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THE INTESTINAL MICROBIOTA AND THE ROLE OF PROBIOTICS IN IRRITABLE BOWEL SYNDROME: a review

Abstracts

Irritable bowel syndrome is a common, chronic relapsing gastrointestinal disorder that affects 7%-22% of the population worldwide. According to Rome III Criteria, the disorder is defined by the coexistence of abdominal discomfort or pain associated with an alteration in bowel habits. Its pathophysiology is not completely understood but, in addition to some important abnormalities, the disturbed intestinal microbiota has also been described supported by several strands of evidence. The treatment of irritable bowel syndrome is based upon several therapeutic approaches but few have been successful or without adverse events and more recently the gut microbiota and the use of probiotics have emerged as a factor to be considered. Probiotics are live micro-organisms which when consumed in adequate amounts confer a health benefit to the host, such as Lactic bacteria among others. An important scientific rationale has emerged for the use of probiotics in irritable bowel syndrome, although the data regarding different species are still limited. Not all probiotics are beneficial: it is important to select the specific strain which should be supported by good evidence base. The mechanisms of action of probiotics are described and the main strains are quoted.

Irritable bowel syndrome; Microbiota; Therapeutics; Probiotics


A síndrome do intestino irritável é uma enfermidade crônica recidivante, que afeta 7%-22% da população mundial. Segundo os denominados Critérios de Roma III, a síndrome do intestino irritável é definida pela coexistência de dor ou desconforto abdominal associados à alteração do hábito intestinal. A fisiopatologia não é completamente esclarecida mas, além algumas importantes alterações descritas, alterações na microbiota intestinal têm tambem sido relatadas, suportadas por diferentes graus de evidência. O tratamento da síndrome do intestino irritável é baseado em diversas abordagens terapêuticas, mas, poucas tem resultados efetivamente satisfatórios ou sem a ocorrência de eventos adversos. Mais recentemente, a microbiota intestinal e o uso de probióticos têm sido considerados como fatores importantes a serem considerados. Probióticos são microrganismos vivos que, quando consumidos em quantidades adequadas, contribuem para a saúde do hospedeiro, como por exemplo, Lactobacillus acidophilus, dentre outras. Importantes justificativas científicas têm sido citadas sobre o uso de probióticos na síndrome do intestino irritável, embora sejam ainda limitados dados sobre as diferentes espécies bacterianas constituintes dos probióticos. Não todos os probióticos são benéficos nesse caso: é importante selecionar as cepas específicas as quais devem ser suportadas por evidências científicas satisfatórias. Os mecanismos de ação dos probióticos são descritos e citadas as principais cepas.

Síndrome do intestino irritável; Microbiota; Terapêutica; Probióticos


INTRODUCTION

The commensal bacteria that normal colonize the gastrointestinal tract (previously referred to as the gut flora but now included in the term microbiota) play a critical role in human health and have been considered an important factor in the pathophysiology of some digestive disorders. This narrative review considers recent advances in our understanding of the gut microbiota, as well as their interactions with the host, in the pathophysiology of irritable bowel syndrome (IBS) and analyzes the role of probiotics in the management of IBS.

To achieve a comprehensive review the relevant literature was assessed in Pubmed, Medline and other online sources using the following search terms: probiotics, irritable bowel syndrome, gastrointestinal, enteric flora, spastic colon, gut microbiota, gut microflora, diarrhea, constipation, motility, functional disorders, dietary guidelines.

IRRITABLE BOWEL SYNDROME

Definition and classification

IBS is defined by the coexistence of abdominal discomfort or pain associated with an alteration in bowel habits. The diagnostic criteria currently used in clinical research and, to some extent in clinical practice, are the Rome III criteria(3434. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology. 2006;130(5):1480-91.). (Figure 1). IBS is a common, chronic, relapsing and remitting gastrointestinal disorder estimated to affect 7%-22% of the general worldwide population(2828. Jones R, Lydeard S. Irritable bowel syndrome in the general population. BMJ. 1992;304(6819):87-90., 3131. Khan S, Chang L. Diagnosis and management of IBS. Nat Rev Gastroenterol Hepatol. 2010;7(10):565-81.).

FIGURE 1.
Rome III criteria for IBS(34).

IBS is commonly diagnosed based upon these symptom criteria and in the absence of alarm signals. The cardinal symptom in IBS is abdominal pain occurring in association with an alteration in bowel habit; diarrhea and/or constipation. Accordingly, given that pain is a defining feature, painless, unexplained diarrhea or constipation would not be included in the definition of IBS. Bloating is reported by the majority of patients with IBS and may be associated with visible abdominal distention(3131. Khan S, Chang L. Diagnosis and management of IBS. Nat Rev Gastroenterol Hepatol. 2010;7(10):565-81.). Complete details on the diagnostic approach to IBS diagnosis are beyond the scope of this paper; the common clinical features supporting the diagnosis of IBS are presented in Figure 2.

FIGURE 2.
IBS diagnosis: clinical features supportive of IB

The American College of Gastroenterology IBS Task Force recommended that diagnostic testing (blood tests, colonoscopy, celiac disease sorology, etc) should not be performed on a routine basis on patients with typical IBS symptoms, except when alarm features are present(33. American College of Gastroenterology Task Force on Irritable Bowel Syndrome1, Brandt LJ, Chey WD, Foxx-Orenstein AE, Schiller LR, Schoenfeld PS, et al. An evidence-based position statement on the management of irritable bowel syndrome. Amer J Gastroenterol. 2009;104(Suppl 1):S1-S35., 1616. Ford AC, Moayyedi P, Lacy BE, Lembo AJ, Saito YA, Schiller LR, et al. American College of Gastroenterology. Monograph on the Management of Irritable Bowel Syndrome and Chronic Idiopathic Constipation. Am J Gastroenterol. 2014;109(Suppl 1):S2-S6.). However, in some cases and in certain contexts, the differential diagnosis of IBS from other intestinal disorders can be difficult. In such instances it is important to consider, among others, enteric infections and infestations, food intolerance, inflammatory bowel disease, adverse drugs reactions (e.g. to antibiotics, tricyclic antidepressants, proton pump inhibitors) and small bowel bacterial overgrowth.

In developing a managment strategy in IBS it is important, where possible, to define the predominant bowel pattern. Accordingly, four IBS sub-types have been proposed by the Rome Foundation Committe on functional bowel disorders (Figure 3):

FIGURE 3.
IBS subtype classification according to bowel habit(34)

  • - Constipation predominant IBS (IBS-C);

  • - Diarrhea-predominant IBS (IBS-D);

  • - Mixed IBS (IBS-M);

  • - Unsubtyped IBS.

The importance to society of IBS rests, not only in its high prevalence but also, for some affected individuals, on the occurrence of very bothersome symptoms which significantly impact on quality of life and social functioing and, as a consequence, impose a substantial economic impact on health-care systems and the community at large(4949. Nellesen D, Yee K, Chawla A, Lewis BE, Carson RT. A systematic review of the economic and humanistic burden of illness in irritable bowel syndrome and chronic constipation. J Manag Care Pharm. 2013;19(9):755-64.). Precise, early diagnosis will minimize exposure to unnecessary and potentially risky investigations and may alleviate suffering and improve quality of life.

Pathophysiology

As a multifactorial functional disorder, the pathophysiology of IBS is not completely understood, but it is commonly viewed as representing dysregulation along the brain-gut axis, which may include abnormalities at any one or more levels in the enteric, autonomic and/or central nervous systems, or altered interactions between these systems(5353. Öhman L, Simrén M. New insights into the pathogenesis and pathophysiology of irritable bowel syndrome. Dig Liver Dis 2007;39(3):201-15.). Peripheral contributors to IBS symptomatology may include abnormal motility(4040. McKee DP, Quigley EM. Intestinal motility in irritable bowel syndrome: is IBS a motility disorder? Part 1. Definition of IBS and colonic motility. Dig Dis Sci. 1993;38(10):1761-2.), a dysregulated intestinal immune response(77. Chadwick VS, Chen WY, Shu DR, Paulus B, Bethwaite P, Tie A, et al. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology. 2002;122(7):1778-83.), low grade inflammation, altered gastrointestinal permeability(7272. Wang LH, Fang XC, Pan GZ. Bacillary dysentery as a causative factor of irritable bowel syndrome and its pathogenesis. Gut. 2004;53(8):1096-101.) and a disturbed intestinal microbiota(7272. Wang LH, Fang XC, Pan GZ. Bacillary dysentery as a causative factor of irritable bowel syndrome and its pathogenesis. Gut. 2004;53(8):1096-101.). Of late, considerable interest has surrounded the posibility that intestinal bacteria could play an important role in triggering symptoms and even in the basic pathophysiology of IBS.

A role for the microbiota in IBS is, indeed, supported by several strands of evidence that include: differences in the colonic microbiota between IBS and non-IBS populations, the development of IBS in the aftermath of infectious gastroenteritis, symptomatic responses to antibiotic, prebiotic and probiotic administration and, more recently, by anecdotal rports of responses to fecal microbial transplantation(1414. DuPont HL. Review article: evidence for the role of gut microbiota in irritable bowel syndrome and its potential influence on therapeutic targets. Aliment Pharmacol Therap. 2014;39(10):1033-42., 2121. Halvorson HA, Schlett CD, Riddle MS. Postinfectious irritable bowel syndrome - a meta-analysis. Am J Gastroenterol. 2006;101(8):1894-9., 3030. Kassinen A, Krogius-Kurikka L, Makivuokko H, Rintilla T, Paulin L, Corander J, et al. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology. 2007;133(1):24-33., 6666. Sha S, Liang J, Chen M, Xu B, Liang C, Wei N, et al. Systematic review: faecal microbiota transplantation therapy for digestive and nondigestive disorders in adults and children. Aliment Pharmacol Ther. 2014;39(10):1003-32.). Perhaps the most convincing illustration of the role of bacteria in IBS is provided by observations that indicate that the risk for IBS is increased sevenfold in patients who have previously experienced an infectious gastroenteritis(2121. Halvorson HA, Schlett CD, Riddle MS. Postinfectious irritable bowel syndrome - a meta-analysis. Am J Gastroenterol. 2006;101(8):1894-9.). Indeed, it would appear that any intervention that can lead to changes in intestinal ecology may lead to the occurrence of IBS and its discomforting symptoms(44. Bixquert M. Treatment of irritable bowel syndrome with probiotics: growing evidence. Indian J med Res. 2013;138:175-7.).

In assessing the role of any putative pathophysiological factor in IBS one must bear in mind the potential impact of an important confounder: co-morbid psychopathology. Co.-morbid depression and anxiety, so common in IBS, can modulate and even intensify the patient's perception of their symptoms(44. Bixquert M. Treatment of irritable bowel syndrome with probiotics: growing evidence. Indian J med Res. 2013;138:175-7.), increase the likelihood of medical consultation and investigation and even impact directly on many of the aforementioned factors thought relevant to the pathophysiology of IBS.

Treatment

The ideal therapeutic approach to any disease or disorder is to consider its pathophysiology and how direct therapy accordingly. However, given its heterogenous phenotype, varying presentation, broad range of severity and, undoubtedly, multifactorial pathophysiology, this approach is not possible in IBS. Given a multitude of possibly relevant therapeutic targets, a simple, unitary approach is currently impossible; not surprisingly many therapeutic approaches have been proposed but few have been very successful or without adverse events (Figure 4).

FIGURE 4
Some treatment approaches to IBS(1414. DuPont HL. Review article: evidence for the role of gut microbiota in irritable bowel syndrome and its potential influence on therapeutic targets. Aliment Pharmacol Therap. 2014;39(10):1033-42., 2020. Gibson PR, Shepherd S. Evidence-based dietary management of functional gastroeintestinal symptoms: the FODMAP approach. J Gastroenterol Hepatol. 2010;25(2):252-8., 2626. Johannesson E, Simrén M, Strid H, Bajor A, Sadik R. Physical activity improves symptoms in irritable bowel syndrome: a randomized controlled trial. Am J Gastroenterol. 2011;106(5):915-22., 4242. Menard O, Butel MJ, Gaboriau-Routhiau V, Waligora-Dupriet AJ. Gnotobiotic mouse immune response induced by Bifidobacterium sp. strains isolated from infants. Appl Environ Microbiol. 2008;74(3):660-6., 4747. Moayyedi P, Quigley EMM, Lacy BE, Lembo AJ, Saito YA, Schiller LR, et al. The effect of fiber supplementation on Irritable Bowel Syndrome: a systematic review and meta-analysis. Am J Gastroenterol. 2014;109(9):1367-74., 5656. Peters SL, Muir JG, Gibson PR. Review article: gut-directed hypnotherapy in the management of irritable bowel syndrome and inflammatory bowel disease. Alim Pharmacol Ther. 2015;41(11):1104-5., 5959. Rao SS, Yu S, Fedewa A. Systematic review: dietary fiber and FODMAP-restricted diet in the management of constipation and irritable bowel syndrome. Alim Pharmacol Ther. 2015;41(12):1256-70., 7373. Weinberg DS, Smalley W, Heidelbaugh JJ, Sultan S. American Gastroenterological Institute Guideline on Pharmacological Management of Irritable Bowel Syndrome. Gastroenterology. 2014;147(5):1146-8.)

Given the aforementioned interest in the gut microbiota and its interactions with the host in this common disorder, the gut microbiota, through the use of antibiotics, prebiotics and probiotics, has emerged as a factor to be considered in the teatment of IBS. Two non-pharmacological approach have amerged as being of particular interest: dietary and lifestyle changes(2222. Hayes P, Fraher MH, Quigley EMM. Irritable Bowel Syndrome: The Role of Food in Pathogenesis and Management. Gastroenterol Hepatol (NY). 2014;10(3):164-74., 4141. McKenzie YA, Alder A, Anderson W, Wills A, Goddard L, Gulia P, et al. British Dietetic Association evidence-based guidelines for the dietary management of irritable bowel syndrome in adults. J Hum Nutr Diet. 2012;25(3):260-74., 5454. Öhman L, Simrén M. Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions. Nat Rev Gastroenterol Hepatol. 2010;7(3):163-73.) and the use of probiotics(2222. Hayes P, Fraher MH, Quigley EMM. Irritable Bowel Syndrome: The Role of Food in Pathogenesis and Management. Gastroenterol Hepatol (NY). 2014;10(3):164-74., 6666. Sha S, Liang J, Chen M, Xu B, Liang C, Wei N, et al. Systematic review: faecal microbiota transplantation therapy for digestive and nondigestive disorders in adults and children. Aliment Pharmacol Ther. 2014;39(10):1003-32., 7272. Wang LH, Fang XC, Pan GZ. Bacillary dysentery as a causative factor of irritable bowel syndrome and its pathogenesis. Gut. 2004;53(8):1096-101.).

THE GUT MICROBIOTA

Humans are colonized with microrganisms that inhabit the skin, oral cavity, vagina and gastrointestinal tract from birth(3333. Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell. 2006;124(4):837-48.). In the gastrointestinal tract, 500 to 1,000 different species of bacteria coexist (gut microbiota), with the precise composition of the gut microbiome varying between individuals(1818. Foxx-Orenstein AE, Chey WD. Manipulation of the gut microflora as a novel treatment strategy for gastrointestinal disorders. Am J Gastroenterol. 2012(Suppl);1:41-6.). The adult human gastrointestinal tract is estimated to contain 1014 viable microorganisms, which is 10 times the number of eukaryotic cells found within the human body(6464. Savage DC. Microbial ecology of the gastrointestinal tract. Annu Rev Microbiol. 1977;31:107-33.). This is a complex ecosystem with the largest population of microorganisms in the gastrointestinal tract residing in the lumen and within, or adjacent to, the mucus layer of the colon(1919. Gareau MG, Sherman PM, Walker A. Probiotics and the gut microbiota in intestinal health and disease. Nat Rev Gastroenterol Hepatol. 2010;7(9):503-14.).

The development of the gut microbiota starts at birth. Its composition is influenced by both the mode of delivery and how the infant is fed: the gut microbiota of breastfed babies, for example, being mainly dominated by Bifidobacteria, in comparison to babies nourished with infant formulas. Early environmental exposure is of primary importance in shaping the microbiota(7171. Turnbaugh PJ, Gordon JI. The core gut microbiome, energy balance and obesity. J Physiol. 2009;587(Pt 17):4153-8.); by 3-4 years of age the microbiota becomes stable and similar to that of adults.

In adults, the composition of the microbiota is influenced by such factors as diet, geographic location and the use of oral antibiotics(2424. Hill DA, Hoffmann C, Abt MC, Du Y, Kobuley D, Kirn TJ, et al. Metagenomic analysis reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis. Mucosal Immunol. 2010;3:148-58.). It is also thought that further changes occur in old age.

The microbiota performs many critical roles, such as the maintenance of mucosal integrity, the protection against pathogens (by means of bacterial antagonism and priming of host immune responses(2424. Hill DA, Hoffmann C, Abt MC, Du Y, Kobuley D, Kirn TJ, et al. Metagenomic analysis reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis. Mucosal Immunol. 2010;3:148-58.)), immune system modulation, synthesis of vitamins and cholesterol, metabolism of bile acids and indigestible dietary components. With the intestinal epithelium, the microbiota of the gut provides the first line of defense against orally introduced invaders(1414. DuPont HL. Review article: evidence for the role of gut microbiota in irritable bowel syndrome and its potential influence on therapeutic targets. Aliment Pharmacol Therap. 2014;39(10):1033-42.).

A relationship between the microbiota and intestinal motility has also been described(5757. Quigley EMM. Microflora modulation of motility. J Neurogastroenterol Motil. 2011;17:140-7.) and may be mediated through substances released by bacteria, by the end products of bacterial fermentation, through the effects of cytokines and chemokines elaborated as part of the immune response, as well as via the release of intestinal neuroendocrine factors(1818. Foxx-Orenstein AE, Chey WD. Manipulation of the gut microflora as a novel treatment strategy for gastrointestinal disorders. Am J Gastroenterol. 2012(Suppl);1:41-6., 3636. Marchesi J, Shanahan F. The normal intestinal microbiota. Current Opin Infect Dis. 2007;20(5):508-13.).

Dysbiosis (also called dysbacteriosis) refers to microbial imbalance on or inside the body, and is most commonly reported in terms of changes in the digestive tract. Many factors can negatively impact on gut commensals and promote dysbiosis, such as antibiotic use, psychological and physical stress, radiation, altered peristalsis and dietary changes. It should be remembered that although dysbiosis has been recognized in various intestinal diseases, in most cases a definitive cause-and-effect relationship remains to be established.

The gut microbiota is considered to be an important factor in the pathophysiology of IBS, either alone or in combination with other factors(1616. Ford AC, Moayyedi P, Lacy BE, Lembo AJ, Saito YA, Schiller LR, et al. American College of Gastroenterology. Monograph on the Management of Irritable Bowel Syndrome and Chronic Idiopathic Constipation. Am J Gastroenterol. 2014;109(Suppl 1):S2-S6., 1818. Foxx-Orenstein AE, Chey WD. Manipulation of the gut microflora as a novel treatment strategy for gastrointestinal disorders. Am J Gastroenterol. 2012(Suppl);1:41-6., 5555. Öhman L, Simrén M. Intestinal microbiota and its role in irritable bowel syndrome (IBS). Curr Gastroenterol Rep. 2013;15(5):323-9.). In some studies, specific changes in the microbiota have been associated with particular IBS presentations and/or phenotype(2424. Hill DA, Hoffmann C, Abt MC, Du Y, Kobuley D, Kirn TJ, et al. Metagenomic analysis reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis. Mucosal Immunol. 2010;3:148-58.). Commensal function thougth especially relevant to IBS will be explored further in the discussion of probiotics in IBS.

PROBIOTICS

Probiotics are live micro-organisms which when consumed in adequate amounts, confer a health benefit to the host(2727. Joint FAO , WHO Working Group Report on Drafting Guidelines for the Evaluation of Probiotics in Food. [Internet]. [Accessed 2015 April 6]. Available from: http://www.fda.gov/ohrms/dockets/dockets/95s0316/95s-0316-rpt0282-tab-03-ref-19-joint-faowho-vol219.pdf. London, Ontario, Canada, April 2002.
http://www.fda.gov/ohrms/dockets/dockets...
).

Most probiotic bacteria are lactic bacteria (lactic acid-producing bacteria), that include Lactobacillus,Lactococcus, Bifidobacterium and Streptococcus(6363. Sarowska J, Choroszy-Król I, Regulska-Ilow B, Frej-Madrzak M, Jama-Kmiecik A. The therapeutic Effect of probiotic bacteria on gastrointestinal Diseases. Adv Clin Exp Med. 2013;22:759-766.). This group of bacteria has the capacity to anaerobically digest dietary sugars and produce lactic acid. Probiotic properties have also been ascribed to the yeast Saccharomyces cerevisae ssp boulardi (S. Boulardi) and other species of bacteria of the genera Escherichia and Bacillus. The natural ecosystem of lactic acid bacteria is the digestive tract.

The use of probiotics has been extensively investigated and efficacy, to a greater or lesser extent, demonstrated in a number of intestinal disorders, as presented in Figure 5. However, not all probiotics all beneficial in all circunstances: it is important to carefully select the specific strain which is supported by a good evidence base for a given indication. A large volume of in vitro and in vivo data has clearly shown that the various biological effects of probiotics are strain specific and it is not possible to extrapolate efficacy or failure from one strain to another, unless a common mechanism of action has been described and appropriate clinical studies performed(6060. Rijkers GT, de Vos WM, Brummer RJ, Morelli L, Corthier G, Mareau P. Health benefits and health claims of probiotics: bridging science and marketing. Br J Nutr. 2011;106(9):1291-6.).

FIGURE 5.
Effects of probiotics in randomized, clinical trials of intestinal disease(19 mod.)

Probiotic mechanisms of action

Not all the mechanisms of action of the probiotics are well understood and some have been primarily, if not exclusively, documented in vitro or in animal models studies. Care should be exerted in extrapolating these results to man. Taking into consideration such limitations, these are some known modes of action of probiotics that may be especially relevant to IBS.

Actions in the intestinal lumen and on the mucosal surface

One mode of action of a probiotic may relate to its effects on the host's microbiota. This includes the so called "barrier" effect whereby resistance to colonization is exerted against pathogenic bacteria thus limiting or even preventing their colonization of the host. Bacterial inhibition by probiotics may be mediated through their production of bacteriocins or biosurfactants with antimicrobial activity or to the elaboration of metabolites that induce a decrease in luminal pH and, thereby, an environment which is less favourable for the growth of certain bacteria(66. Butel MJ. Probiotics, gut microbiota and health. Med Mal Infect. 2014;44(1):1-8.). In addition to the production of antimicrobials, probiotics may also modify the metabolic behaviour of the indigenous microbiota(6767. Shanahan F. Probiotics in Perspective. Gastroenterology. 2010;139(6):1808-12.). Paneth cells, stimulated by probiotics, produce antimicrobial peptides and mucus that function to prevent direct contact between luminar pathogens and the epithelium. All of these effects could be important in the prevention of post-infections IBS.

Probiotics can also enhance epithelial integrity by promoting mucus secretion, the production of defensins and the synthesis of proteins critical to the structure of tight junctions between enterocytes; effects that collectively improve gut barrier function, whose function may be compromised in IBS(66. Butel MJ. Probiotics, gut microbiota and health. Med Mal Infect. 2014;44(1):1-8., 5555. Öhman L, Simrén M. Intestinal microbiota and its role in irritable bowel syndrome (IBS). Curr Gastroenterol Rep. 2013;15(5):323-9., 6060. Rijkers GT, de Vos WM, Brummer RJ, Morelli L, Corthier G, Mareau P. Health benefits and health claims of probiotics: bridging science and marketing. Br J Nutr. 2011;106(9):1291-6., 6363. Sarowska J, Choroszy-Król I, Regulska-Ilow B, Frej-Madrzak M, Jama-Kmiecik A. The therapeutic Effect of probiotic bacteria on gastrointestinal Diseases. Adv Clin Exp Med. 2013;22:759-766., 6767. Shanahan F. Probiotics in Perspective. Gastroenterology. 2010;139(6):1808-12.).

Metabolic effects, though little studied in the context of IBS, could also be relevant. Thus changes in bacterial fermentation could impact on "gas-related" symptoms and modulation of bile salt conjugation influence stool volume and consistency.

Immune effects and systemic actions

Probiotics modulate the immune system and, in particular, that important population of immune cells that exist in the small bowel, the gut-associated (or mucosa-associated) lymphoid tissue (GALT or MALT). Peyer's patches constitute a gateway for entry for antigens and the activation of immune responses involves recognition of antigen by the specific receptors on innate immune cells, epithelial cells, dendritic cells and macrophages. Some probiotics protect against pathogen-induced tissue damage by stimulating induction of regulatory T-cells, as has been described with the probiotic B. Infantis 35624 in mice(5252. O'Mahony C, Scully P, O'Mahony D, Murphy S, O'Brien F, Lyons A, et al. Commensal-induced regulatory T-cells mediate protection against pathogen-stimulated NF-κB activation. PLoS Pathogens. 2008;4(8):e1000112.). These receptors are recognized by structural components on the surface of the micro-organisms, the microbial associated molecular patterns (MAPS), which may interact with the intestinal epithelium and stimulate the cells of the intestinal immune system at the lamina propria level(4242. Menard O, Butel MJ, Gaboriau-Routhiau V, Waligora-Dupriet AJ. Gnotobiotic mouse immune response induced by Bifidobacterium sp. strains isolated from infants. Appl Environ Microbiol. 2008;74(3):660-6.). Subsequently, T-cells are activated and the differentiation of T-helper lymphocytes promoted with the production of anti-inflammatory cytokines. Various probiotics and, especially, lactic acid bacteria, may exert differing biological effects depending on the cytokine profile they induce(4242. Menard O, Butel MJ, Gaboriau-Routhiau V, Waligora-Dupriet AJ. Gnotobiotic mouse immune response induced by Bifidobacterium sp. strains isolated from infants. Appl Environ Microbiol. 2008;74(3):660-6.). Furthermore, effects may be local, limited to the stimulation of the intestinal immunity, or may be systemic(6767. Shanahan F. Probiotics in Perspective. Gastroenterology. 2010;139(6):1808-12.). Given that a number of immunological changes have been demonstrated, albeit not consistently, in IBS, any one or combination of these immunological effects of probiotics could be relevant to their benefits.

PROBIOTICS IN GASTROENTEROLOGY

Probiotic effects are strain dependent. A wide range of probiotics are currently available as presented in Figure 5. In this regard, it is important to emphasize that the clinical efficacy of a probiotic product is determined by factors such as the dosage (number of colony forming units, cfu's), the formulation, the viability (outside and inside the intestine), the method of dosing and the specific microbial species and strain(s) that it includes. A good product should be characterized at the level of the genome, its range of biological effects defined and its stability in the conditions and over the duration of time that it is recommended to be stored, validated(6161. Ringel Y, Quigley EMM, Lin HC. Using probiotics in Gastrointestinal Disorders. Am J Gastroenterol. 2012(Suppl);1:34-40.).

Currently, gastrointestinal disorders for which the use of probiotics has been proposed include: acute infectious diarrhea(1111. Correa NB, Penna FJ, Lima FMLS, Nicoli JR, Filho LA. Treatment of acute diarrhea with Saccaromyces boulardii in infants. J Ped Gastroenterol Nutr. 2011;53(5):497-501., 6565. Sazawal S, Hiremath G, Dhingra U, Malik P, Deb S, Black RE. Efficacy of probiotics in prevention of acute diarrhoea: a meta-analysis of masked, randomised placebo-controlled trials. Lancet Infec Dis. 2006;6(6):374-82.), traveler's diarrhea(3838. McFarland LV. Meta-analysis of probiotics for the prevention of traveler's diarrhea. Travel Med infect Dis. 2007;5(2):97-105., 6565. Sazawal S, Hiremath G, Dhingra U, Malik P, Deb S, Black RE. Efficacy of probiotics in prevention of acute diarrhoea: a meta-analysis of masked, randomised placebo-controlled trials. Lancet Infec Dis. 2006;6(6):374-82.), antibiotic-associated diarrhea(3737. McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease Am J Gastroenterol. 2006;101(4):812-22., 6969. Szajewska H, Ruszczynski M, Radzikowski A. Probiotics in the prevention of antibiotic-associated diarrhea in children: a meta-analysis of randomyzed controlled trials. J Pediatr. 2006;149(3):367-72.), constipation(1717. Ford AC, Quigley EMM, Lacy BE, Lembo AJ, Saito YA, Schiller LR, et al. Efficacy of prebiotics, probiotics, and synbiotics in Irritable bowel syndrome and chronic idiopatic constipation: systematic review and meta-analysis. Am J Gastroenterol. 2014;109(10):1547-61., 2929. Kajander K, Myllyluoma E, Rajilic-Stojanovic M, Kyronpalo S, Rasmussen M, Järvenpää S, et al. Clinical trial; multispecies probiotic supplemenation alleviates the symptoms of irritable bowel syndrome and stabilizes intestinal microbiota. Aliment Pharmacol Ther. 2008;27(1):48-57., 4646. Moayyedi P, Ford AC, Talley NJ, Cremonini F, Foxx-Orenstein AE, Brandt LJ, et al. The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut. 2010;59(3):325-32.), necrotizing enterocolitis(4545. Mihatsch WA, Braegger CP, Decsi T, Kolacek S, Lanzinger H, Mayer B, et al. Critical systematic review of the level of evidence for routine use of probiotics for reduction of mortality and prevention of necrotizing enterocolitis and sepsis in preterm infants. Clinical Nutri. 2012;31(1):6-15.), inflammatory bowel disease(1515. Fedorak RN. Probiotics in the management of ulcerative colitis. Gastroenterol Hepatol. (NY) 2010;6(11):688-90., 2323. Hedin C, Whelan K, Lindsay JO. Evidence for the use of probiotics and prebiotics in inflammatory bowel disease: a review of clinical trials. Proc Nutr Soc. 2007;66(3):307-15., 2525. Isaacs K, Herfarth H. Role of probiotic therapy in IBD. Inflamm Bowel Dis. 2008;14(11):1597-605., 4444. Miele E, Pascarella F, Gianetti E, Quaglietta L, Baldassaro RN, Staiano A. Effect of a probiotic preparation (VSL#3) on induction and maintenance of remission in children with ulcerative colitis. Am J Gastroenterol. 2009;104(2):437-43.) and IBS(77. Chadwick VS, Chen WY, Shu DR, Paulus B, Bethwaite P, Tie A, et al. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology. 2002;122(7):1778-83., 3737. McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease Am J Gastroenterol. 2006;101(4):812-22., 6666. Sha S, Liang J, Chen M, Xu B, Liang C, Wei N, et al. Systematic review: faecal microbiota transplantation therapy for digestive and nondigestive disorders in adults and children. Aliment Pharmacol Ther. 2014;39(10):1003-32., 7272. Wang LH, Fang XC, Pan GZ. Bacillary dysentery as a causative factor of irritable bowel syndrome and its pathogenesis. Gut. 2004;53(8):1096-101.) (Figure 6). It must be emphasized that not all of these indications are supported by compelling clinical data.

FIGURE 6 .
Probiotics strains available in most countries(61mod.,50mod.).

Probiotics in IBS

IBS is a good example of the limitations of clinical data; though many studies have been published, few have achieved standards appropriate for clinical trials in man. Recommendations for probiotic use in man continue to be constrained by poor methodological standards in many studies resulting in low levels of evidence and, at best, conditional recommendations. Recognizing these limitations, the observations included here represent a summary of an extensive and updated review of the current literature of the role of the probiotics in the therapeutic approach of the IBS.

Studies in patients with IBS have shown alterations in microbiota such as an increased ratio of Firmicutes to Bacteroides and a reduction in Lactobacillus or Bifidobacterium species(5858. Rajilic-Stojanovic M, Biagi E, Heilig HG, Kajander K, Kekkonen RA, Tims S, et al. Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology. 2011;141(5):1792-801.). It is known that Lactobacillus and Bifidobacterium species have anti-inflammatory effects in the intestine and their depletion could contribute to low-grade inflammation(5151. O'Mahony L, McCarthy J, Kelly P, Hurley G, Luo Fy, Chen KS, et al. Lactobacillus and Bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology. 2005;128(3):541-51.). Proinflammatory cytokine levels (e.g. interleukin (IL)-6, IL-8, tumor necrosis factor-α, and IL-1β) are elevated in the systemic circulation of patients with IBS(1313. Dinan TG, Quigley EMM, Ahmed SMM, Scully P, O'Brien S, Omahony L, et al. Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker? Gastroenterology. 2006;130(2):304-11.); phenomena that may be triggered and perpetuated by the alterations in the gut microbiota observed in IBS, as evidenced by experiments in germ- free animals(4848. Natividad JMM, Petit V, Huang X, Palma G, Jury J, Sanz Y, et al. Commensal and probiotic bacteria influence intestinal barrier function and susceptibility to colitis in Nod1-l-, Nod2-l- mice. Inflamm Bowel Dis. 2012;18(8):1434-46.).

Taking into consideration the large number and highly variable characteristics and properties of microorganisms that have been studied, it may be inappropriate to combine the results of different trials(44. Bixquert M. Treatment of irritable bowel syndrome with probiotics: growing evidence. Indian J med Res. 2013;138:175-7.). Furthermore, probiotic formulations may contain a single strain or a combination of multiple species and/or strains. In IBS, the most studied strains belong to Lactobacillus sp. and Bifidobacterium sp. As such, a consistent trend toward an improvement of bloating and constipation has been reported with the use of Bifidobacterium infantis, B. brevis and B. Animalis and abdominal pain, bloating, diarrhea and constipation have been shown to improve with Lactobacillus plantarum, L casei, L. reuteri, L. acidophilus, L. Rhamnosus(11. Agrawal A, Houghton LA, Morris J, Reilly B, Guyonnet D, Feuillerat NG, et al. Clinical trial: the effects of a fermented milk product containing Bifidobacterium lactis DN-173-010 on abdominal distension and gastrointestinal transit in irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2009;29(1):104-114., 99. Ciorba MA. A gastroenterologist's guide to probiotics. Clin Gastroenterol Hepatol. 2012;10(9):960-8., 1212. Cui S, Hu Y. Multistrain probiotic preparation significantly reduces symptoms of irritable bowel syndrome in a double-blind placebo-controlled study. Int J Clin Exp Med. 2012;5(3):238-44., 1717. Ford AC, Quigley EMM, Lacy BE, Lembo AJ, Saito YA, Schiller LR, et al. Efficacy of prebiotics, probiotics, and synbiotics in Irritable bowel syndrome and chronic idiopatic constipation: systematic review and meta-analysis. Am J Gastroenterol. 2014;109(10):1547-61., 3232. Ki Cha B, Mun Jung S, Hwan Choi C, Song ID, Woong Lee H, Joon Kim H, et al. The effect of a multispecies probiotic mixture on the symptoms and fecal microbiota in diarrhea-dominant irritable bowel syndrome: a randomized, double-blind, placebo-controlled trial. J Clin Gastroenterol. 2012;46(3):220-7., 5151. O'Mahony L, McCarthy J, Kelly P, Hurley G, Luo Fy, Chen KS, et al. Lactobacillus and Bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology. 2005;128(3):541-51., 6868. Simrén M, Doré J. Gut microbiota for health - current insights and understanding. Eur Gastroenterol Hepatol Ver. 2012;8:77-81., 7474. Whorwell PJ, Altringer L, Morel J, Bond Y, Charbonneau D, O'Mahony L, et al. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol. 2006;101(7):1581-90.). Bifidobacterium infantis 35624 has been shown to, not only improve individual symptoms, but also produce global improvement(55. Brenner DM, Moeller MJ, Chey WD, Schoenfeld PS. The utility of probiotics in the treatment of irritable bowel syndrome: a systematic review. Am J Gastroenterol. 2009;104(4):1033-49., 5151. O'Mahony L, McCarthy J, Kelly P, Hurley G, Luo Fy, Chen KS, et al. Lactobacillus and Bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology. 2005;128(3):541-51., 7474. Whorwell PJ, Altringer L, Morel J, Bond Y, Charbonneau D, O'Mahony L, et al. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol. 2006;101(7):1581-90.).

Management strategies in IBS are highly variable (Figure 4) and may be driven by illness severity, predominant symptoms and physician preference. In this context, certain probiotics, by virtue of their safety and tolerability are options to consider as they have been shown to improve global symptoms, bloating and flatulence. A number of reviews(55. Brenner DM, Moeller MJ, Chey WD, Schoenfeld PS. The utility of probiotics in the treatment of irritable bowel syndrome: a systematic review. Am J Gastroenterol. 2009;104(4):1033-49., 1717. Ford AC, Quigley EMM, Lacy BE, Lembo AJ, Saito YA, Schiller LR, et al. Efficacy of prebiotics, probiotics, and synbiotics in Irritable bowel syndrome and chronic idiopatic constipation: systematic review and meta-analysis. Am J Gastroenterol. 2014;109(10):1547-61., 3939. McFarland LV, Dublin S. Meta-analysis of probiotics for the treatment of irritable bowel syndrome. World J Gastroenterol. 2008;14(17):2650-61., 4646. Moayyedi P, Ford AC, Talley NJ, Cremonini F, Foxx-Orenstein AE, Brandt LJ, et al. The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut. 2010;59(3):325-32., 5050. Nikfar S, Mozaffari S, Didari T, Abdollari M. Effectiveness of probiotics in irritable bowel syndrome: a systematic review with meta-analysis. Value in Health. 2014;17:A363.) as well as a recent well conducted systematic review and meta-analysis have demonstrated that probiotics have a therapeutic benefit in the IBS and may improve global symptoms, abdominal pain, bloating and flatulence(1717. Ford AC, Quigley EMM, Lacy BE, Lembo AJ, Saito YA, Schiller LR, et al. Efficacy of prebiotics, probiotics, and synbiotics in Irritable bowel syndrome and chronic idiopatic constipation: systematic review and meta-analysis. Am J Gastroenterol. 2014;109(10):1547-61.) although the quality of evidence, according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) assessment, was low.

CONCLUSIONS

The relative lack of effective therapeutic options for the treatment of IBS opens the way for new approaches and, among these, probiotics, which are generally regarded as safe and may act on the global symptoms, bloating and flatulence, which have considerable appeal. Furthermore, a rather impressive scientific rationale has emerged for the use of probiotics in gastrointestinal conditions, including IBS. Such data is, of course, highly strain specific(1010. Clarke G, Cryan JF, Dinan TG, Quigley EM. Review article: probiotics for the treatment of irritable bowel syndrome - focus on lactic acid bacteria. Aliment Pharmacol Ther. 2012;35(4):403-13.). However, recommendations regarding individual species or strains continue to be limited by a lack of data and the poor quality of much of the available data(1717. Ford AC, Quigley EMM, Lacy BE, Lembo AJ, Saito YA, Schiller LR, et al. Efficacy of prebiotics, probiotics, and synbiotics in Irritable bowel syndrome and chronic idiopatic constipation: systematic review and meta-analysis. Am J Gastroenterol. 2014;109(10):1547-61.).

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  • Disclosure of funding: no funding received

Publication Dates

  • Publication in this collection
    Oct-Dec 2015

History

  • Received
    14 July 2015
  • Accepted
    13 Aug 2015
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