A review of the role of the gut microflora in irritable bowel syndrome and the effects of probiotics

British Journal of Nutrition (2002), 88, Suppl. 1, S67–S72 A review of the role of the gut microflora in irritable bowel syndrome and Gastroenterology Research Unit, Unit E7, Box 201 A, Addenbrookes NHS Trust, Hill’s Road, Cambridge CB2 2QQ, UK Irritable bowel syndrome (IBS) is a multi-factorial gastrointestinal condition affecting 8 – 22 %of the population with a higher prevalence in women and accounting for 20 – 50 % of referrals togastroenterology clinics. It is characterised by abdominal pain, excessive flatus, variable bowelhabit and abdominal bloating for which there is no evidence of detectable organic disease.
Suggested aetiologies include gut motility and psychological disorders, psychophysiologicalphenomena and colonic malfermentation. The faecal microflora in IBS has been shown to beabnormal with higher numbers of facultative organisms and low numbers of lactobacilli andbifidobacteria. Although there is no evidence of food allergy in IBS, food intolerance hasbeen identified and exclusion diets are beneficial to many IBS patients. Food intolerancemay be due to abnormal fermentation of food residues in the colon, as a result of disruptionof the normal flora. The role of probiotics in IBS has not been clearly defined. Some studieshave shown improvements in pain and flatulence in response to probiotic administration,whilst others have shown no symptomatic improvement. It is possible that the future role ofprobiotics in IBS will lie in prevention, rather than cure.
Gut microflora: Irritable bowel syndrome: Probiotics: Fermentation several drug classes, including antineoplastic drugs,immunosuppressive agents and histamine H2 antagonists Irritable bowel syndrome (IBS) is a poorly understood gas- (Hooker & dePiro, 1988; Neilson et al. 1994). Over 40 % trointestinal (GI) condition that typically begins in early of patients questioned in a retrospective study attributed adult life (Maxwell et al. 1997). It is believed to affect the onset of their symptoms to a definite event, such as a approximately one-fifth of the population, though it is esti- course of antibiotics, abdominal or pelvic surgery, or a mated that 60 – 75 % of symptomatic people do not seek bout of gastroenteritis (Hunter & Alun Jones, 1985).
medical attention in the UK (Farthing, 1995). Typical The role of bacterial gastroenteritis in the onset of IBS symptoms include abdominal pain, excessive flatus and symptoms has been extensively studied. Gwee et al.
variable bowel habit for which no endoscopic, radiological, (1996) provided questionnaires to a group of seventy histological, biochemical or microbiological cause is patients admitted to hospital with acute gastroenteritis.
apparent. The lack of positive tests makes the diagnosis of Twenty-two of these patients later developed symptoms IBS one of exclusion (Maxwell et al. Modified compatible with IBS and, of these, twenty still had persist- Rome Criteria (Thompson et al. 1999; provide a ent symptoms after six months. Similarly, Neal et al.
means of standardisation of patients with IBS recruited to (1997) investigated a cohort of 544 people with a lab- research studies, but do not allow a specific diagnosis.
oratory-confirmed diagnosis of bacterial gastroenteritis.
The cause of IBS is not yet known. Suggestions include Questionnaires were sent to the patients relating to their psychosocial factors, altered GI motility, heightened sen- bowel habit prior to, and after, their episode of gastroenter- sory function of the intestine, or malfermentation of food itis. The Modified Rome Criteria were used to assess the residues (Hunter, 1991; Camilleri, 2001). It may be that questionnaires for IBS symptoms. Twenty-five per cent IBS is, in reality, a group of separate conditions producing of subjects reported persistence of altered bowel habit after six months, with one in fourteen developing symp- Interest in fermentation arose from the suggestion that toms consistent with IBS. The risk of developing IBS disruption of the intestinal microflora may be important was increased in women and those in whom the gastroen- in the pathogenesis of IBS. Gastroenteritis, surgery and teritis caused diarrhoea of longer duration.
antibiotics are all known to alter the microflora as are In a similar study, Rodrı´guez & Ruigo´mez (1999) Abbreviations: GI, gastrointestinal; IBS, irritable bowel syndrome.
* Corresponding author: Dr J. O. Hunter, fax +44 1223 211443, email [email protected] Table 1. The Modified Rome Criteria for IBS (Thompson et al.
antibiotics (Finegold et al. 1983). Antibiotics are some- times valuable in the treatment of IBS, supporting sugges-tions that the indigenous microflora may play an important At least 6 months of recurrent symptoms of abdominal pain/discom-fort which is: The possible role of antibiotics in the aetiology of IBS and/or associated with a change in stool frequency has been investigated in two prospective studies. Alun and/or associated with a change in stool consistency Jones et al. (1984) initiated a prospective, double-blind controlled study involving 300 patients undergoing hyster- ectomy who were administered either prophylactic metro- nidazole or a placebo. They found a greater incidence of IBS-type symptoms following antibiotic prophylaxis than those receiving the placebo and postulated that a form of IBS exists which follows antibiotic administration. Men- bloating or feeling of abdominal distension at least 25 % of the dall & Kumar (1998) investigated 421 subjects attendinga general practice clinic. Using the Manning Criteria,forty-eight subjects screened had symptoms of IBS and investigated the risk of IBS after bacterial gastroenteritis.
this was strongly associated with the use of antibiotics They examined a group of patients with a first episode of (odds ratio (OR) 3·7; 95 % CI 1·80, 7·60).
bacterially confirmed gastroenteritis and compared them The risk of developing IBS following a course of anal- with a large control cohort of patients obtained from the gesics (paracetamol, aspirin, or non-aspirin anti-inflammatory General Practice Research Database. Those with a previous drugs) was also examined in one study. A self-reporting history of IBS, cancer or alcoholism were excluded. A questionnaire was sent to 892 eligible subjects, of whom follow-up after one year showed that, of the 575 169 643 responded. Of the responders, 12 % reported symptoms people in the control group, 2027 developed IBS (inci- related to IBS and the presence of IBS was significantly dence/1000 persons years 3·5). In contrast, twelve of the associated with the use of analgesics (adjusted OR 4·25; 303 gastroenteritis patients developed IBS (incidence/ 95 % CI 1·36, 13·31) It was suggested, however, that the 1000 persons years 39·7; relative risk 11·9). These data use of analgesics was to relieve somatic pains associated provide strong evidence that at least one form of IBS with IBS, rather than that analgesics were important in may be caused by bacterial infections. Such is the evidence the pathogenesis of IBS (Locke et al. 2000).
supporting the role of bacterial infection in the aetiology ofIBS that Gwee (2001) suggested that the term post-infec-tious irritable bowel syndrome should be used in patients The intestinal microflora in irritable bowel syndrome who present with IBS-type symptoms following a recentconfirmed or presumed exposure to infectious organisms, There is considerable evidence to show that factors that or those who have recently returned from a tropical or disturb the gut microflora may contribute to the develop- ment of IBS. It seems that such damage to the flora may Antibiotics have also been implicated in the pathogen- become permanent. The intestinal microflora in IBS esis of IBS. Antibiotics are one of the most likely (instead patients has been studied extensively by conventional of potential) causes of disruption of the normal GI micro- microbiological techniques. Balsari et al. (1982) investi- flora and are widely used in both human and veterinary gated the faecal flora of twenty patients with IBS. The medicine. The composition of the GI microflora of man faecal flora of IBS patients had significantly lower numbers is known to be relatively stable in normal conditions, so of coliforms compared with controls and also significantly that certain bacterial species can be consistently detected lower numbers of both lactobacilli and bifidobacteria. They in samples collected from the GI tract (Savage, 1977).
concluded that, although the faecal microflora of patients The stability of the normal human GI microflora is the con- with IBS was qualitatively very similar to healthy individ- sequence of several factors including gastric acidity, gut uals, there were considerable quantitative differences in motility, bile salts, immunological defence factors, colonic pH and competition between micro-organisms for nutrients Bradley et al. (1987) examined in detail the faecal flora and intestinal binding sites (Marshall, 1999). These of a patient who suffered from food-related IBS. They together provide a barrier to disruption of the flora that is found a considerable variation in total bacterial counts known as colonisation resistance (Van der Waiij, 1983).
over an 18-month period ranging between 1·3 £ 1010 and Antibiotics are unarguably important for the treatment 5·9 £ 1011 cfu=g dry weight with a high proportion of and prophylaxis of disease (Lidbeck & Nord, 1994) but it facultative organisms, dominated by Streptococcus spp., has been demonstrated both in humans and animals that Escherichia coli and Proteus spp. The dominant anaerobic they can detrimentally affect the ecological balance of organisms were Clostridium spp. rather than the usual Bac- the GI microbiota by affecting the indigenous bacterial teroides spp. or Bifidobacterium spp.
populations as well as the target population (Lidbeck & Wyatt et al. (1988) examined the faecal microflora of Nord, 1993; Witsell et al. 1995). The indigenous flora two patients with food-related IBS before and after chal- takes part in many physiological and pathophysiological lenge with foods known to provoke symptoms. There was reactions and may influence the metabolic activities of little change in the major bacterial species during the food certain drugs. All these activities can be affected by challenges, though in one patient, levels of bifidobacteria and lactobacilli increased from 21 % to 43 % of the total Factors influencing fermentation in the colo summarised by Macfarlane & Gibson (1995; It The caecal biopsy-associated, caecal luminal and faecal has been shown that fermentation gases an microflora were investigated in six IBS patients fulfilling important role in the aetiology of IBS. The quantity of the Modified Rome Criteria and six controls. Patients gas in IBS patients was shown to be greater than in healthy received a single 100 ml phosphate enema, rather than subjects (Koide et al. 2000) while patients with IBS were full bowel preparation, to clear the left side of the bowel shown to have impaired transit and tolerance of intestinal leaving the right side, including the caecum, undisturbed.
gas, which may in turn cause bloating (Haderstorfer et al.
Carbon dioxide rather than oxygen was used to insufflate the bowel, to maintain anaerobic conditions. There were It has been suggested that IBS may be caused by malfer- significantly higher numbers of anaerobes in the stools of mentation of food residues entering the caecum from the healthy subjects compared with IBS patients. In IBS small bowel, leading to over-production of fermentation patients, lactobacilli were present in the caecal mucosae gases, particularly hydrogen. The role of colonic malfer- and caecal lumen, but were not detectable in the faeces.
mentation was illustrated in a study by King et al. (1998) Aerobes were detected in the caecal mucosae of five IBS in a controlled cross-over trial consisting of six female patients compared with two of the healthy subjects patients fulfilling the Rome Criteria for IBS. These and six female control subjects, both carefully matched for Thus there is evidence that the intestinal microflora of macronutrients and substrates for fermentation, were patients with IBS differs from that of healthy individuals.
placed for two weeks on a standard diet followed by an However, it is not yet possible to be certain whether the exclusion diet for the same period. On the final day of changes in the intestinal microflora seen in IBS patients each diet period, total excretion of hydrogen and methane are the cause of IBS, or are merely a result of the disturbed was measured over a 24 h period by indirect calorimetry.
gut motility that IBS causes. More studies are desirable to After this period, patients ingested 20 g lactulose and breath hydrogen and methane excretion were measured It is possible that the differences in the gut microflora of over a 3 h fasting period. On the standard diet, IBS patients patients with IBS produce abnormal colonic fermentation.
had a significantly higher maximum rate of gas production Fermentation can be defined as the anaerobic breakdown although total gas production was not greater than in con- of carbohydrate and protein by bacteria (Cummings & trols. Following the exclusion diet, the maximum rate of Macfarlane, 1991). Digestible material such as acetate, gas production and hydrogen production fell in IBS butyrate and propionate are removed from the lumen patients and coincided with a significant improvement in through the wall of the small bowel so indigestible material symptoms. The authors postulated that this may be asso- must provide the major nutrient source to the colonic ciated with alterations in fermentation activities of hydro- microflora, alongside desquamated mucosal cells from gen-utilising bacteria and that fermentation may be of the small bowel and small bowel secretions (Hill, 1995).
importance in the pathogenesis of IBS.
Stephen & Cummings (1980) showed that bacterial fer- It is thought that malfermentation in IBS may be linked mentation not only generated energy from carbohydrates, inextricably with food intolerances, which are a feature in a but also the intermediates required for protein production subgroup of patients with IBS. The term ‘food intolerance’ to support bacterial mass. It is thought that the bacterial can be defined as a non-immunologically mediated adverse mass in the colon is partly determined by the amount of reaction to food, which can be resolved following dietary complex carbohydrate. This would in turn ultimately deter- elimination and reproduced by food challenge (Zar et al.
mine the types of bacterial species present and may con- 2001). Generally, patients who suffer from food intoler- tribute to some of the symptoms present in IBS patients.
ance and/or colonic malfermentation present with abdomi-nal pain, excess flatus and diarrhoea (Hunter & Alun Jones,1985). The role of food in the aetiology of IBS is Table 2. Factors influencing fermentation in the colon (Macfarlane illustrated in Alun Jones et al. (1982) found that, in a study of twenty-one patients, specific foods were found toprovoke symptoms in fourteen patients. However, no Chemical composition of the substrateAmount of available substrate changes were found in levels of plasma glucose, histamine, Physical form of the substrate, including particle size, solubility and immune complexes, haematocrit, eosinophil count or association with indigestible complexes such as lignins, tannins breath hydrogen excretion produced after either control or symptom-provoking foods. As there are no raised serum levels of immunoglobulin E, it is unlikely that Composition of the gut microbiota with respect to species diversity and relative numbers of different types of bacteria patients with food-intolerant IBS suffer from classical Ecological factors, including competitive and cooperative immunologically mediated food allergies. Nanda et al.
(1989) invited 200 patients with IBS to take part in an exclusion diet for three weeks. Of the 189 who completed Substrate specificities and catabolite regulatory mechanisms of the study, ninety-one (48·2 %) showed symptomatic Fermentation strategies of individual substrate-utilising bacteria improvement and 50 % of these identified two to five Availability of inorganic electron receptors One hundred and twenty-nine patients given an exclu- sion diet for two weeks led to an improvement in 41 % criteria, in the Lacteol group in comparison to those receiv-ing placebo.
Hunter et al. (1996) administered 1010 cfu/d of Entero- coccus faecium PR88 to twenty-eight patients with highvolume diarrhoea caused by food intolerance for twelveweeks. The probiotic organism was identified in thestools of all subjects at 108/g. An increase in levels ofPR88 corresponded with a decrease in excretion of Strepto-coccus faecalis, which ceased when PR88 feeding wasstopped. There was also a symptomatic improvement innineteen of the twenty-eight patients and a significantdecrease in faecal weight. PR88 was undetectable in thefaeces of all subjects within two weeks of cessation of sup-plementation. There were no alterations in the faecalmicroflora and normal biochemical and haematologicalparameters throughout the study. Although this was a suc-cessful study, the lack of controls means that it must beinterpreted with caution.
Several trials of probiotics in IBS have used Lacto- bacillus plantarum 299v as the main probiotic organism,with varying results. Niedzielin et al. (1998) administrateda solution of L. plantarum 299v to IBS patients in fourforms: on its own, with either trimebutin or merbeverine(two drugs frequently used in the treatment of IBS), or insolution in a pasteurised form. They found that supplemen- Fig. 1. The potential role of food in the aetiology of IBS.
tation of the probiotic in active form, with or without thedrugs, produced a greater improvement of symptoms than of the patients, though subsequent identification of more administration of the inactivated probiotic, or of the uncommon food intolerances in 22 % patients resulted in drugs alone. Nobaeck et al. (2000) studied sixty patients an overall success rate of 63 % (Parker et al. 1995). Six with IBS who were administered a rose-hip drink contain- hundred and forty-three subjects responded to a question- ing 2 £ 1010 cfu L. plantarum (DSM 9843), or a placebo naire relating food to IBS symptoms. Of these, 25 % drink similar in taste and colour for four weeks. This reported having sensitivity to foods (OR 2·35; 95 % CI strain was the same as that used in the previously men- 0·41, 3·93), with just 3 % of these reporting a swelling of tioned study. Over 40 % of patients in the study group the lips, or a rash. The authors suggested that these food reported a less than 50 % reduction in flatulence, compared sensitivities were a consequence of the IBS, rather than with 18 % in the placebo. However, gut function in this its cause (Locke et al. 2000). However, the objective study was based entirely on subjective assessments. Fur- changes demonstrated in gas production, prostaglandins thermore, although flatus was reduced in the test group, and cytokines in other reports after food challenges in it also fell significantly in the controls suggesting an over- IBS patients make this unlikely (Alun Jones et al. 1982; all placebo effect. There was no difference between the King et al. 1998; Jacobsen et al. 2000).
two groups regarding stomach bloating.
Sen et al. (2001) investigated the role of L. plantarum 299v on symptoms and colonic fermentation in twelvepatients with IBS, in a double-blind, controlled, cross- The role of probiotics in irritable bowel syndrome over 4-week trial. Patients received 6·25 £ 109 cfu/d L.
Probiotics are living micro-organisms that, upon ingestion plantatrum 299v, or a placebo drink similar in taste and in certain numbers, exert health benefits beyond basic colour. Fermentation was assessed by indirect calorimetry inherent nutrition (Guarner & Schaafsma, 1998). There over a 24 h period, after which breath hydrogen was have been few studies involving probiotics and IBS. This measured for 3 h after ingestion of 20 ml of lactulose.
may be because IBS is a multi-factorial condition making Although there was a significant decrease in breath hydro- it difficult to study homogeneous groups of patients.
gen levels in the probiotic group at 120 min after ingestion Halpern et al. (1996) carried out a randomised, double- of lactulose (P¼ 0·019), there was no decrease in total blind cross-over trial involving eighteen patients in the hydrogen production, or any symptomatic improvement.
treatment of IBS using Lacteol Fortw, an anti-diarrhoel The role of Lactobacillus casei strain GG (LGG) in IBS drug containing 5 £ 1010 heat-killed organisms/capsule of was studied in a randomised, double-blind cross-over trial.
Lactobacillus acidophilus, or a placebo. Each patient Twenty-four patients fulfilling the Rome Criteria for IBS received a 6-week treatment of Lacteol Fortw or placebo were entered into the study and randomised to receive and then, following a 2-week washout period, a further either 1 £ 1010 cfu/d enterocoated LGG or a placebo. Nine- 6-week period with either placebo or Lacteol Fortw.
teen patients completed the trial and there was no signifi- They demonstrated a statistically significant difference cant difference in pain, urgency or bloating between the (P¼ 0·018) in overall GI function, defined by clinical two groups, though there was a reduction in diarrhoea in the LGG group. The authors concluded that LGG alone did Fort: a randomized, double-blind, cross-over trial. American not have an effect on symptoms of IBS, though further Journal of Gastroenterology 91, 1579 – 1585.
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