase levels that hydrolyze b1-2 glycosidic bonds in oligofructose and inulin, representing a possible mechanism for the effect of prebiotics.100 The utility of prebiotics alone or in combination with probiotics in IBS is being explored. Prokinetic medications Drugs that stimulate gut propulsion may benefit patients with pathologic gas retention (Table 2). The 5-HT4 agonist tegaserod reduced bloating in controlled trials of constipation-predominant IBS.101 In healthy volunteers, tegaserod stimulates transit of jejunally perfused gas mixtures but its actions on gas transit in IBS are not well characterised.102 However, tegaserod was withdrawn from the US market in March 2007 because of cardiovascular adverse events. Likewise, the acetylcholinesterase inhibitor neostigmine stimulates flow of intestinal gas in IBS patients and those with functional bloating and reduces distention and symptoms.103 The benefit of neostigmine to treat gas and bloating has not been confirmed in controlled trials. Effects of other IBS medication classes on bloating Other therapies are effective for selected IBS patients with gas and bloating. In placebocontrolled trials, selective serotonin reuptake inhibitors such as citalopram and fluoxetine reduce bloating independent of effects to reduce anxiety or depression.104,105 Herbal extracts containing Mentha spicata and Coriandrum sativum reduce bloating more than placebo in IBS, purportedly due to their antispasmodic effects.106 Hypnotherapy and acupuncture have been reported to reduce gaseous symptoms in IBS.107 SUMMARY Gas and including bloating are commonly reported by IBS patients and have significant impact on normal daily function. Bloating may result from increased gas production

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from bacterial fermentation of undigested food, retarded gas transit, heightened sensitivity of the gut to normal luminal gas volumes, or dysfunctional abdominal wall musculature. Patients who satisfy the Rome criteria for IBS may need only limited diagnostic evaluation. In addition to screening tests, patients with prominent bloating may undergo serologic testing to exclude coeliac disease and breath testing to screen for carbohydrate intolerance or small intestinal bacterial overgrowth. Treatment of gaseous symptoms in IBS should target pathophysiologic defects if possible. If no pathogenic factor is identified, many empiric therapies are available. The diet may be adjusted to exclude malabsorbed carbohydrates or gas-forming foods, while lifestyle modifications include measures to limit aerophagia and initiation of exercise. Enzyme preparations include lactase, a-galactosidase, and pancreatic enzymes. Luminally active agents such as simethicone and charcoal are often recommended. There is limited evidence that these agents are beneficial in most patients. Current investigation is focussing on probiotic, antibiotic, and prebiotic preparations to modify the colonic microflora. Finally, agents that promote gut transit are propose to facilitate gas expulsion in patients with gas retention.

Practice points  Bloating in IBS may be secondary to increases in gas production from bacterial fermentation of undigested food residue, retardation of luminal gas transit, heightened sensitivity of the gut to normal amounts of retained gas, and dysfunction of the abdominal wall musculature.  Most IBS patients may not need additional diagnostic evaluation for bloating. Serologic testing for coeliac disease may be performed; breath testing can screen for carbohydrate intolerance syndromes and small intestinal bacterial overgrowth.  Treatment of gaseous symptomatology in IBS should be targeted to pathophysiologic defects whenever possible.  Available therapies include lifestyle alterations, dietary modifications, enzyme preparations, adsorbents and agents which reduce surface tension, treatments that alter gut flora, and drugs that modulate gut transit.

Research agenda  Further investigation into the pathogenesis of bloating must define the relative importance of visceral motor and sensory defects and somatic muscular dysfunction in the induction of gaseous symptomatology in IBS.  Abnormal gut flora composition and distribution, including small intestinal bacterial overgrowth, must be characterised in IBS patients with bloating.  Similarly, the benefits of therapies designed to modify enteric microbial populations including antibiotics for bacterial overgrowth as well as abnormal colonic flora, probiotics, and prebiotic oligosaccharides must be defined.  Use of prokinetic treatments to prevent gas retention is conceptually compelling, however, evidence needs to be provided to support the prescription of these agents.

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