Prebiotics and probiotics for gastrointestinal health

Clinical Nutrition (2001) 20(Supplement 1): 41-45 9 2001 Harcourt Publishers Ltd doi: 10.1054/clnu.2001.0403

Prebiotics and probiotics for gastrointestinal health E MARTEAU Gastroenterology Unit, European Hospital Georges Pompidou, AP-HR and Paris V University, Paris, France (Correspondence to."PM, Service de Gastro-ent#rologie, HOp#a~Europ6en Georges Pompidou, 25 rue Leblanc, 75015 Paris, France) Abstract--Accumulating research evidence suggests that probiotics and prebiotics, which both influence the endogenous flora, may have a role in human therapies, especially in the prevention of digestive diseases. This article summarises the current knowledge on their fate in the gastrointestinal tract (survival, adherence, colonization, or metabolism), mechanisms of action, potential adverse effects and proven effects. It presents and comments on the results of randomized controlled trials using various probiotics to treat lactose intolerance, antibiotic associated diarrhoea, gastroenteritis, intestinal infections and colonization by pathogenic bacteria, and inflammatory bowel disease. Finally, the results of randomized controlled trials that used prebiotics to treat constipation and hepatic encephalopathy are also discussed, as well as potential applications, especially colon cancer prevention. 9 2001 Harcourt Publishers Ltd.

Key words: probiotics; prebiotics; human health; gastroenteritis; antibiotic associated diarrhoea; inflammatory bowel disease

fate in the gastrointestinal tract and effects differ between strains (4). Some of them have a high survival capacity in the small bowel, and sometimes large bowel, whilst others are rapidly destroyed when they pass through the stomach or when they have contact with bile salts in the duodenum (4). Some strains can adhere to epithelial cell lines whilst others do not (5). Usually they do not colonize the intestinal mucosa for long periods of time, and are eliminated within a few days after the subject stops ingesting them (2); however, a few subjects have been shown to be colonized for long periods by some strains (6, 7). Whether this is good, bad or does not matter is not established at the present time. The effects can be direct or indirect through modulation of the endogenous flora or of the immune system (2). For example, the enhancement of the digestion of lactose is a direct effect of the presence of lactase in some bacteria such as LactobaciIlus delbrueckii subsp, bulgaricus (8). Administration of S. boulardii decreased the intestinal levels of Clostridium difficile in some patients (9). L. johnsonii strain LA1 significantly increased the blood levels of IgA in two studies (10, 11). The active ingredients of probiotics which are responsible for the biological effects are often unknown, except for some enzymes and cell wall components with immunomodulating properties. Probiotics are safe (12). Only a few cases of fungaemia during oral treatment with S. boulardii have been reported, all of them observed in hospitalized patients with a central catheter and they were probably due to the contamination of the air, environmental surfaces, or hands of the nurses following the opening of the packets of probiotics (13). One case of liver abscess due to a micro-organism similar to the probiotic strain L. rhamnosus GG was published (14). Chaiken reported

Introduction There is a growing interest in trying to improve gastrointestinal health (i.e. in trying to protect against gastrointestinal diseases or disturbances) with functional foods including probiotics and prebiotics. Probiotics are defined as living non-pathogenic micro-organisms which, when ingested, exert a positive influence on host health or physiology (1, 2). Prebiotics have been defined as non-digestible food ingredients that benefit the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon, that have the potential to improve host health (3). At the present time they essentially constitute non-digestible oligosaccharides (NDOs) which stimulate the growth of bifidobacteria. Many health claims have been made concerning probiotics and prebiotics; however only a few products have been shown to be efficacious in randomized placebo-controlled clinical trials (RCTs). This article reviews the current knowledge on the pharmacology and the proven effects of probiotics and prebiotics in man.

Pharmacology Probiotics Probiotics consist of either yeast, especially Saccharomyces, or bacteria, especially lactic acid bacteria. Their 41

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PREBIOTICS AND PROBIOTICS F O R GASTROINTESTINAL HEALTH

a patient in whom the ingestion of large amounts of yoghurt over a prolonged period may have favoured the relapse of autoimmune hepatitis (15).

Prebiotics NDO are not or incompletely absorbed in the small bowel. They exert an osmotic effect in the intestinal lumen, and are totally or partly fermented in the colon into short chain fatty acids and gas. They include lactose in lactose maldigesters, polyols, fructo-oligosaccharides, etc. Resistant starch has a similar fate. They are not only present in normal foods, but are also used in functional food products or as drugs (16). NDOs influence the endogenous ecosystem: they decrease colonic pH, and some of them increase the population of bifidobacteria (16,17). Intolerance symptoms can be due to the osmotic effect and/or fermentation, and can originate from the small bowel and/or the colon. The osmotic effect may induce borborygmi, abdominal pain, and eventually diarrhoea if the capacity of the colon to absorb water and electrolytes is exceeded. Fermentation produces gas that may also induce borborygmi, abdominal pain, and excessive flatus, but it decreases or may even suppress diarrhoea (18). As a rule, the first symptoms are borborygmi and excessive flatus; painful symptoms, i.e. bloating and cramps, occur at higher doses, and diarrhoea is always the last intolerance symptom occurring with high doses. The tolerance of NDOs is usually very good (19). It depends on the type of NDO, the time of consumption (worse in the fasting state than after a meal), and individual factors such as absorption capacities, motility patterns, colonic responses, intestinal sensitivity, and the presence of irritable bowel syndrome (19).

Effects of probiotics in the gastrointestinal tract

S. cerevisiae, i.e. a yeast which contains the enzyme sucrase (21). A recent trial has shown that a genetically modified bacterial strain producing lipase could help lipid digestion in pigs with experimental pancreatic insufficiency (22). Antibiotic associated diarrhoea Diarrhoea is a frequent complication of antibiotic treatment which results from a microbial imbalance (decreased colonization resistance and fermentation capacity). CloStridium difficile is involved in some cases. Several randomized double blind RCTs have demonstrated a significant effect with S. boulardii, L. rhamnosus GG, and Enterocococcus faecium SF68 (see details and references in 20). The therapeutic efficacy of other probiotics is not so well established. Gastroenteritis Several RCTs have demonstrated a beneficial effect of probiotics in infantile or adult gastroenteritis, but this is not a general property of all probiotics (20). L. rhamnosus GG (L. GG, Valio, Finland) has been shown to be effective in the treatment of infant rotavirus diarrhoea and reduced the duration of diarrhoea by about 50% in several controlled trials. Guandalini et al. performed a double-blind multicentre trial in 287 children with acute diarrhoea who received an oral rehydration solution plus L. GG or placebo (23). The duration of diarrhoea was significantly reduced by L. GG in the children with rotavirus infection: 56 + 17 h vs. 77_+ 42, but not in those who were rotavirus negative. E. faecium strain SF 68 (Bioflorin | Giuliani, Switzerland) significantly shortened diarrhoea in four RCTs (see 20 for review). Saavedra et al. (24) showed in a double-blind placebo controlled trial that giving B. bifidum and S. thermophilus to infants significantly reduced the risk of diarrhoea and shedding of rotavirus during a long stay in hospital.

Proven effects Improved lactose digestion and other direct enzymatic effects Lactose maldigestion is frequent in adults ('primary lactose maldigestion'), and in subjects with small bowel resection or enteritis ('secondary lactose maldigestion'). The better digestion and tolerance of the lactose contained in yoghurt than that contained in milk in lactose maldigesters is well-established (2,8). Two mechanisms are involved: digestion of lactose in the intestine by the lactase contained in the yoghurt bacteria, and slower gastrointestinal transit time of yoghurt as compared to milk (2, 8, 20). In practice, replacement of milk by fermented dairy products allows better digestion and decreases intolerance symptoms in subjects with lactose intolerance (see 20 for review). Enhanced digestion of a sucrose load has been shown in infants with sucrase deficiency when they consumed

Other potential applications Intestinal infections and colonization by pathogenic bacteria Protective effects of probiotics against intestinal infections have been observed in animal models (2). The mechanisms may include the production of acids, hydrogen peroxide or anti-microbial substances, competition for nutrients or adhesion receptors, anti-toxin actions, and stimulation of the immune system. Open trials suggested that some probiotics may help to eradicate Salmonella, Campylobacter or C. difficile (20); however, they do not have the same degree of scientific rigour as RCTs. McFarland et al. performed a randomized study in 124 patients with C. difficile infection who received either S. boulardii or a placebo in combination with standard antibiotic treatment (25). The risk of recurrence was significantly reduced in the

CLINICAL NUTRITION

subjects with several episodes of C. difficile infection who received S. boulardii. Some probiotic strains are clearly antagonistic against Helicobacter pylori in vitro, but attempts to eradicate H. pylori in vivo with a probiotic have failed until now (20). A significant reduction of urease activity in vivo (which reflects the activity of H. pylori) has been reported in patients treated with a supernatant of L. johnsonii LA1 (26).

Traveller's diarrhoea Seven RCTs have attempted to demonstrate a protective effect of some probiotics against traveller's diarrhoea (see 20 for review). Three were negative, and the others had methodological problems that limit their interpretation. A protective effect of L. GG has been suggested in two. Various conditions with diarrhoea S. boulardii decreased diarrhoea associated with tube feeding in three trials (see 20 for review). The most recent was double-blind, and compared S. boulardii with placebo in 128 critically ill tube-fed patients (27). Treatment with the probiotic significantly reduced the percentage of days with diarrhoea from 18.9% to 14.2%. Inflammatory bowel disease Several studies have shown interesting effects of probiotics in animal models of inflammatory bowel disease (IBD). A growing number of studies have been performed in patients. Two RCTs suggested that an Escherichia coli preparation (E. coli strain Nissle, Mutaflor | Ardeypharm GmbH, Herdecke, Germany) was as effective as mesalazine (i.e. standard treatment) in maintaining remission of ulcerative colitis (28, 29). Two recent trials by Gionchetti and co-workers showed that the probiotic VSL#3 (CSL, Milan, Italy), containing 300 billion viable lyophilized bacteria of 4 strains of lactobacilli (L. casei, L. plantarum, L. acidophilus, L. bulgaricus), 3 strains of bifidobacteria (B. longum, B. breve, B. infantis), and 1 strain of S. thermophilus per gram, was more effective than placebo in reducing the risk of pouchitis (30, 31). Colon cancer The endogenous flora and the immune system play a role in the modulation of carcinogenesis. Both may be influenced by probiotics, and this has led to trials investigating the role of probiotics in preventing or curing tumours in animals (2). Several authors have shown that some probiotics may decrease the faecal levels of enzymes, mutagens, and secondary bile salts that may be involved in colon carcinogenesis (2). Clinical studies are currently ongoing in Europe to study the effects of some probiotics in subjects with colon adenomas.

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Effects of prebiotics in the gastrointestinal tract Proven effects

Treatment of constipation Several RCTs have demonstrated that lactulose is an effective treatment of constipation (16,32-34). The mechanism involved in the laxative effect is not fully understood, and seems to be multifactoriat. At high doses, lactulose (and probably all NDO) can induce an osmotic diarrhoea, however, at low doses (at which lactulose has a significant effect in patients), the osmotic effect is limited by fermentation (34, 35). An increase in faecal hydration, faecal bacterial mass and a stimulation of colonic motility by end products may contribute to clinical efficacy. Lactitol and other NDOs such as galacto-oligosaccharides, fructo-oligosaccharides, and lactose are also probably effective in alleviating constipation as well (16,36), although this needs to be confirmed.

Treatment of hepatic encephalopathy Substances derived from the metabolism of the gut flora are involved in the pathogenesis of hepatic encephalopathy (34, 37, 38). The therapeutic efficacy of lactulose has been demonstrated in RCTs. The side effects calculated from 18 studies concerning 298 patients were the following: flatulence 18%, diarrhoea 14.5%, abdominal pain 13% (38). The possible mechanisms of action include stimulation of bacterial growth, incorporation of ammonia into bacterial proteins, colon acidification, laxative effect, and possibly a shift in production of medium chain fatty acids to short chain fatty acids (34).

Other potential applications of prebiotics Prevention of colon carcinoma Fermentation reduces colonic pH, and may reduce the 7-dehydroxylation of primary bile salts. A role of carbohydrate fermentation in colon cancer prevention has thus been hypothesized (39), and studies in animal models have been encouraging. Several studies have shown that lactulose administration to healthy volunteers (40-60g/d) lowered faecal concentrations of secondary bile salts (40,41). However, in one study, administration of 60ml of lactulose/d for 12 weeks did not influence crypt cell proliferation assessed in rectal biopsies (42). Roncucci et al. reported in 1993 that lactulose decreased the recurrence rate of colon adenomas (43). Two hundred and fifty five patients with colon adenomas were randomized after removal of the adenomas to receive vitamins, lactulose (20 g/d) or no treatment. Colonoscopy was performed thereafter every 6 months. After a mean follow-up of 18 months, the percentages of recurrence of adenomas were 5.7% in the vitamin group, 14.7% in the lactulose group, and 35.9%

44 PREBIOTICS AND PROBIOTICS FOR GASTROINTESTINAL HEALTH

in the untreated patients. This study which may have important consequences needs to be confirmed.

Conclusions

Accumulating evidence suggests that probiotics and prebiotics, which both influence the endogenous flora, may have a therapeutic role in humans, especially in the prevention of digestive diseases. They are however obviously not a panacea, and results obtained with one product cannot be extrapolated to others. More randomized controlled studies are required to better establish their efficacy and tolerance in clearly defined groups of subjects.

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