JACN
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Quigley, E. M M
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Quigley, E. M M
Journal of the American College of Nutrition, Vol. 26, No. 6, 684S-690S (2007)
Published by the American College of Nutrition

Probiotics in Irritable Bowel Syndrome: An Immunomodulatory Strategy?

Eamonn M M Quigley, MD

Alimentary Pharmabiotic Centre, University College Cork, Cork, IRELAND

Address reprint requests to: Eamonn M M Quigley, Alimentary Pharmabiotic Centre, University College Cork, Cork, IRELAND. E-mail: e.quigley{at}ucc.ie


   ABSTRACT
TOP
 FOOTNOTES
 ABSTRACT
INTRODUCTION
 THE PROBIOTIC CONCEPT
 IS THERE A RATIONALE...
 WHAT IS THE EVIDENCE...
 REFERENCES
 
The clear delineation of a post-infective variety of IBS, as well as the description, in a number of studies, of evidence of low-grade inflammation and immune activation in IBS, suggest a role for a dysfunctional relationship between the indigenous flora and the host in IBS and, accordingly, provide a clear rationale for the use of probiotics in this disorder. Other modes of action, including bacterial displacement and alterations in luminal contents, are also plausible. While clinical evidence of efficacy is now beginning to emerge, a review of available trials emphasizes the importance of a clear definition of strain selection, dose and viability. The possible roles of co-therapy or sequential therapy with antibiotics, probiotics, prokinetics, or other agents also deserves further study. The role of the enteric flora is evidently an area of great potential in IBS; we are on the threshold of a new era of research and therapy for this common disorder.


   INTRODUCTION
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
THE PROBIOTIC CONCEPT
 IS THERE A RATIONALE...
 WHAT IS THE EVIDENCE...
 REFERENCES
 
Reflecting, perhaps, the paucity of truly disease-modifying therapies that are available to relieve the disorder, irritable bowel sufferers commonly have recourse to the use of complimentary and alternative medical remedies and practices [1]. Foremost among such approaches have been various dietary manipulations including exclusion diets [2,3], and a variety of dietary supplements. In Europe in particular, where several such products are advertised widely for their general "immune-boosting" and "health-enhancing" properties, probiotics have been widely used as dietary supplements by irritable bowel syndrome (IBS) patients. Recently, based on data from the experimental laboratory as well as some evidence from clinical trials, the concept of probiotic use in IBS has begun to wend its way into the realm of conventional medicine [4] and an assessment of the potential role of these agents in IBS is timely. This chapter will address two specific questions:

  1. Is their a rational basis for the use of probiotics in IBS?
  2. What is the evidence base for the efficacy of probiotics in IBS?


   THE PROBIOTIC CONCEPT
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 THE PROBIOTIC CONCEPT
IS THERE A RATIONALE...
 WHAT IS THE EVIDENCE...
 REFERENCES
 
Probiotics, a word derived from the Greek and meaning "for life", are defined as live organisms that, when ingested in adequate amounts, exert a health benefit on the host [5]. While the aforementioned definition confines the use of the term probiotic to products which contain live organisms, the probiotic concept has, of late, and perhaps inappropriately, been extended to include the use of killed organisms or even bacterial DNA. Prebiotics are defined as non-digestible but fermentable products that beneficially affect the host by selectively stimulating the growth and activity of one species, or a limited number of species of bacteria, in the colon [6]. Prebiotics stimulate the preferential growth of a limited number of health-promoting commensal microbiota already residing in the colon, especially, but not exclusively, lactobacilli and bifidobacteria [7,8]. The potency of this stimulus is, in part, dependent both on the baseline density of the target probiotic populations (bifidobacteria and/or lactobacilli) and luminal pH [9]. The oligosaccharides in human breast milk are considered the proteotypic prebiotic as they facilitate the preferential growth of bifidobacteria and lactobacilli in the colon in exclusively breast-fed neonates [10,11]. A combination of a probiotic and a prebiotic is referred to as synbiotic.

The interpretation of the literature on probiotics, not to mind the many claims that are made in the lay press and other media, is fraught with difficulties, many related to factors intrinsic to this area. Firstly, it is not unusual for the benefits of a given species or organism to be touted based on evidence derived from studies involving other organisms and species despite the fact that detailed studies have demonstrated in terms of a probiotic property, be it immune modulation [12–15] or anti-bacterial activity [13,16,17], there are tremendous differences between different lactobacilli and bifidobacteria, not to mind between lactobacilli and bifidobacteria, for example. No two probiotics are the same and extrapolations from one to another should be resisted at all times. Secondly, an individual who is about to consume a given probiotic preparation should know exactly what he or she is about to take: is it live, what is its concentration, will the organism survive as it makes contact with acid, bile, and digestive enzymes as it transits the gut, and what will be the actual concentration of the organism at it's desired site of action? Few probiotic preparations have been characterized and formulated with sufficient rigor to allow the manufacturer to provide answers to these critical questions. Of further concern, critical examinations of the actual constituents of commercially-available probiotic preparations have revealed worrying deviations from those included in the product label [18]. Finally, even fewer have been characterized in detail in terms of their microbiological properties, immunological, or physiological effects and only a handful have been subjected to clinical trial in man.


   IS THERE A RATIONALE FOR THE USE OF PROBIOTICS IN IRRITABLE BOWEL SYNDROME?
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 THE PROBIOTIC CONCEPT
 IS THERE A RATIONALE...
WHAT IS THE EVIDENCE...
 REFERENCES
 
While the precise cause of IBS remains obscure and theories of symptom pathogenesis abound, most hypotheses center on one or more of the following areas: an altered intraluminal milieu, immune activation, enteric neuromuscular dysfunction, and brain-gut axis dysregulation.

Alterations in the Intraluminal Milieu
For some time, various studies have suggested the presence of qualitative changes in the colonic flora in IBS patients; a relative decrease in the population of bifidobacteria being the most consistent finding [19–24]. It should be noted, however, that these findings have not always been reproduced and the methods employed have been subject to question. Nevertheless, qualitative changes in the colonic microbiota, be they primary or secondary, could lead to the proliferation of species that produce more gas [25], short chain fatty acids, and are more avid in the deconjugation of bile acids. The latter could, in turn, lead to clinically significant changes in water and electrolyte transport in the colon and affect colonic motility and/or sensitivity. Similarly, a repopulation of the flora with the deficient commensal could restore homeostasis. More recently, the role of the gut microbiota in IBS has been taken a stage further with the suggestion that some IBS patients may harbor quantitative changes in the indigenous microbiota in the small intestine: i.e. they have developed small intestinal bacterial overgrowth (SIBO) [26–30]. The occurrence of SIBO has been associated with abnormalities in small intestinal motor function [31] and its eradication with symptomatic relief [26,27]. Further evidence for a role for an altered indigenous flora in IBS is provided by a very recent study which described improvements in IBS symptomatology in the short term, following the administration of the non-absorbable antibiotic rifaximin to a group of patients who did not have SIBO at baseline [32]. Furthermore, a very recent study [33] has suggested more sustained effects for rifaximin therapy in IBS. Given reports of efficacy of probiotics in SIBO in other contexts [34], one can readily visualize opportunities for probiotic administration in this context. Such interventions, if successful, could lead to the elimination of symptoms resulting from bacterial fermentation [35]. One could, similarly, speculate that the efficacy of some probiotics in preferentially relieving "gas-related" symptoms may be related either to qualitative changes in the colonic flora as described above, or through the suppression of SIBO [36–43]. Manipulation of the bacterial flora may affect other aspects of the metabolic activity of the colonic microbiota [44]. Clearly, this is an area deserving of further study [45].

Certain probiotics possess potent anti-bacterial and anti-viral properties. Probiotic anti-bacterial activity may derive from the direct secretion of bacteriocins [46], the elaboration of proteases directed against bacterial toxins [47], or through their ability to adhere to epithelial cells and thus exclude pathogens. There is now a considerable body of evidence to support the concept of post-infectious irritable bowel syndrome (PI-IBS) [48,49]. An effective anti-bacterial probiotic could well play a role in preventing the 5–10% incidence of IBS that may follow an episode of confirmed bacterial gastroenteritis, especially among high-risk individuals [49,50]. The demonstrated anti-viral properties of some probiotic organisms, together with the well-documented efficacy of certain probiotics in the therapy of rotavirus diarrhea [51], suggests the potential for a broader role for these agents in bowel dysfunction triggered by infectious agents.

Immune Activation
Post-infectious IBS has been associated with a persistent, albeit subtle, inflammatory process in the colonic epithelium [52–55]. This inflammatory process has been associated with increases in enterochromaffin cells and intra-epithelial lymphocytes [53,54].

Evidence now accumulates to suggest an association between IBS, in general, and immune activation. Colonic biopsies have demonstrated, in some cases, frank inflammation and, in others, more subtle evidence of immune activation [56]. More recently, studies on cytokine levels in peripheral blood mononuclear cells [15] and even in serum [57] have revealed a pro-inflammatory state. It is interesting to note that constipation has also been associated with a partially reversible inflammatory activation of the colonic mucosa [58]. These studies have, to date, been performed in relatively small patient numbers and require confirmation. Even if ultimately only a subset of IBS is found to be associated with mucosal inflammation, it still provides yet another rationale for the use of probiotics. In experimental animal models of inflammatory bowel disease, various probiotics and probiotic cocktails have demonstrated potent anti-inflammatory properties, suppressing mucosal inflammation and restoring cytokine balance towards an anti-inflammatory state [12,13,15,17,59]. In man, the probiotic cocktail, VSL#3 (composed of Streptococcus thermophilus and several species of Lactobacillus and Bifidobacteria), has proven highly effective in preventing the initial development of pouchitis and dramatically reducing relapse rates among those who have been successfully treated by a course of antibiotics [60,61]. Most recently, the same probiotic cocktail has been shown to promote secretion of the anti-inflammatory cytokine IL-10, and suppress the secretion of the pro-inflammatory cytokine IL-12 in dendritic cells derived from the peripheral blood [14]. In the same study, a detailed evaluation of the various organisms that comprise this cocktail indicated that most of the immune modulating activity resided in bifidobacterial species [14]. Similar observations have been made in other models [17]. The suggestion that bifidobacteria may be especially potent as immuno-modulatory agents is consistent with our own observation that a symptomatic response to bifidobacterium infantis 35624 in IBS was associated with a normalization of a baseline abnormality in the ratio of IL-10 to IL-12 in peripheral blood mononuclear cells which was tilted towards a pro-inflammatory state [15]. The finding that some IBS patients exhibit polymorphisms in the anti-inflammatory cytokine IL-10 [62,63] suggests that IBS subjects may be predisposed to an abnormal immune response to an infectious agent.

Enteric Neuromuscular Dysfunction
For decades, dysmotility and visceral hypersensitivity have reigned supreme as the dominant factors in the pathophysiology of IBS [64]. Of late, visceral hypersensitivity has been in the ascendancy with the description, by some, of this phenomenon as ubiquitous in IBS [65–67] and the suggestion that many of the previously documented motor abnormalities may be non-specific and mere epiphenomena [64,68–70]. This is not to deny a role for dysmotility in symptom pathogenesis but rather to indicate that disturbed motor function may not be the primary abnormality in IBS. Both dysmotility and visceral hypersensitivity may indeed be secondary to other primary etiological factors. There is, for example, an abundant literature largely derived from animal models that indicates that immune activation can lead to disturbed motor function and increased activity in sensory pathways from the gut [71,72]. A recent study by Barbara and colleagues has extended this concept in man. In their IBS subjects, they observed an increased density of mast cells, the consequence perhaps of immune activation in the colonic mucosa and further noted a close correlation between the proximity of mast cells to neural elements and pain severity [73].

Probiotics have the potential to influence both motility and visceral sensation. In an animal model of post-infectious IBS, Collins’ group has demonstrated the ability of a probiotic to prevent and reverse dysmotility consequent upon an intestinal infestation [74]. Probiotics could, in theory, reverse many of the processes involved in the initiation or perpetuation of immune-mediated hypersensitivity through anti-pathogenic, barrier enhancing, and immune modulating effects [4]. Experimental data indeed now supports an effect of probiotics on visceral hypersensitivity [75–77] and has linked these benefits to anti-inflammatory [75], barrier enhancing [76], and neuromodulatory [75,76] actions. Most recently, Rousseaux and colleagues found that oral administration of specific Lactobacillus strains induced the expression of mu-opioid and cannabinoid receptors in intestinal epithelial cells and mediated analgesic functions in the gut-similar to the effects of morphine [78]. The idea that probiotics may reduce access for bacteria to the gut wall and, thereby, prevent a related immune activation is supported by other studies with other organisms [79,80].

Brain-Gut Axis Dysregulation
The advent of functional brain imaging as well as tests of autonomic function and the hypothalamic-pituitary-adrenal (HPA) axis have permitted an exploration of the various components of the gut-brain axis in IBS. Such studies have revealed aberrant cerebral activation, exaggerated HPA responses, and autonomic nervous dysfunction among some IBS subjects [81–85]. There is ample evidence from experimental animal studies for the ability of pro-inflammatory cytokines, and TNF{alpha}, in particular, to influence the hypothalamic-pituitary-adrenal axis [86]. Evidence is also beginning to accrue to suggest a role for inflammation in cerebral processes, such as depression [87]. Given their apparent ability to modulate cytokine balance in the periphery, could probiotics also exert an influence on these processes? In experimental animal models, orally-administered probiotics have been shown to abrogate inflammatory processes far from the bowel, such as in the liver [88] and synovial joints [89], raising the possibility of efficacy in such extra-intestinal accompaniments of IBS as fibromyalgia and fatigue [90]. Very recently, Dinan and colleagues have been able to detect elevated levels of the pro-inflammatory cytokine IL-6 in plasma among IBS patients, and documented a direct correlation between IL-6 and exaggerated ACTH and cortisol responses to corticotrophin releasing factor [57]. This intriguing finding suggests a direct link in IBS between inflammation, presumably of intestinal origin, and brain-gut axis dysregulation. Given the aforementioned demonstration of a normalization of systemic cytokine balance by a probiotic in IBS [15], it is appropriate to speculate that some, at least, of the efficacy of probiotics in IBS may be related to this effect. Clearly, this is an area deserving of further enquiry.


   WHAT IS THE EVIDENCE FOR PROBIOTIC EFFICACY IN IBS?
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 THE PROBIOTIC CONCEPT
 IS THERE A RATIONALE...
 WHAT IS THE EVIDENCE...
REFERENCES
 
A small number of studies have evaluated the response of IBS to probiotic preparations. While results between studies are difficult to compare because of differences in design, probiotic dose, and strain, there has been some, but by no means consistent, evidence of symptom improvement [15,36–43,91–94]. The overall impact of probiotics in IBS remains unclear. Hamilton-Miller, reviewing the evidence relating to the efficacy of probiotics in IBS in 2001 while drawing attention to the shortcomings of prior trials in terms of study design, concluded that there was sufficient evidence of efficacy to warrant further evaluation [95]. Most studies reviewed were small in size and almost certainly underpowered to demonstrate anything other than a very striking benefit. Several did not verify bacterial transit and survival by confirmatory stool studies. Many different organisms and strains were employed and dosage varied from as little as 105 to 1013. Furthermore some, including more recent studies, employed probiotic "cocktails" rather than single isolates, rendering it impossible to induce what if any, were the active moieties [36,37]. Nevertheless, some positive results were noted. Niedzielin reported resolution of abdominal pain in all 20 patients treated for four weeks with lactobacillus plantarum 299V, in contrast to only 11 of 20 patients who received a placebo [91]. Halpern and colleagues noted a significant reduction in an IBS symptom index with a capsule containing 5x109 heat-killed lactobacillus acidophilus organisms [92]. O'Sullivan and colleagues, while failing to detect an effect of lactobacillus casei GG on overall symptomatology, did note a trend towards reduction in bloating [93]. Nobaek et al, employing lactobacillus plantarum (DSM 9843) [94], described a similar benefit in terms of relief of bloating as did Kim and colleagues in their evaluation of the probiotic "cocktail" VSL#3 [36].

In our pilot study we compared, for the first time, the effects of two probiotic strains on symptoms in patients with irritable bowel syndrome [15]. We demonstrated superiority for bifidobacterium infantis 35624 over both a lactobacillus and placebo for each of the cardinal symptoms of the irritable bowel syndrome (abdominal pain/discomfort, distension/bloating and difficult defecation), as well as for a composite score. For each individual symptom, with the notable exceptions of bowel movement frequency and consistency, the group randomized. B. infantis experienced a greater reduction in symptom scores during the treatment period. These symptomatic benefits were associated with parallel trends in a quality of life measure developed specifically for IBS [15]. Furthermore, this therapy was well tolerated and free of significant adverse events. As these benefits were observed independent of any change in stool frequency or form, they could not be attributed to either a laxative or an anti-diarrheal effect. We have recently followed up this study with a larger, four-week duration, dose-ranging study of the same bifidobacterium in over 360 community-based subjects with IBS and confirmed efficacy for this organism in a dose of 108. All of the primary symptoms of IBS were significantly improved in the four-week study and a global assessment of IBS symptoms at the end of therapy revealed a greater than 20% therapeutic gain for the effective dose of probiotic over placebo [96]. While neither of these studies involved a comparison with any other therapeutic modality and their study design differed in some aspects from recent large trials of serotonergic agonists and antagonists, the therapeutic gain observed for bifidobacterium over placebo (20–25%) was certainly no less than that reported for tegaserod and alosetron (10–20%) [97,98]. This study with bifidobacterium infantis provides, therefore, clear evidence of a benefit in IBS for a clearly-defined single-organism probiotic preparation and suggests that some strains, bifidobacterium in particular, may be more effective than others for this indication. Further large, randomised controlled trials of this bifidobacterium strain are warranted in IBS and detailed explorations of its mechanism(s) of action are indicated. The possible roles of co-therapy or sequential therapy with antibiotics, probiotics, prokinetics, or other agents also deserve further study [99,100].


   FOOTNOTES
TOP
 FOOTNOTES
ABSTRACT
 INTRODUCTION
 THE PROBIOTIC CONCEPT
 IS THERE A RATIONALE...
 WHAT IS THE EVIDENCE...
 REFERENCES
 
Disclosure: Eamonn Quigley is associated with a campus company "Alimentary Health" which holds patents in probiotic technologies.

Received August 21, 2007.
   REFERENCES
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 THE PROBIOTIC CONCEPT
 IS THERE A RATIONALE...
 WHAT IS THE EVIDENCE...
 REFERENCES
 

  1. Hussein Z, Quigley EM: Complementary and alternative medicine in irritable bowel syndrome. Aliment Pharmacol Ther23 :465 –471,2006 .[Medline]
  2. Atkinson W, Sheldon TA, Shaath N, Whorwell PJ: Food elimination based on IgG antibodies in IBS: A randomised controlled trial. Gut53 :1459 –1464,2004 .[Abstract/Free Full Text]
  3. Zar S, Mincher L, Benson MJ, Kumar D: Food specific IgG4 antibodies guided exclusion diet improves symptoms and rectal compliance in IBS. Scand J Gastroenterol40 :800 –807,2005 .[Medline]
  4. Quigley EM: The use of probiotics in functional bowel disease. Gastroenterol Clin North Am34 :533 –545,2005 .[Medline]
  5. Schrezenmeir J, de Vrese M: Probiotics, prebiotics, and synbiotics-approaching a definition. Am J Clin Nutr73(Suppl2) :361S –364S,2001 .
  6. Gibson GR, Roberfroid MB: Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr125 :1401 –1412,1995 .[Abstract/Free Full Text]
  7. Roberfroid MB: Prebiotics: preferential substrates for specific germs?. Am J Clin Nutr73 (Suppl) :406S –409S,2001 .[Abstract/Free Full Text]
  8. Bouhnik Y, Flourie B, D'Agay-Abensour L, Pochart P, Gramet G, Durand M, Rambaud JC: Administration of transgalacto-oligosaccharides increases fecal bifidobacteria and modifies colonic fermentation metabolism in healthy humans. J Nutr127 :444 –448,1997 .[Abstract/Free Full Text]
  9. Duggan C, Gannon J, Walker WA: Protective nutrients and functional foods for the gastrointestinal tract. Am J Clin Nutr75 :789 –808,2002 .[Abstract/Free Full Text]
  10. Gnoth MJ, Kunz C, Kinne-Saffran E, Rudloff S: Human milk oligosaccharidases are minimally digested in vitro. J Nutr130 :3014 –3020,2000 .[Abstract/Free Full Text]
  11. Dai D, Walker WA: Prospective nutrients and bacterial colonization in the immature human gut. Adv Pediatr46 :353 –382,1999 .[Medline]
  12. McCarthy J, O'Mahony L, O'Callaghan L, Sheil B, Vaughan EE, Fitzsimons N, Fitzgibbon J, O'Sullivan GC, Kiely B, Collins JK, Shanahan F: Double blind, placebo controlled trial of two probiotic strains in interleukin 10 knockout mice and mechanistic link with cytokine balance. Gut52 :975 –980,2003 .[Abstract/Free Full Text]
  13. Madsen K, Cornish A, Soper P, McKaigney, C, Jijon H, Yachimel C, Doyle J, Jewell L, De Simone C: Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology121 :580 –591,2001 .[Medline]
  14. Hart AL, Lammers K, Brigidi P, Vitali B, Rizzello F, Gionchetti P, Campieri M, Kamm MA, Knight SC, Stagg AJ: Modulation of human dendritic cell phenotype and function by probiotic bacteria. Gut53 :1602 –1609,2004 .[Abstract/Free Full Text]
  15. O'Mahony L, McCarthy J, Kelly P, Shanahan F, Quigley EM: Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology128 :541 –551,2005 .[Medline]
  16. O'Mahony L, O'Callaghan L, McCarthy J, Shilling D, Scully P, Sibartie S, Kavanagh E, Kirwan WO, Redmond RP, Collins JK, Shanahan F: Differential cytokine response from dendritic cells to commensal and pathogenic bacteria in different lymphoid compartments in humans. Am J Physiol290 :G839 –G845,2006 .
  17. Jijon H, Backer J, Diaz H, Yeung H, Thiel D, McKagney C, De Simone C, Madsen K: DNA from probiotic bacteria modulates murine and human epithelial and immune function. Gastroenterology126 :1358 –1373,2004 .[Medline]
  18. Drisko J, Bischoff B, Giles C, Adelson M, Rao RV, McCallum R: Evaluation of five probiotic products for label claims by DNA extraction and polymerase chain reaction analysis. Dig Dis Sci50 :1113 –1117,2005 .[Medline]
  19. Madden JA, Hunter JO: A review of the role of the gut microflora in irritable bowel syndrome and the effects of probiotics. Br J Nutr88(Suppl 1) :S67 –S72,2002 .
  20. Si JM, Yu YC, Fan YJ, Chen SJ.: Intestinal microecology and quality of life in irritable bowel syndrome patients. World J Gastroenterol10 :1802 –1805,2004 .[Medline]
  21. Malinen E, Rinttila T, Kajander K, Matto J, Kassinen A, Krobius L, Saarela M, Korpela R, Palva A: Analysis of the fecal microbiota of irritable bowel patients and healthy controls with real-time PCR. Am J Gastroenterol100 :373 –382,2005 .[Medline]
  22. Sun X, Cai G Wang WG: Observation on intestinal flora in patients of IBS after treatment of Chinese integrative medicine. Zhong Xi Yi Jie He Xue Bao2 :340 –342,2004 .[Medline]
  23. Balsari A, Ceccarelli A, Dubini F, Fesce E, Poli G: The fecal microbial population in the irritable bowel syndrome. Microbiologica5 :185 –194,1982 .[Medline]
  24. Bradley HK, Wyatt GM, Bayliss CE, Hunter JO: Instability in the faecal flora of a patient suffering from food-related irritable bowel syndrome. J Med Microbiol23 :29 –32,1987 .[Abstract/Free Full Text]
  25. King TS, Elia M, Hunter JO: Abnormal colonic fermentation in the irritable bowel syndrome. Lancet352 :1187 –1189,1998 .[Medline]
  26. Pimentel M, Chow EJ, Lin HC: Eradication of small bowel bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol95 :3503 –3506,2000 .[Medline]
  27. Pimentel M, Chow E, Lin H: Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome: a double-blind, randomized, placebo-controlled study. Am J Gastroenterol98 :412 –419,2003 .[Medline]
  28. Pimentel M, Wallace D, Hallegua D, Chow E, Kong Y, Park S, Lin HC: A link between irritable bowel syndrome and fibromyalgia may be related to findings on lactulose breath testing. Ann Rheum Dis63 :450 –452,2004 .[Abstract/Free Full Text]
  29. Pimentel M, Lin HC, Enayati P, van den Berg B, Lee HR, Chen JH, Park S, Kong Y, Conklin J: Methane, a gas produced by enteric bacteria, slows intestinal transit and augments small intestinal contractile activity. Am J Physiol Gastrointest Liver Physiol29 :G1089 –G1095,2006 .
  30. Lin HC: Small intestinal bacterial overgrowth: a framework for understanding irritable bowel syndrome. JAMA292 :852 –858,2004 .[Abstract/Free Full Text]
  31. Pimentel M, Soffer EE, Chow EJ, Kong Y, Lin HC: Lower frequency of MMC is found in IBS subjects with abnormal lactulose breath test suggesting bacterial overgrowth. Dig Dis Sci47 :2639 –2642,2002 .[Medline]
  32. Sharara AI, Aoun E, Abdul-Baki H, Mounzer R, Sidani S, Elhajj I: A randomized double-blind placebo-controlled trial of rifaxamin in patients with abdominal bloating and flatulence. Am J Gastroenterol101 :326 –333,2006 .[Medline]
  33. Pimentel M, Park S, Mirocha J, Kane SV, Kong Y: The effect of a nonabsorbed antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med145 :557 –563,2006 .[Abstract/Free Full Text]
  34. Quigley EM, Quera R: Small intestinal bacterial overgrowth: roles of antibiotics, prebiotics and probiotics. Gastroenterology130(2Suppl 1) :S78 –S90,2006 .
  35. Jiang T, Savaiano DA: Modification of colonic fermentation by bifidobacteria and ph in vitro: impact on lactose metabolism, short-chain fatty acid, and lactate production. Dig Dis Sci42 :2370 –2377,1997 .[Medline]
  36. Johanson ML, Molin G, Ahrne S, Jeppsson B: Alteration of intestinal microflora is associated with reduction in abdominal bloating and pain in patients with irritable bowel syndrome. Am J Gastroenterol95 :1231 –1238,2000 .[Medline]
  37. Kim HJ, Camilleri M, McKenzie S, Lempke MB, Burton DD: A randomized controlled trail of a probiotic, VSL#3 on gut transit and symptoms in diarrhoea-predominant IBS. Aliment Pharmacol Ther17 :895 –904,2003 .[Medline]
  38. Kim HJ, Vazquez Roque MI, Camilleri M, Stephens D, Burton DD, Baxter K, Thomforde G, Zinsmeister AR: A randomised controlled trial of probiotic combination VSL#3 and placebo in IBS with bloating: Neurogastroenterol Motil17 :687 –696,2005 .[Medline]
  39. Kajander K, Hatakka K, Poussa T, Farkkila M, Korpela R: A probiotic mixture alleviates symptoms in irritable bowel syndrome patients: a controlled 6-month intervention. Aliment Pharmacol Ther22 :387 –394,2005 .[Medline]
  40. Niv E, Naftali T, Hallak R, Vaisman N: The efficacy of Lactobacillus reuteri ATCC 55730 in the treatment of patients with irritable bowel syndrome - a double blind, placebo-controlled, randomized study. Clin Nutr24 :925 –931,2005 .[Medline]
  41. Tsuchiya J, Barreto R, Okura R, Kawakita S, Fesce E, Marotta F: Single-blind follow-up study on the effectiveness of a symbiotic preparation in irritable bowel syndrome. Chin J Dig Dis5 :169 –174,2004 .[Medline]
  42. Sen S, Mulan MM, Parker TJ, Tarry SA, Hunter JO: Effect of Lactobacillus plantarum 299V on colonic fermentation and symptoms of irritable bowel syndrome. Dig Dis Sci47 :2615 –2620,2002 .[Medline]
  43. Bausserman M, Michail S: The use of Lactobacillus GG in irritable bowel syndrome in children: a double-blind randomized control trial. J Pediatr147 :197 –201,2005 .[Medline]
  44. Brigidi P, Vitali B, Swennen E, Bazzocchi G, Matteuzzi D: Effects of probiotic administration upon the composition and enzymatic activity of human fecal microbiota in patients with irritable bowel syndrome or functional diarrhea. Res Microbiol152 :735 –741,2001 .[Medline]
  45. Quigley EM: Bacterial flora in irritable bowel syndrome: role in pathophysiology, implications for management. Chin J Dig Dis8 :2 –7,2007 .
  46. Cotter PD, Hill C, Ross RP: Bacteriocins: developing innate immunity for food. Nat Rev Microbiol3 :777 –788,2005 .[Medline]
  47. Castigliuolo I, Riegler MF, Valenick L, La Mont JT, Pothoulakis C: Saccharomyces boulardii protease inhibits the effects of Clostridium difficile toxins A and B in human colonic mucosa. Infect Immun67 :302 –307,1999 .[Abstract/Free Full Text]
  48. Spiller RC: Estimating the importance of infection in IBS. Am J Gastroenterol98 :238 –241,2003 .[Medline]
  49. Spiller RC: Postinfectious irritable bowel syndrome. Gastroenterology124 :1662 –1571,2003 .[Medline]
  50. Mearin F, Perez-Oliveras M, Perello A, Vinyet J, Ibanez A, Coderch J, Perona M: Dyspepsia and irritable bowel syndrome after a Salmonella outbreak: a one year follow-up cohort study. Gastroenterology129 :98 –104,2005 .
  51. Allen SJ, Okoko B, Martinez E, Gregorio G, Dans LF: Probiotics for treating infectious diarrhoea. Cochrane Database Syst Rev CD003048,2004 .
  52. Gwee K-A, Leong Y-L, Graham C, McKendrick MW, Collins SM, Walters SJ, Underwood JE, Read NW: The role of psychological and biological factors in post-infective gut dysfunction. Gut44 :400 –406,1999 .[Abstract/Free Full Text]
  53. Spiller RC, Jenkins D, Thornley JP, Hebden JM, Wright T, Skinner M, Neal KR: Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut47 :804 –811,2000 .[Abstract/Free Full Text]
  54. Dunlop SP, Jenkins D, Neal KR, Spiller RC: Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterology125 :1651 –1659,2003 .[Medline]
  55. Gwee KA, Collins SM, Read NW, Rajnakova A, Deng Y, Graham JC, McKendrick MW, Moochhala SM: Increased rectal mucosal expression of interleukin 1 beta in recently acquired post-infectious irritable bowel syndrome. Gut52 :523 –526,2003 .[Abstract/Free Full Text]
  56. Chadwick V, Chen W, Shu D, Paulus B, Bethwaite P, Tie A, Wilson I: Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology122 :1778 –1783,2002 .[Medline]
  57. Dinan TG, Quigley EM, Ahmed SM, Scully P, O'Brien S, O'Mahony L, O'Mahony S, Shanahan F, Keeling PW: Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker? Gastroenterology130 :304 –311,2006 .[Medline]
  58. Khalif IL, Quigley EM, Konovitch EA, Maximova ID: Alterations in the colonic flora and intestinal permeability and evidence of immune activation in chronic constipation. Dig Liver Dis37 :838 –849,2005 .[Medline]
  59. Rachmilewitz D, Katakura K, Karmeli F, Hayashi T, Reinus C, Rudensky B, Akira S, Takeda K, Lee J, Takabayashi K, Raz E: Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. Gastroenterology126 :520 –528,2004 .[Medline]
  60. Gionchetti P, Rizzello F, Helwig U, Venturi A, Lammers KM, Brigidi P, Vitali B, Poggioli G, Miglioli M, Campieri M: Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology124 :1202 –1209,2003 .[Medline]
  61. Mimuar T, Rizzello F, Helwig U, Poggioli G, Schreiber S, Talbot IC, Nicholls RJ, Gionchetti P, Campieri M, Kamm MA: Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis. Gut53 :108 –114,2004 .[Abstract/Free Full Text]
  62. Gonsalkorale WM, Perrey C, Pravica V, Whorwell PJ, Hutchinson IV: Interleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component? Gut52 :91 –93,2003 .[Abstract/Free Full Text]
  63. van der Veek PP, van der Berg M, de Kroon YE, Verspaget HW, Masclee AA: Role of tumor necrosis factor-alpha and interleukin-10 gene polymorphisms in irritable bowel syndrome. Am J Gastroenterol100 :2510 –2516,2005 .[Medline]
  64. Quigley EM: Disturbances of motility and visceral hypersensitivity in irritable bowel syndrome: biological markers or epiphenomenon. Gastroenterol Clin North Am.34 :221 –233,2005 .[Medline]
  65. Lawal A, Kern M, Sidhu H, Hofmann C, Shaker R: Novel evidence for hypersensitivity of visceral sensory neural circuitry in irritable bowel syndrome patients. Gastroenterology130 :26 –33,2006 .[Medline]
  66. Camilleri M: Testing the sensitivity hypothesis in practice: tools and methods, assumptions and pitfalls. Gut51 :i34 –i40,2002 .[Abstract/Free Full Text]
  67. Bouin M, Plourde V, Boivin M, Riberdy M, Lupien F, Laganiere P, Verrier P, Poitras P: Rectal distension testing in patients with the irritable bowel syndrome: sensitivity, specificity, and predictive values of pain sensory thresholds. Gastroenterology122 :1771 –1777,2002 .[Medline]
  68. McKee DP, Quigley EMM: Intestinal motility in irritable bowel syndrome: Is IBS a motility disorder? Part 1: Definition of IBS and colonic motility. Dig Dis Sci38 :1761 –1772,1993 .[Medline]
  69. McKee DP, Quigley EMM: Intestinal motility in irritable bowel syndrome: Is IBS a motility disorder? Part 2: Motility of the small bowel, esophagus, stomach and gall bladder. Dig Dis Sci38 :1763 –1782,1993 .
  70. Quigley EMM: Disturbances in small bowel motility. Bailliere's Best Pract Res Clin Gastroenterol13 :385 –395,1999 .
  71. Collins SM: A case for an immunological basis for irritable bowel syndrome. Gastroenterology122 :2078 –2080,2002 .[Medline]
  72. Mayer EA, Collins SM: Evolving pathophysiological models of functional gastrointestinal disorders. Gastroenterology122 :2032 –2048,2002 .[Medline]
  73. Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, Pasquinelli G, Morselli-Labate AM, Grady EF, Bunnett NW, Collins SM, Corinaldesi R: Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology126 :693 –702,2004 .[Medline]
  74. Verdu EF, Bercik P, Bergonzelli GE, Huang XX, Blenerhasset P, Rochat F, Fiaux M, Mansourian R, Corthesy-Theulaz I, Collins SM: Lactobacillus paracasei normalizes muscle hypercontractiltiy in a murine model of postinfective gut dysfunction. Gastroenterology127 :826 –837,2004 .[Medline]
  75. Verdu EF, Bercik P, Verma-Gandhu M, Huang X-X, Blenerhasset P, Jackson W, Mao Y, Wang L, Rochat F, Collins SM: Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut55 :182 –190,2006 .[Abstract/Free Full Text]
  76. Ait-Belgnaoui A, Han W, Lamine F, Eutamene H, Fioramonti J, Bueno L, Theodorou V: Lactobacillus farciminis treatment suppresses stress-induced visceral hypersensitivity: a possible action through interaction with epithelial cells cytoskeleton contraction. Gut55 :1090 –1094,2006 .[Abstract/Free Full Text]
  77. Kamiya T, Wang L, Forsythe P, Goettsche G, Mao Y, Wang Y, Tougas G, Bienenstock J: Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats. Gut55 :191 –196,2006 .[Abstract/Free Full Text]
  78. Rousseaux C, Thuru X, Gelot A, Barnich N, Neut C, Dubuquoy L Dubuquoy C, Merour E, Geboes K, Chamaillard M, Ouwehand A, Leyer G, Carcano D, Colombel JF, Ardid D, Desreumaux P: Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med.13 :35 –37,2007 .[Medline]
  79. Resta-Lenert S, Barrett KE: Live probiotics protect intestinal epithelial cells from the effects of infection with enteroinvasive Escherichia coli (EIEC). Gut52 :988 –997,2003 .[Abstract/Free Full Text]
  80. Zareie M, Johnson-Henry KC, Jury J, Yang PC, Ngan BY, McKay DM, Soderholm JD, Perdue MH, Sherman PM: Probiotics prevent bacterial translocation and improve intestinal barrier function in rats following chronic psychological stress. Gut55 :1553 –1560,2006 .[Abstract/Free Full Text]
  81. Hobday D, Thompson DG: Role of functional brain imaging in gastroenterology in health and disease. Digest Liver Dis32 :101 –103,2000 .
  82. Aziz Q, Thompson DG: Clinical relevance of the gut brain axis. Gastroenterology114 :559 –578,1997 .
  83. Mertz H, Morgan V, Tanner G, Pickens D, Price R, Shyr Y, Kessler R: Regional cerebral activation in irritable bowel syndrome with painful and nonpainful stimuli. Gastroenterology118 :842 –848,2000 .[Medline]
  84. Patacchioli FR, Angelucci L, Delleba G, Monnazzi P, Leci O: Actual stress, psychopathology and salivary cortisol levels in the irritable bowel syndrome (IBS). J Endocrinol Invest24 :173 –177,2001 .[Medline]
  85. Ellenbruch S, Orr WC: Diarrhea- and constipation-predominant IBS patients differ in postprandial autonomic and cortisol responses. Am J Gastroenterol96 :460 –466,2001 .[Medline]
  86. Beishuizen A, Thijs LG: Endotoxin and the hypothalamic-pituitary-adrenal (HPA) axis. J Endotoxin Res9 :3 –24,2003 .[Medline]
  87. O'Brien SM, Scully P, Scott LV, Dinan TG: Cytokine profiles in bipolar affective disorders: focus on acutely ill patients. Affect Disord90 :263 –267,2006 .
  88. Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB, Desimone C, Song XY, Diehl AM: Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology37 :343 –350.
  89. Sheil B, McCarthy J, O'Mahony L, Bennett MW, Ryan P, Fitzgibbon JJ, Kiely B, Collins JK, Shanahan F: Is the mucosal route of administration essential for probiotic function? Subcutaneous administration is associated with attenuation of murine colitis and arthritis. Gut53 :694 –700,2004 .[Abstract/Free Full Text]
  90. Whitehead WE, Palsson O, Jones KR: Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? Gastroenterology122 :1140 –1156,2002 .[Medline]
  91. Niedzielin K, Kordecki H, Birkenfeld B: A controlled, double-blind, randomized study on the efficacy of Lactobacillus plantarum 299V in patients with irritable bowel syndrome. Eur J Gastroenterol Hepatol13 :1143 –1147,2001 .[Medline]
  92. Halpern GM, Prindiville T, Blankenburg M, Hsia T, Gershwin ME: Treatment of irritable bowel syndrome with lacteol fort: a randomized, double-blind, cross-over trial. Am J Gastroenterol91 :1579 –1585,1996 .[Medline]
  93. O'Sullivan MA, O'Morain CA: Bacterial supplementation in the irritable bowel syndrome. A randomised double-blind placebo-controlled crossover study. Dig Liver Dis32 :302 –304,2000 .[Medline]
  94. Nobaek S, Johanson ML, Molin G, Ahrne S, Jeppsson B: Alteration of intestinal microflora is associated with reduction in abdominal bloating and pain in patients with irritable bowel syndrome. Am J Gastroenterol95 :1231 –1238,2000 .[Medline]
  95. Hamilton-Miller JMT: Probiotics in the Management of Irritable Bowel Syndrome: A Review of Clinical Trials. Microb Ecol Health Dis13 :212 –216,2001 .
  96. Whorwell PJ, Altringer L, Morel J, Bond Y, Charbonneau D, O'Mahony L, Kiely B, Shanahan F, Quigley EMM: Efficacy of an encapsulated probiotic Bifidobacterium Infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol, in press,2006 .
  97. Evans BW, Clark WK, Moore DJ, Whorwell PJ: Tegaserod for the treatment of irritable bowel syndrome. The Cochrane Database of Systematic Reviews2004 , Issue 1. Art. No.: CD003960. DOI: 10.1002/14651858.CD003960.pub2.
  98. Cremonini F, Delgado-Aros S, Camilleri M: Efficacy of alosetron in irritable bowel syndrome: a meta-analysis of randomized controlled trials. Neurogastroenterol Motil15 :79 –86,2003 .[Medline]
  99. Fanigliulo L, Comparato G, Aragona G, Cavallaro L, Iori V, Maino M, Cavestro GM, Soliani P, Sianesi M, Franze A, Di Mario F: Role of gut microflora and probiotic effects in the irritable bowel syndrome. Acta Biomed.77 :85 –89,2006 .[Medline]
  100. Drisko J, Bischoff B, Hall M, McCallum R.: Treating irritable bowel syndrome with a food elimination diet followed by food challenge and probiotics. J Am Coll Nutr.25 :514 –522,2006 .[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Quigley, E. M M
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Quigley, E. M M

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS