microbiome-directed therapies: past, present, and …
TRANSCRIPT
Clinical Gastroenterology and Hepatology 2019;17:333–344
MICROBIOME-DIRECTED THERAPIES: PAST, PRESENT,AND FUTURE
Prebiotics and Probiotics in Digestive Health
Eamonn M. M. Quigley
Division of Gastroenterology and Hepatology, Lynda K. and David M. Underwood Center for Digestive Disorders,Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas
Abbreviations used in this paper: IL, interleukin; ISAPP, InternationalScientific Association for Probiotics and Prebiotics.
Most current article
© 2019 by the AGA Institute1542-3565/$36.00
https://doi.org/10.1016/j.cgh.2018.09.028
As the importance of the gut microbiota in health anddisease is increasingly recognized interest in interventionsthat can modulate the microbiota and its interactions withits host has soared. Apart from diet, prebiotics and pro-biotics represent the most commonly used substancestaken in an effort to sustain a healthy microbiome orrestore balance when it is believed bacterial homeostasishas been disturbed in disease. While a considerable vol-ume of basic science attests to the ability of various pre-biotic molecules and probiotic strains to beneficiallyinfluence host immune responses, metabolic processes andneuro-endocrine pathways, the evidence base from humanstudies leaves much to be desired. This translational gapowes much to the manner in which this sector is regulatedbut also speaks to the challenges that confront the inves-tigator who seeks to explore microbiota modulation ineither healthy populations or those who suffer from com-mon digestive ailments. For many products marketed asprobiotics, some of the most fundamental issues relating toquality control, such as characterization, formulation,viability safety are scarcely addressed.
Keywords: Microbiota; Probiotic; Prebiotic; Synbiotics.
Given the intimate relationships that are known toexist between what happens in the lumen of the
gastrointestinal tract and various homeostatic phenom-ena, both locally in the gut and throughout the organism,it should come as no surprise that considerable interesthas been kindled in the modulation of 1 critical compo-nent of the enteric microenvironment—the gut micro-biota.1 The possibility that one could beneficially influenceimmune, motility, sensory, secretory, and neuroendocrineresponses in the gut, as well as more systemic physio-logical activities such as metabolism and brain function(via the microbiota-gut-brain axis),2–6 drives an ever-burgeoning research endeavor directed at strategies thatpositively modify our indigenous microbial communities.The advent of a number of molecular techniques includinghigh throughput sequencing, shotgun sequencing andmetabolomics7 has provided considerable impetus toresearch into microbiome-gut-body interactions in healthand disease; research that has identified a host of putativeclinical targets for microbiota directed therapies.8–15
Over recent decades basic science research hasrevealed, not only the intimacy and complexity of
mutually beneficial interactions between gut microbiota,the epithelium, the gut barrier7,16 and the mucosal im-mune system,2,3 but also the interplay between luminalcommensals and the enteric nervous system and gutmuscle.4,5,18,19 That the microbiota might play a role insuch gastrointestinal disorders as celiac disease,17 in-flammatory bowel disease,16 and functional and motilitydisorders11,20 should therefore come as no surprise.Indeed, through effects on neuroendocrine,5 immune,2
and metabolic functions,21 a role for the microbiota hasbeen invoked in disorders as diverse as arthritis22 andliver disease.21 The recent proposal that interactionsbetween microbiota and gut could extend all the way tothe central nervous system via what is referred to as themicrobiota-gut-brain axis6 now provides a frameworkfor the incrimination of gut microbes in neurologicaldisorders such as Parkinson’s disease.13 The list of mal-adies in which the microbiome has been implicated,albeit with varying levels of evidence, continues toexpand and now includes autism, Alzheimer’s disease,atherosclerosis, obesity, metabolic syndrome, diabetes,colon cancer, depression, and anxiety.12,13,21 This is thecontext in which all interventions, including prebioticsand probiotics, that seek to modulate the microbiotamust now be viewed.
It is likely that foods and supplements that may wellhave exhibited prebiotic or probiotic properties havebeen around for centuries, if not millennia, and usedempirically in health maintenance as well as in themanagement of gastrointestinal symptoms and disor-ders. Now, this unregulated and over-the-counter marketin products that claim prebiotic and probiotic propertieshas begun to attract the scrutiny of the scientific com-munity and the regulatory authorities. The biologicaleffects of these substances are being investigated, plau-sible hypotheses for their use in health or diseasedeveloped and, albeit too slowly, rigorous clinical studiesof their impact in humans are beginning to emerge.
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Whether prodded by regulators or demanded by pre-scribers and consumers, prebiotics and probiotics areemerging from the dark and into the light of scientificscrutiny. This review will focus on recent developmentsin their definition, biology and clinical effects. Commentswill be limited to issues pertinent to the gastrointestinaltract and its related organs.
Definitions and Their Implications
Prebiotic
The most widely quoted definition of a prebiotic isthat provided by Gibson and Roberfroid23 in 1995 as “anon-digestible food ingredient that beneficially affects thehost by selectively stimulating the growth and/or activityof one or a limited number of bacteria in the colon.” Apanel of experts convened by the International ScientificAssociation for Probiotics and Prebiotics (ISAPP) in 2016modified this to “a substrate that is selectively utilized byhost microorganisms conferring health benefit.”24 Selec-tivity is regarded as central to the prebiotic concept; incontrast to fibers, such as cellulose, pectins, and xylans,which promote the growth of many microorganisms inthe gut, prebiotics such as fructo-oligosaccharides andgalacto-oligosaccharides primarily stimulate the prolif-eration of Lactobacillus and Bifidobacterium. This hasclinically important ramifications as selectivity mitigatesagainst the promotion of potential pathogens, or of gas-producing organisms, such as Clostridium, that mightinduce unwanted side effects. An insistence on selectivitydoes not, as pointed out by Gibson et al24, exclude effectson species or strains other than Lactobacillus and Bifi-dobacterium. Relationships between fibers and prebioticscan be the source of some confusion—depending on thefiber and the host that ingests it, some fibers can exertprebiotic effects whereas others, as already mentioned,do not. As prebiotics are typically “carbohydrate poly-mers that are neither digested nor absorbed in the hu-man small intestine,”25 most prebiotics, in contrast, canbe classified as fibers.26 Molecules classically regarded asprebiotics include human milk oligosaccharides, inulin,fructo-oligosaccharides, and galacto-oligosaccharides.The concept of selectivity has been challenged. Bindelset al27 proposed an alternative definition of a prebiotic as“a nondigestible compound that, through its metabo-lization by microorganisms in the gut, modulatescomposition and/or activity of the gut microbiota thusconferring a beneficial physiologic effect on the host.” Inso doing, they ditched the requirement for selectivity andspecificity and expanded metabolism beyond fermenta-tion. In support of the latter, they draw attention to thedemonstration of potentially beneficial effects of pre-biotics which are not dependent on fermentation.27 Theyalso proposed that noncarbohydratesmay act as prebioticsand added the following candidate prebiotics to the usuallist: “resistant starch, pectin, arabinoxylan, whole grains,various dietary fibers, and noncarbohydrates that exert
their action through amodulation of the gutmicrobiota.”27
For now, however, the concept of selectivity prevails butmaywell be refined as research progresses. Indeed, recentstudies support the concept of selectivity. Thus, whenVandeputte et al28 examined the impact of inulin-typefructans on the fecal microbiota of healthy adults withmild constipation, they found, as expected, increasedrelative abundance of Bifidobacterium spp., but also notedincreases in Anaerostipes spp. and a decrease in the pop-ulation of Bilophila; the latter effect correlating with achange in stool consistency.
Probiotic
Though probably in existence for centuries, probioticswere first defined by Lilly and Stillwell29 in 1965 as“substances secreted by one microorganism whichstimulate (in contrast to antibiotics) the growth ofanother.” This definition of a probiotic was subsequentlyexpanded to “a preparation of, or a product containingviable, defined microorganisms in sufficient numbers,which alter the microflora (by implantation or coloniza-tion) in a compartment of the host and by that exertbeneficial health effects on the host.”30 The widelyquoted Food and Agricultural Organization of the WorldHealth Organization is more succinct in defining a pro-biotic as being “live microorganisms which whenadministered in adequate amounts confer a healthbenefit on the host.”31 Another ISAPP panel recentlyrevisited the term probiotic and came out in support ofthe retention of the Food and Agricultural Organizationof the World Health Organization definition.32 They listed4 categories of compounds or products that contain livemicroorganisms and are intended for human use andaddressed their regulatory implications:
1. Live or active cultures
These products, such as yogurts, simply claim thatthey contain live and active cultures but, unless evi-dence is provided that they confer a health benefit(which some do), this descriptor should not be takento imply probiotic activity.
2. Probiotic in food or supplement without a healthclaim
Such products state that they “contain probiotics.”They should be safe and provide evidence of a generalhealth benefit in humans. In some jurisdictions, theuse of the term “probiotic” has been regarded as animplied health claim (based on the aforementioneddefinitions of a probiotic) and, therefore, forbidden inthe absence of acceptable evidence of a healthbenefit.33 Definitions do matter!
3. Probiotic in food or supplement with a specifichealth claim
This category requires that the product has demon-strated convincing evidence of a specific health claim
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such as “reinforces the body’s natural defenses.” Forexample, in Europe, the European Food Safety Au-thority requires the following evidence to support ahealth claim34,35:
a. Characterization of the strain or each of thestrains in a probiotic mix or combination
b. Identification of the health relationship that isconsidered as a beneficial physiological effect tothe target population (ie, the general populationor a defined part of it)
c. Demonstration of health effects in a normalhealthy population.
Few probiotics have met these requirements.
4. Probiotic drug
Here the probiotic is used to treat or prevent a spe-cific disease. In the United States, and elsewhere, thisis now categorized as a drug (defined as an articleintended for use in the diagnosis, cure, mitigation,treatment, or prevention of disease) andmust satisfy allthe regulatory requirements to be approved as such.
If a probiotic is intended as a dietary supplement (ie,categories 1–3 above) and is not being proposed as adrug, it is regulated in the United States under the Di-etary Supplement Health and Education Act of 1994 andis regarded as a food. Dietary supplements do notrequire approval by the Food and Drug Administrationbefore being marketed but, according to Dietary Sup-plement Health and Education Act of 1994, must provideevidence of safety and follow Current GoodManufacturing Practice requirements for dietary sup-plements. Serious adverse events must be reported tothe Food and Drug Administration.36 The regulatoryapproach in other jurisdictions varies considerably fromtreating nonfood probiotics as drugs or biological agentsto classifying them as functional foods. In others, there isminimal oversight.37
The current definition of a probiotic has furtherramifications. Two issues deserve special emphasis: thefocus on “live” organisms and the insistence onconferring “a health benefit on the host.” Firstly, while itis readily acknowledged that studies in a number ofanimal models have demonstrated efficacy for killedbacteria, or even bacterial products or components,38–40
in generating a number of anti-inflammatory and anti-infective effects, this strategy has not, as yet, beenexplored or validated in humans. It seems improbablethat effects of probiotics in humans will be confined tolive organisms so this aspect of the definition will ulti-mately have to be refined or the term abandonedcompletely. The term pharmabiotic has been proposedto encompass all biological active moieties derived fromthe microbiota. Second, it is obvious from the latter part ofthe definition that clinical claims in humans, be they in theaugmentation of health or in the treatment of disease,must be supported by credible clinical trial data.
Synbiotic
As its name suggests, a synbiotic refers to the com-bination of a prebiotic with a probiotic. The intent is toamplify the benefits of the probiotic as well as stimulatethe growth of indigenous beneficial microbes.
Implications
The tersely worded legalize of the documents whichtypify the seemingly esoteric promulgations of thevarious regulatory bodies do have significant practicalimplications. In the United States, for example, where, incomparison with drugs, prebiotics, probiotics and syn-biotics appear relatively unregulated, the consumer isconfronted with products and formulations all claimingto be (or contain) probiotics whose range seems to belimited only by the imagination of the manufacturer.Claims deftly skirt around preventing or treating diseaseby the use of vague terms such as “immune boosting” or“restoring digestive balance” yet are seldom supportedby any clinical data. How is the hapless consumer todifferentiate between high quality products with sup-portive data and those which have none in an environ-ment of such “light touch” regulation? It seems inevitablethat regulatory oversight must increase.
A change in the regulatory climate may also demand amore rigorous approach to clinical trials. This will posechallenges for potential investigators; specifically, whowill fund the trials which will be required to satisfy thenew demands of regulatory authorities—requirementsthat are already beginning to emerge in Europe?41,42 If itis decided that a given probiotic product is to be regardedas a food, profit margins will be slim and the targetpopulation will, by definition, be the healthy population.Such trials will by virtue of their endpoints require verylarge numbers of participants and be very expensive.Within the food category one acceptable endpoint wouldbe the demonstration of a reduction in risk for a givenentity in the general population. This requires a validatedbiomarker of risk, of which there are few (eg, cholesterolfor heart disease), not a biomarker of early disease (whichimmediately moves the product into the drug category).Both issues, the size of study population and need forvalidated biomarkers of risk pose huge problems for thefood industry, which does not have a tradition of fundingsuch trials. In other words, it may be cheaper to studyprobiotics as drugs for narrow indications within thepharmaceutical sector (paradoxically lower costs andhigher margins on licensable product) unless new mi-crobial biomarkers of risk emerge.
Practical Considerations
Quality Control
Any prebiotic that is recommended for use in humansshould be thoroughly characterized in terms of its
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structural biochemistry and it should be resistant to theeffects of gastric acid, bile, and digestive enzymes so thatit arrives at its proposed site of action (usually the colon)intact. Dose ranging studies should be performed toensure that an effective dose is delivered without causingadverse effects.24 Needless to say, any and all healthclaims should be supported by clinical evidence andevery effort should be made to establish a cause-and-effect relationship between the administration of theprebiotic, changes in microbial populations and theirmetabolism and the health benefit.
For probiotics (and synbiotics) the guidelines for theevaluation of probiotics in food proposed in 2001 stillform a reasonable basis for quality control36,43:
1. “Identification of the genus and species of theprobiotic strain by using a combination of pheno-typic and genotypic tests as clinical evidence sug-gesting that the health benefits of probiotics maybestrain specific.”
Though proposed almost 20 years ago this has provenremarkably prescient. The complete genomes ofseveral probiotic strains have now been sequencedand, in so doing, some have even been reclassified.44,45
Knowledge of the genome also facilitates batch-by-batch testing of product to ensure consistency.
2. “In vitro testing to delineate the mechanism of theprobiotic effect”
In the decades since the publication of these guide-lines there have been extensive studies of the in vitroand in vivo properties and effects of a host of putativeprobiotic strains. Such studies have identified anumber of effects of relevance to the gastrointestinalhealth and disease, including effects on motility,visceral sensation, gut barriers, immune responses,and the microbiota-gut-brain axis.46–50
3. “Substantiation of the clinical health benefit ofprobiotic agents with human trials”
This remains an absolutely fundamental principle.
4. “Additionally, safety assessment of the probioticshould at a minimum determine:
1. Patterns of antimicrobial drug resistance
2. Metabolic activities
3. Side effects noted in humans during trialsand after marketing
4. Toxin production and hemolytic potential ifthe probiotic strain is known to possessthese properties
5. Lack of infectivity in animal models”
Also fundamental to the development of a probiotic isthe demonstration of survivability in transiting thegastrointestinal tract, as well as throughout the shelf life
of the product. While this painstaking approach to pro-biotic discovery has been adopted by investigators51–53
and reputable manufacturers, many products on themarket have not been subjected to even the most basicaspects of quality control. Many other aspects of pro-biotic and prebiotic usage have been given scant atten-tion, such as optimal dose and ideal formulation. Strainselection is critical. While certain bacterial propertiesmay be common to some or all members of a givenspecies, others, including those that may well be relevantto a given gastrointestinal ailment may well be strainspecific and dependent on certain segments of thegenome.54
Safety
Despite their widespread use over many decades bythe general population, as well as by individualsharboring a broad spectrum of intestinal and systemicdiseases, the safety record of probiotics, prebiotics andsynbiotics has been excellent,55,56 even in potentially atrisk populations.57–60 Rare instances of bacteremia,fungemia and abscesses have been reported,55–60 and 1study associated probiotic use with increased mortalitydue to intestinal ischemia in a group of patients withsevere acute pancreatitis.61 For all of these reason pro-biotics are “generally regarded as safe.”62 Though reas-suring, the literature on probiotic and prebiotic safetylacks the rigor that one associates with drug safetymonitoring and better, prospective data is needed.63
These optimistic views of safety also assume high stan-dards in quality control which may not be always met.
Economic Impact
It has been estimated that the global prebiotic marketwill exceed $8.5 billion by 2024 (https://www.gminsights.com/pressrelease/prebiotics-market-size) andthat that for probiotics will exceed $64 billion by 2022(https://www.marketsandmarkets.com/Market-Reports/probiotic-market-advanced-technologies-and-global-market-69.html?gclid¼Cj0KCQjwtb_bBRCFARIsAO5fVvH2HmbgwjWxqdjbfiOmBiieJ2r5wf9_Fu5NCh9JAmh-3wkrYPFlzroaAppAEALw_wcB). For now, given the manner inwhich these products are regulated in most countries,the cost is borne by the consumer; costs that varytremendously between products and countries.
Mechanisms of Action
Prebiotics
Central to the very definition of a prebiotic are itsimpacts on bacterial proliferation and metabolism.64,65
Recent studies employing a variety of prebiotic mole-cules have consistently demonstrated increases in the
January 2019 Prebiotics and Probiotics in Digestive Health 337
relative numbers of Lactobacillus and Bifidobacteriumspp. as well as changes in bacterial metabolism, as evi-denced, in particular, by an increased production ofshort-chain fatty acids such as butyrate and propionate(summarized in).26 Short-chain fatty acids, in turn,possess antimicrobial activity and promote homeostasisthrough effects on the integrity of the colonic epitheliumand metabolic and immunological actions.25–27 Aspointed out by Bindels et al27 and acknowledged in theISAPP document, the metabolic impact of prebiotics ex-tends beyond fermentation and some of the beneficialeffects may rely on interactions with the epithelium orimmune system through effects on bile acid metabolism,and neuroendocrine responses (summarized in Gibsonet al).24 Impacts remote from the gut and within thecentral nervous system have also been demonstrated.66
As ever more selective prebiotic molecules are devel-oped, targeting of very specific biological effects willbecome more possible.
Probiotics
Probiotics have been extensively studied in animalmodels and beneficial effect of several species andstrains demonstrated in immunological, metabolic, andneuroendocrine dysfunction (Figure 1).
Many probiotics are derived from the commensalmicrobiota in the healthy human gut; their propertieswill, understandably, mimic those of the homeostaticeffects of the intact microbiota. A substantial literatureattests to the anti-inflammatory effects of probiotics.Probiotics engaging with the mucosal immune system viaToll-like receptors to promote type 1 T helper cell dif-ferentiation. As a consequence antibody production isincreased, phagocytic and natural killer cell activityaugmented, and the nuclear factor kappa-light-chain-enhancer of activated B cells (nuclear factor-kB)pathway inhibited. These lead, in turn to the induction ofT cell apoptosis, upregulation of anti-inflammatory cy-tokines, such as interleukin (IL)-10, and transforminggrowth factor beta and downregulation of proin-flammatory cytokines such as tumor necrosis factoralpha, interferon gamma, and IL-8.45,67–73 In this way, aprobiotic mimics the tolerance induced by commensalorganisms and contrasts with the inflammatory responseto pathogens. Faecalibacterium prausnitzii has beenidentified as protective against inflammatory bowel dis-ease in humans74 and has been shown to induce the anti-inflammatory interleukin, IL-10 in human and murinedendritic cells75 and suppress chronic inflammation in amurine model.76 This research has generated much in-terest in the potential of this organism as a probiotic forIBD.
Critical to their potential role in enteric infectionsprobiotics have been shown to beneficially modulate thecomposition of the microbiota by inhibiting the growth ofpotentially pathogenic bacteria through the production
of bacteriocins and the creation of a more acidic milieuthat is inimical to proinflammatory bacteria, yet pro-motes the growth of beneficial species such as Lactoba-cilli and Bifidobacteria.77–80
The positive impacts of probiotics on gut barrierfunction have relevance to a number of conditionsranging from irritable bowel syndrome to inflammatorybowel disease as well to the host of conditions thathave, wrongly or rightly, been linked to a “leaky gut”and bacterial translocation. This hypothesis, is indeedcentral to the proposed role of the microbiota in thepathogenesis of a range of liver diseases and theircomplications.81 The structural, physiological, and mo-lecular effects of various probiotics on the componentsof gut defense have been amply demonstrated in animalmodels.82–89
Effects of probiotics on processes relevant to dysmo-tility and functional disorders have also been demon-strated in animal models. These include reducing visceralhypersensitivity.39,90–94 Effects on smooth muscle func-tion and transit have also been demonstrated.81,95,96
Beneficial effects on gut function could also be exer-ted via the microbiome-gut-brain axis and a plethora ofrecent studies, mostly, it must be conceded, from animalmodels, attest to the ability of microbes in the gut tomodulate brain development, structure and function andinfluence emotions and behavior97–101
Many other effects of probiotics and, most notably,those on metabolic processes have been demonstratedbut are beyond the scope of this review; they may,however, be highly relevant to obesity, the metabolicsyndrome and nonalcoholic fatty liver disease.21
These almost universally positive effects of probioticsin animal models should translate into tangible benefitsin humans. Do they? While some success has achieved indemonstrating beneficial immunological, physiologicaland metabolic effects in humans, results have proven lessconsistent and often difficult to demonstrate. This shouldcome as no surprise.
Studies of the administration of probiotics on thecomposition of the fecal microbiota have demonstrated,at best, modest effects.102,103 This should not be taken toimply that probiotic have no effects—effects of an orallyadministered probiotic on the systemic immune sys-tem104,105 and on brain responses106 have, indeed, beendemonstrated in healthy volunteers and irritable bowelsufferers, respectively. What these findings speak to isthe likelihood the probiotic effects are subtle, may occuron the mucosal surface and may even be exerted in thesmall intestine or stomach107 and not in the colon—phenomena that may not detected on analyzing the feces.It should also be noted, parenthetically, that the poorlyabsorbed antibiotic, rifaximin, is also associated withrelatively minor shifts in gut microbiota populations—afurther illustration of the subtlety of interventions thatclearly modulate microbiota activity and benefitpatients.108
Figure 1.Mechanisms of action of probiotics. (A) Effects on the microbiota and luminal milieu. (B) Effects on gut barrier. (C)Immune effects. (D) Effects on neuromuscular function. (E) Impact on the microbiota-gut-brain axis. IgA, immunoglobulin A;SCFA, short-chain fatty acid; TLR, Toll-like receptor; Treg, regulatory T lymphocyte.
338 Eamonn M.M. Quigley Clinical Gastroenterology and Hepatology Vol. 17, No. 2
Clinical Evidence
There continue to be major shortcomings in relationto clinical studies of prebiotics, probiotics, and syn-biotics. Even among probiotic studies (which greatlyoutnumber those performed with prebiotics and syn-biotics), the clinician will encounter challenges inattempting to derive clinically useful messages. Hetero-geneity is the rule with studies differing widely in studyprotocol, selection of study population, sample size,strain or strains employed, dosage, formulation, durationof therapy and outcome measures, even for the sameindication,109,110 For example, the recent systematic
review with meta-analysis performed by Ford et al111
evaluating data from 43 randomized controlled trialswhile showing that probiotics, in general, are effective inirritable bowel syndrome, was unable to define whichindividual strains or species were most beneficialbecause of a lack of adequate comparative data.
Effects in Healthy Adults
As clinicians we are frequently asked by family,friends, and colleagues whether taking a probiotic isbeneficial to otherwise healthy individuals. Khalesiet al112 recently completed a comprehensive review of
Table 1. Clinical Utility of Probiotics in Gastrointestinal and Liver Diseases
Indication Endpoint(s) - Outcome Preferred Strain(s) Comments Reference(s)
AAD and CDAD Prevention - effective Lactobacillus GG and S Saccharomycesboulardii (in children)
No differences in efficacy betweenprobiotics
Quality of evidence moderate to highEffective if background risk >5%Probiotics most effective if given close to
the first dose of antibioticNo increase in AEs
118–121
Chemoradiation-induced diarrhea Prevention - probable effectTreatment - possible benefit
Some studies limited to abdominal andpelvic radiation therapy, someinclude chemotherapy
122,123
Crohn’s disease Any outcome - no benefit Included prevention of postoperativerecurrence, maintenance of remission
124
Diarrhea in children Reduce duration of diarrhea - effective Lactobacillus reuterii DSM 17938 andLactobacillus GG
May not be effective againstgastroenteritis in developedcountries. Limited evidence forpersistent diarrhea.
125–127
Helicobacter pylori 1. Increase eradication rate as adjunc-tive therapy - conflicting data onefficacy
2. Reduce antibiotic-related adverseevents - more consistent datasupport efficacy
Lactobacillus- and Bifidobacterium-containing probiotics
Saccharomyces boulardiiLactobacillus-containing probioticsSaccharomyces boulardii
Benefits may be greater in Asianpopulations
Impact on compliance with eradicationregimens unclear
128–130
Hepatic encephalopathy 1. Symptom improvement - someefficacy
2. Reduce rate of progression of MHE toovert HE - some benefits seen
No effect on mortalityAs effective as lactuloseLow quality of evidence
131
IBS 1. Overall symptom relief - effective2. Relief of major symptoms individually
-effective
In general, evidence insufficient todistinguish between strains orproducts
Low quality of evidence overall 111,132
Pouchitis Primary prevention and prevention ofrelapse
VSL #3 124,133
Recurrent abdominal pain inchildhood
Reduce pain frequency and severity -some evidence of efficacy
Moderate-to-low quality of evidence 134
Travelers’ diarrhea Prevention - effective Low quality of evidence 135UC Induce remission in active UC - some
efficacyPrevent relapse of UC in remission -
some efficacy
VSL #3 Effects greatest in mild-to-moderatelysevere UC
As effective as 5-ASA preparations
124
AAD, antibiotic-associated diarrhea; AE, adverse event; CDAD, Clostridium difficile–associated disease, HE, hepatic encephalopathy; MHE, minimal hepatic encephalopathy; UC, ulcerative colitis; 5-ASA, 5-aminosalicylic acid.
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the literature on the impact of probiotics among healthyadults and concluded first, that probiotics had minor andtransient effects on the fecal microbiota; second, thatprobiotics reduced the incidence, duration and symp-toms of the common cold but not influenza; and third,that probiotics had little or inconclusive effects on lipidprofiles, body mass index, or blood sugar or insulinlevels.112 The effects on the common cold, they hypoth-esized, could be explained on the basis of positiveimmunological effects.112
Benefits for prebiotics on satiety and metabolic pa-rameters, including reductions in postprandial glucoseand insulin concentrations, have been demonstrated inhealthy adults; studies of impact on other metabolicparameters provided conflicting results.113 Beneficialeffects have also been demonstrated in obese women.114
For reasons that are, in part, related to the re-strictions of the regulatory environment many probioticsare marketed employing vague promises such as“restores balance” and “boosts immunity”—claims thatmay have some basis in basic science experiments butare scarcely supported by clinical trial data or evidenceof improved quality of life for those who consume them.
Effects in Gastrointestinal Diseasesand Disorders
Despite the presence of considerable evidence for arole for the microbiota at a number of levels in thepathogenesis of a variety of gastrointestinal disordersand the demonstration, in the laboratory, of prebioticand probiotic properties that should be of benefit inthese same disorders, clinical evidence of efficacy stillremains patchy. There is no shortage of studies; deficitsin clinical design, coupled with variations betweenstudies in product and formulation used, study popula-tion and endpoints have frustrated their interpretation.In selecting a prebiotic or probiotic for his or her patientthe clinician faces additional challenges, few dose-ranging studies or head-to-head comparisons and greatvariability in the availability and cost of a given species,cocktail, or prebiotic formulation in different parts of theworld.
A comprehensive review of all studies of prebiotics,probiotics, and synbiotics across the complete range ofgastrointestinal disorders is beyond the scope of thisreview. Fortunately, The World Gastroenterology Orga-nization Global Guideline on Probiotics and Probiotics,published in 2017, provides an up-to-date and evidence-based assessment of the value of prebiotics and pro-biotics in adults and children.115 Evidence was gradedaccording to the system developed by the Oxford Centrefor Evidence-Based Medicine with level 1, the highestlevel, indicating that benefits were based on the resultsof a systematic review of randomized trials or n-of-1trials and level 5, the lowest, based merely onmechanism-based reasoning.116 Few products were
supported by level 1 evidence for an indication in adults.Indications achieving level 1 evidence for a given pro-biotic or probiotic cocktail included the prevention ofantibiotic-associated diarrhea in various clinical settings,reduction of side effects related to eradication therapyfor Helicobacter pylori, prevention of postoperativesepsis in those undergoing elective gastrointestinal sur-geries, maintenance of remission in pouchitis andreducing symptoms related to lactose maldigestion.115
For prebiotics only 1 indication achieved level1—lactulose in the management of hepatic encephalop-athy. While other systematic reviews attest to a positiveimpact for probiotics, in general, in a variety of clinicalscenarios, most are either guarded in their recommen-dation or unable to distinguish between species in termsof efficacy, due to limitations in available data. Table 1lists gastrointestinal diseases and disorders wherethere is, at the very least, some evidence to permit anassessment of the impact of probiotics; other disorders,such as collagenous colitis, constipation and nonalcoholicfatty liver disease where available evidence does notallow for such an assessment are not presented.
Conclusions
The importance of the gut microbiome in homeostasisin health and in the pathogenesis of disease becomesever more evident by the hour and studies in animalmodels continue to provide more clear-cut signals.Humans are complex, messy individuals. The same holdstrue for the microbiota-modulating interventions dis-cussed here—impressive results in mice in rats whiledata from human studies are often conflicting andinconclusive. This frustration owes much to the in-adequacies of clinical trials. That high-quality trials canbe completed and yield positive and clinically meaningfulresults is amply illustrated by the recent study of theimpact of a synbiotic on infections among high-riskchildren in India.117 It is to be hoped that well-characterized and appropriately formulated productswill emerge from the laboratory supported by a clearrationale for their use in a given clinical indication.136
Regrettably, it is likely that progress in terms of qualitycontrol will only come from tighter regulation of thesector. Only then can the health care profession guide theconsumer through the confusion that prebiotics andprobiotics currently present.
References
1. Barbara G, Feinle-Bisset C, Ghoshal UC, et al. The intestinalmicroenvironment and functional gastrointestinal disorders.Gastroenterology 2016 Feb 18 [E-pub ahead of print].
2. Thaiss CA, Zmora N, Levy M, Elinav E. The microbiome andinnate immunity. Nature 2016;535:65–74.
3. Kabouridis PS, Pachnis V. Emerging roles of gut microbiota andthe immune system in the development of the enteric nervoussystem. J Clin Invest 2015;125:956–964.
January 2019 Prebiotics and Probiotics in Digestive Health 341
4. O’Mahony SM, Dinan TG, Cryan JF. The gut microbiota as a keyregulator of visceral pain. Pain 2017;158(Suppl 1):S19–S28.
5. Farzi A, Fröhlich EE, Holzer P. Gut microbiota and the neuro-endocrine system. Neurotherapeutics 2018;15:5–22.
6. Dinan TG, Cryan JF. The microbiome-gut-brain axis in healthand disease. Gastroenterol Clin North Am 2017;46:77–89.
7. Claesson MJ, Clooney AG, O’Toole PW. A clinician’s guide tomicrobiome analysis. Nat Rev Gastroenterol Hepatol 2017;14:585–595.
8. O’Toole PW, Jeffery IB. Microbiome-health interactions in olderpeople. Cell Mol Life Sci 2018;75:119–128.
9. Di Pilato V, Freschi G, Ringressi MN, Pallecchi L, Rossolini GM,Bechi P. The esophageal microbiota in health and disease. AnnN Y Acad Sci 2016;1381:21–33.
10. Hunt RH, Yaghoobi M. The esophageal and gastric microbiomein health and disease. Gastroenterol Clin North Am 2017;46:121–141.
11. Ringel Y. The gut microbiome in irritable bowel syndrome andother functional bowel disorders. Gastroenterol Clin North Am2017;46:91–101.
12. Flemer B, Warren RD, Barrett MP, et al. The oral microbiota incolorectal cancer is distinctive and predictive. Gut 2018;67:1454–1463.
13. Quigley EMM. Microbiota-brain-gut axis and neurodegenerativediseases. Curr Neurol Neurosci Rep 2017;17:94.
14. Quigley EMM. Gut microbiome as a clinical tool in gastrointes-tinal disease management: are we there yet? Nat Rev Gastro-enterol Hepatol 2017;14:315–320.
15. Kayshap PC, Quigley EM. Therapeutic implications of thegastrointestinal microbiome. Curr Opin Pharmacol 2018;38:90–96.
16. Martini E, Krug SM, Siegmund B, Neurath MF, Becker C. Mendyour fences: the epithelial barrier and its relationship withmucosal immunity in inflammatory bowel disease. Cell MolGastroenterol Hepatol 2017;4:33–46.
17. Cukrowska B, Sowi�nska A, Bierła JB, Czarnowska E, Rybak A,Grzybowska-Chlebowczyk U. Intestinal epithelium, intra-epithelial lymphocytes and the gut microbiota - key players inthe pathogenesis of celiac disease. World J Gastroenterol 2017;23:7505–7518.
18. Guarino MP, Cicala M, Putignani L, Severi C. Gastrointestinalneuromuscular apparatus: An underestimated target of gutmicrobiota. World J Gastroenterol 2016;22:9871–9879.
19. Rolig AS, Mittge EK, Ganz J, et al. The enteric nervous systempromotes intestinal health by constraining microbiota compo-sition. PLoS Biol 2017;15:e2000689.
20. Parthasarathy G, Chen J, Chen X, et al. Relationship betweenmicrobiota of the colonic mucosa vs feces and symptoms,colonic transit, and methane production in female patients withchronic constipation. Gastroenterology 2016;150:367–379.
21. Quigley EM, Abu-Shanab A, Murphy EF, Stanton C,Monsour HP Jr. The Metabolic role of the microbiome: impli-cations for NAFLD and the metabolic syndrome. Semin Liver Dis2016;36:312–316.
22. Taneja V. Arthritis susceptibility and the gut microbiome. FEBSLett 2014;588:4244–4249.
23. Gibson GR, Roberfroid MB. Dietary modulation of the humancolonic microbiota. Introducing the concept of prebiotics. J Nutr1995;125:1401–1412.
24. Gibson GR, Hutkins R, Sanders ME, et al. The InternationalScientific Association for Probiotics and Prebiotics (ISAPP)
consensus statement on the definition and scope of prebiotics.Nat Rev Gastroenterol Hepatol 2017;14:491–502.
25. Codex Alimentarius Committee. Guidelines on nutrition labellingCAC/GL 2-1985 as last amended 2010. In: Joint FAO/WHOFood Standards Programme, Secretariat of the Codex Ali-mentarius Commission. Rome, Italy: FAO, 2010.
26. Holscher HD. Dietary fiber and prebiotics and gastrointestinalmicrobiota. Gut Microbes 2017;8:172–184.
27. Bindels LB, Delzenne NM, Cani PD, Walter J. Towards a morecomprehensive concept for prebiotics. Nat Rev GastroenterolHepatol 2015;12:303–310.
28. Vandeputte D, Falony G, Vieira-Ailva S, et al. Prebiotic inulin-type fructans induce specific changes in the human gut micro-biota. Gut 2017;66:1968–1974.
29. Lilly DM, Stillwell RH. Probiotics. Growth promoting factorsproduced by micro-organisms. Science 1965;147:747–748.
30. Schrezenmeir J, de Vrese M. Probiotics, prebiotics, andsynbiotics—approaching a definition. Am J Clin Nutr 2001;73(Suppl):361S–364S.
31. Food and Agriculture Organization of the United Nations andWorld Health Organization. Health and nutritional propertiesof probiotics in food including powder milk with live lacticacid bacteria. World Health Organization. 2001. Available at:http://www.who.int/foodsafety/publications/fs_management/en/probiotics.pdf. Accessed October 29, 2018.
32. Hill C, Guarner F, Reid G, et al. Expert consensus document.The International Scientific Association for Probiotics and Pre-biotics consensus statement on the scope and appropriate useof the term probiotic. Nat Rev Gastroenterol Hepatol 2014;11:506–514.
33. Food Safety Authority of Ireland. Probiotic health claims. Avail-able at: http://www.fsai.ie/faq/probiotic_health_claims.html:Accessed October 29, 2018.
34. Salminen S, van Loveren H. Probiotics and prebiotics: healthclaim substantiation. Microb Ecol Health Dis 2012;23:40–42.
35. van Loveren H, Sanz Y, Salminen S. Health claims in Europe:probiotics and prebiotics as case examples. Annu Rev Food SciTechnol 2012;3:247–261.
36. Venugopalan V, Shriner KA, Wong-Beringer A. Regulatoryoversight and safety of probiotic use. Emerging Inf Dis 2010;16:1661–1665.
37. Arora M, Baldi A. Regulatory categories of probiotics across theglobe: a review representing existing and recommended cate-gorization. Indian J Med Microbiol 2015;33(Suppl):2–10.
38. Rachmilewitz D, Kayatura, Karmeli F, et al. Toll-like receptor 9signaling mediates the anti-inflammatory effects of probiotics inmurine experimental colitis. Gastroenterology 2004;126:520–528.
39. Jijon H, Backer J, Diaz H, et al. DNA from probiotic bacteriamodulates murine and human epithelial and immune function.Gastroenterology 2004;126:1358–1373.
40. Kamiya T, Wang L, Forsythe P, et al. Inhibitory effects ofLactobacillus reuteri on visceral pain induced by colorectaldistension in Sprague-Dawley rats. Gut 2006;55:191–196.
41. Gibson GR, Brummer RJ, Isolauri E, et al. The design of pro-biotic studies to substantiate health claims. Gut Microbes 2011;2:299–305.
42. Binnendijk KH, Rijkers GT. What is a health benefit? An evalu-ation of EFSA opinions on health benefits with reference toprobiotics. Benef Microbes 2013;4:223–230.
43. Joint Food and Agriculture Organization of the United Nations/World Health Organization Working Group. Report on drafting
342 Eamonn M.M. Quigley Clinical Gastroenterology and Hepatology Vol. 17, No. 2
guidelines for the evaluation of probiotics in food. 2002. Availableat: https://www.who.int/foodsafety/fs_management/en/probiotic_guidelines.pdf. Accessed October 29, 2018.
44. Lewis ZT, Shani G, Masarweh CF, et al. Validating bifidobacterialspecies and subspecies identity in commercial probiotic prod-ucts. Pediatr Res 2016;79:445–452.
45. Quigley EMM. Bifidobacteria as probiotic organisms. An intro-duction. In: Floch MH, Ringel Y, Walker MA, eds. The Microbiotain Gastrointestinal Pathophysiology. London: Elsevier AcademicPress, 2017:125–126.
46. Shanahan F, Quigley EM. Manipulation of the microbiota fortreatment of IBS and IBD-challenges and controversies.Gastroenterology 2014;146:1554–1563.
47. Victor DW 3rd, Quigley EM. Microbial therapy in liver disease:probiotics probe the microbiome-gut-liver-brain axis. Gastro-enterology 2014;147:1216–1218.
48. Quigley EM. Probiotics in irritable bowel syndrome: the scienceand the evidence. J ClinGastroenterol 2015;49(Suppl 1):S60–S64.
49. Abraham BP, Quigley EMM. Probiotics in inflammatory boweldisease. Gastroenterol Clin North Am 2017;46:769–782.
50. Giron F, Quigley EMM. Pharmabiotic manipulation of themicrobiota in gastrointestinal disorders: a clinical perspective.J Neurogastroenterol Motil 2018;24:355–366.
51. Dunne C, Murphy L, Flynn S, et al. Probiotics: from myth to reality.Demonstration of functionality in animal models of disease and inhuman clinical trials. Antonie Van Leeuwenhoek 1999;76:279–292.
52. Dunne C, O’Mahony L, Murphy L, et al. In vitro selection criteriafor probiotic bacteria of human origin: correlation with in vivofindings. Am J Clin Nutr 2001;73:386s–392s.
53. Altmann F, Kosma P, O’Callaghan A, et al. Genome analysis andCharacterisation of the exopolysaccharide produced by Bifido-bacterium longum subsp. longum 35624. PLoS One 2016;11:e0162983.
54. Schiavi E, Gleinser M, Molloy E, et al. The surface-associatedexopolysaccharide of Bifidobacterium longum 35624 plays anessential role in dampening host proinflammatory responsesand repressing local TH17 responses. Appl Environ Microbiol2016;82:7185–7196.
55. Didari T, Solki S, Mozaffari S, Nikfar S, Abdollahi M.A systematic review of the safety of probiotics. Expert Opin DrugSaf 2014;13:227–239.
56. Doron S, Snydman DR. Risk and safety of probiotics. Clin InfectDis 2015;60(Suppl 2):S129–S134.
57. AlFaleh K, Anabrees J. Efficacy and safety of probiotics in pre-term infants. J Neonatal Perinatal Med 2013;6:1–9.
58. Redman MG, Ward EJ, Phillips RS. The efficacy and safety ofprobiotics in people with cancer: a systematic review. Ann Oncol2014;25:1919–1929.
59. Urben LM, Wiedmar J, Boettcher E, Cavallazzi R, Martindale RG,McClave SA. Bugs or drugs: are probiotics safe for use in thecritically ill? Curr Gastroenterol Rep 2014;16:388.
60. Wang Y-H, Yao N, Wei KK, et al. The efficacy and safety ofprobiotics for prevention of chemoradiotherapy-induced diar-rhea in people with abdominal and pelvic cancer: a systematicreview and meta-analysis. Eur J Clin Nutr 2016;70:1246–1212.
61. Besselink MG, van Santvoort HC, Buskens E, et al. Dutch AcutePancreatitis Study Group. Probiotic prophylaxis in predictedsevere acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 2008;371:651–659.
62. EFSA Scientific Colloquium Summary Report. QPS: qualifiedpresumption of safety of microorganisms in food and feed.
2004. Available at: https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/sp.efsa.2005.EN-109. Accessed October 29, 2018.
63. Sanders ME, Akkermans LM, Haller D, et al. Safety assessmentof probiotics for human use. Gut Microbes 2010;1:164–185.
64. Gibson GR, Beatty ER, Wang X, Cummings JH. Selectivestimulation of bifidobacteria in the human colon by oligofructoseand inulin. Gastroenterology 1995;108:975–982.
65. Hidaka H, Hirayama M, Tokunaga T, Eida T. The effects of un-digestible fructooligosaccharides on intestinal microflora andvarious physiological functions on human health. Adv Exp MedBiol 1990;270:105–117.
66. Burokas A, Arboleya S, Moloney RD, et al. Targeting themicrobiota-gut-brain axis: prebiotics have anxiolytic andantidepressant-like effects and reverse the impact of chronicstress in mice. Biol Psychiatry 2017;82:472–487.
67. Petrof EO, Kojima K, Ropeleski MJ, et al. Probiotics inhibit nu-clear factor-kappaB and induce heat shock proteins in colonicepithelial cells through proteasome inhibition. Gastroenterology2004;127:1474–1487.
68. Di Marzio L, Russo FP, D’Alo S, et al. Apoptotic effects ofselected strains of lactic acid bacteria on a human T leukemiacell line are associated with bacterial arginine deiminase and/orsphingomyelinase activities. Nutr Cancer 2001;40:185–196.
69. Maassen CB, van Holten-Neelen C, Balk F, et al. Strain-dependent induction of cytokine profiles in the gut by orallyadministered Lactobacillus strains. Vaccine 2000;18:2613–2623.
70. Morita H, He F, Fuse T, et al. Adhesion of lactic acid bacteria tocaco-2 cells and their effect on cytokine secretion. MicrobiolImmunol 2002;46:293–297.
71. Ma D, Forsythe P, Bienenstock J. Live Lactobacillus reuteri isessential for the inhibitory effect on tumor necrosis factor alpha-induced interleukin-8 expression. Infect Immun 2004;72:5308–5314.
72. West CE, Jenmalm MC, Prescott SL. The gut microbiota and itsrole in the development of allergic disease: a wider perspective.Clin Exp Allergy 2015;45:43–53.
73. Konieczna P, Akdis CA, Quigley EM, et al. Portrait of animmunoregulatory Bifidobacterium. Gut Microbes 2012;3:261–266.
74. Cao Y, Shen J, Ran ZH. Association between Faecalibacteriumprausnitzii reduction and inflammatory bowel disease: a meta-analysis and systematic review of the literature. GastroenterolRes Pract 2014;2014:872725.
75. Rossi O, van Berkel LA, Chain F, et al. Faecalibacteriumprausnitzii A2-165 has a high capacity to induce IL-10 in humanand murine dendritic cells and modulates T cell responses. SciRep 2016;6:18507.
76. Martín R, Miquel S, Chain F, et al. Faecalibacterium prausnitziiprevents physiological damages in a chronic low-grade inflam-mation murine model. BMC Microbiol 2015;15:67.
77. Shiba T, Aiba Y, Ishikawa H, et al. The suppressive effect ofbifidobacteria on Bacteroides vulgatus, a putative pathogenicmicrobe in inflammatory bowel disease. Microbiol Immunol2003;47:371–378.
78. Servin AL. Antagonistic activities of lactobacilli and bifidobac-teria against microbial pathogens. FEMS Microbiol Rev 2004;28:405–440.
79. Sartor RB. Therapeutic manipulation of the enteric microflora ininflammatory bowel diseases: antibiotics, probiotics, and pre-biotics. Gastroenterology 2004;126:1620–1633.
January 2019 Prebiotics and Probiotics in Digestive Health 343
80. Constante M, Fragoso G, Lupien-Meilleur J, Calvé A,Santos MM. Iron supplements modulate colon microbiotacomposition and potentiate the protective effects of probioticsin dextran sodium sulfate-induced colitis. Inflamm Bowel Dis2017;23:753–766.
81. Victor DW 3rd, Quigley EM. The microbiome and the liver: thebasics. Semin Liver Dis 2016;36:299–305.
82. Picard C, Fioramonti J, Francois A, Robinson T, Neant F,Matuchansky C. Review article: bifidobacteria as probioticagents—physiological effects and clinical benefits. AlimentPharmacol Ther 2005;22:495–512.
83. Lomasney KW, Cryan JF, Hyland NP. Converging effects of aBifidobacterium and Lactobacillus probiotic strain on mouseintestinal physiology. Am J Physiol Gastrointest Liver Physiol2014;307:G241–G247.
84. Srutkova D, Schwarzer M, Hudcovic T, et al. Bifidobacteriumlongum CCM 7952 promotes epithelial barrier function andprevents acute dss-induced colitis in strictly strain-specificmanner. PLoS One 2015;10:e0134050.
85. Yan F, Polk DB. Probiotic bacterium prevents cytokine-inducedapoptosis in intestinal epithelial cells. J Biol Chem 2002;277:50959–50965.
86. Ahrne S, Hagslatt ML. Effect of lactobacilli on paracellularpermeability in the gut. Nutrients 2011;3:104–117.
87. Lomasney KW, Houston A, Shanahan F, et al. Selective influ-ence of host microbiota on cAMP-mediated ion transport inmouse colon. Neurogastroenterol Motil 2014;26:887–890.
88. Souza ÉL, Elian SD, Paula LM, et al. Escherichia coli strainNissle 1917 ameliorates experimental colitis by modulating in-testinal permeability, the inflammatory response and clinicalsigns in a faecal transplantation model. J Med Microbiol 2016;65:201–210.
89. Mack DR, Ahrne S, Hyde L, Wei S, Hollingsworth MA. Extra-cellular MUC3 mucin secretion follows adherence of Lactoba-cillus strains to intestinal epithelial cells in vitro. Gut 2003;52:827–833.
90. Verdu EF, Bercik P, Verma-Gandhu M, et al. Specific probiotictherapy attenuates antibiotic induced visceral hypersensitivity inmice. Gut 2006;55:182–190.
91. Ait-Belgnaoui A, Han W, Lamine F, et al. Lactobacillus farciministreatment suppresses stress-induced visceral hypersensitivity: apossible action through interaction with epithelial cells cyto-skeleton contraction. Gut 2006;55:1090–1094.
92. Eutamene H, Lamine F, Chabo C, et al. Synergy betweenLactobacillus paracasei and its bacterial products to counteractstress-induced gut permeability and sensitivity increase in rats.J Nutr 2007;137:1901–1907.
93. McKernan DP, Fitzgerald P, Dinan TG, et al. The probioticBifidobacterium infantis 35624 displays visceralantinociceptive effects in the rat. Neurogastroenterol Motil 2010;22:1029–1035.
94. Johnson AC, Greenwood-Van Meerveld B, McRorie J. Effects ofBifidobacterium infantis 35624 on post-inflammatory visceralhypersensitivity in the rat. Dig Dis Sci 2011;56:3179–3186.
95. Agrawal A, Houghton LA, Morris J, et al. Clinical trial: the effectsof a fermented milk product containing Bifidobacterium lactisDN-173-010 on abdominal distension and gastrointestinaltransit in irritable bowel syndrome with constipation. AlimentPharmacol Ther 2009;29:104–114.
96. Verdu EF, Bercik P, Bergonzelli GE, et al. Lactobacillus para-casei normalizes muscle hypercontractility in a murine model of
postinfective gut dysfunction. Gastroenterology 2004 Sep;127:826–837.
97. Desbonnet L, Garrett L, Clarke G, et al. Effects of the probioticBifidobacterium infantis in the maternal separation model ofdepression. Neuroscience 2010;170:1179–1188.
98. Bercik P, Denou E, Collins J, et al. The intestinal microbiotaaffect central levels of brain-derived neurotrophic factor andbehavior in mice. Gastroenterology 2011;141:599–609.
99. Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillusstrain regulates emotional behavior and central GABA receptorexpression in a mouse via the vagus nerve. Proc Natl Acad SciU S A 2011;108:16050–16055.
100. Desbonnet L, Clarke G, Shanahan F, Dinan TG, Cryan JF.Microbiota is essential for social development in the mouse. MolPsychiatry 2014;19:146–148.
101. Emge JR, Huynh K, Miller EN, et al. Modulation of themicrobiota-gut-brain axis by probiotics in a murine model ofinflammatory bowel disease. Am J Physiol Gastrointest LiverPhysiol 2016;310:G989–G998.
102. Charbonneau D, Gibb RD, Quigley EM. Fecal excretion of Bifi-dobacterium infantis 35624 and changes in fecal microbiotaafter eight weeks of oral supplementation with encapsulatedprobiotic. Gut Microbes 2013;4:201–211.
103. Kolmeder CA, Salojarvi J, Ritari J, et al. Faecal metaproteomicanalysis reveals as personalized and stable functional micro-biome and limited effects of a probiotic intervention in adults.PLoS One 2016;11:e0153294.
104. Konieczna P, Groeger D, Ziegler M, et al. Bifidobacteriuminfantis 35624 administration induces Foxp3 T regulatory cells inhuman peripheral blood: potential role for myeloid and plas-macytoid dendritic cells. Gut 2012;61:354–366.
105. Groeger D, O’Mahony L, Murphy EF, et al. Bifidobacteriuminfantis 35624 modulates host inflammatory processes beyondthe gut. Gut Microbes 2013;4:325–339.
106. Pinto-Sanchez MI, Hall GB, Ghajar K, et al. Probiotic Bifido-bacterium longum NCC3001 reduces depression scores andalters brain activity: a pilot study in patients with irritable bowelsyndrome. Gastroenterology 2017;153:448–459.
107. Panpetch W, Spinler JK, Versalovic J, Tumwasorn S.Characterization of Lactobacillus salivarius strains B37 andB60 capable of inhibiting IL-8 production in Helicobacterpylori-stimulated gastric epithelial cells. BMC Microbiol 2016;16:242.
108. Zeber-Lubecka N, Kulecka M, Ambrozkiewicz F, et al. Limitedprolonged effects of rifaximin treatment on irritable bowelsyndrome-related differences in the fecal microbiome andmetabolome. Gut Microbes 2016;7:397–413.
109. Mazurak N, Broelz E, Storr M, Enck P. Probiotic therapy of theirritable bowel syndrome: why is the evidence still poor and whatcan be done about it? J Neurogastroenterol Motil 2015;21:471–485.
110. Abraham BP, Quigley EMM. A probiotic for ulcerative colitis: theculture wars continue. Dig Dis Sci 2018;63:1678–1680.
111. Ford AC, Quigley EM, Lacy BE, et al. Efficacy of prebiotics,probiotics, and synbiotics in irritable bowel syndrome andchronic idiopathic constipation: systematic review and meta-analysis. Am J Gastroenterol 2014;109:1547–1561.
112. Khalesi S, Bellissimo N, Vandelanotte C, Williams S, Stanley D,Irwin C. A review of probiotic supplementation in healthy adults:helpful or hype? Eur J Clin Nutr 2018 Mar 26 [E-pub ahead ofprint].
344 Eamonn M.M. Quigley Clinical Gastroenterology and Hepatology Vol. 17, No. 2
113. Kellow NJ, Coughlan MT, Reid CM. Metabolic benefits of dietaryprebiotics in human subjects: a systematic review of rando-mised controlled trials. Br J Nutr 2014;111:1147–1161.
114. Dewulf EM, Cani PD, Claus SP, et al. Insight into the prebioticconcept: lessons from an exploratory, double blind interventionstudy with inulin-type fructans in obese women. Gut 2013;62:1112–1121.
115. Guarner F, Sanders ME, Eliakim R, et al. Probiotics and pre-biotics. World Gastroenterology Organisation Global Guidelines.2017. Available at: http://www.worldgastroenterology.org/UserFiles/file/guidelines/probiotics-and-prebiotics-english-2017.pdf.Accessed October 29, 2018.
116. OCEBM levels of evidence. Available at: http://www.cebm.net/index.aspx?o¼5653; 2016:Accessed October 29, 2018.
117. Panigrahi P, Parida S, Nanda NC, et al. A randomized synbiotictrial to prevent sepsis among infants in rural India. Nature 2017;548:407–412.
118. Goldenberg JZ, Lytvyn L, Steurich J, Parkin P, Mahant S,Johnston BC. Probiotics for the prevention of pediatricantibiotic-associated diarrhea. Cochrane Database Syst Rev2015;12:CD004827.
119. Goldenberg JZ, Yap C, Lytvyn L, et al. Probiotics for the pre-vention of Clostridium difficile-associated diarrhea in adults andchildren. Cochrane Database Syst Rev 2017;12:CD006095.
120. Shen NT, Maw A, Tmanova LL, et al. Timely use of probiotics inhospitalized adults prevents clostridium difficile infection: asystematic review with meta-regression analysis. Gastroenter-ology 2017;152:1889–1900.
121. Johnston BC, Lytvyn L, Lo CK, et al. Microbial preparations(probiotics) for the prevention of clostridium difficile infection inadults and children: an individual patient data meta-analysis of6,851 participants. Infect Control Hosp Epidemiol 2018;39:771–781.
122. Liu MM, Li ST, Shu Y, Zhan HQ. Probiotics for prevention ofradiation-induced diarrhea: A meta-analysis of randomizedcontrolled trials. PLoS One 2017;12:e0178870.
123. Lawrie TA, Green JT, Beresford M, et al. Interventions to reduceacute and late adverse gastrointestinal effects of pelvic radio-therapy for primary pelvic cancers. Cochrane Database SystRev 2018;1:CD012529.
124. Derwa Y, Gracie DJ, Hamlin PJ, Ford AC. Systematic reviewwith meta-analysis: the efficacy of probiotics in inflammatorybowel disease. Aliment Pharmacol Ther 2017;46:389–400.
125. Bernaola Aponte G, Bada Mancilla CA, Carreazo NY, RojasGalarza RA. Probiotics for treating persistent diarrhoea in chil-dren. Cochrane Database Syst Rev 2013;8:CD007401.
126. Freedman SB, Pasichnyk D, Black KJ, et al. Pediatric Emer-gency Research Canada Gastroenteritis Study Group.
Gastroenteritis therapies in developed countries: systematicreview and meta-analysis. PLoS One 2015;10:e0128754.
127. Urba�nska M, Gieruszczak-Białek D, Szajewska H. Systematicreview with meta-analysis: Lactobacillus reuteri DSM 17938 fordiarrhoeal diseases in children. Aliment Pharmacol Ther 2016;43:1025–1034.
128. Lu C, Sang J, He H, et al. Probiotic supplementation does notimprove eradication rate of Helicobacter pylori infectioncompared to placebo based on standard therapy: a meta-analysis. Sci Rep 2016;6:23522.
129. Lü M, Yu S, Deng J, et al. Efficacy of probiotic supple-mentation therapy for Helicobacter pylori eradication: a meta-analysis of randomized controlled trials. PLoS One 2016;11:e0163743.
130. Malfertheiner P, Megraud F, O’Morain CA, et al. European Hel-icobacter and Microbiota Study Group and Consensus panel.Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report. Gut 2017;66:6–30.
131. Dalal R, McGee RG, Riordan SM, Webster AC. Probiotics forpeople with hepatic encephalopathy. Cochrane Database SystRev 2017;2:CD008716.
132. Ford AC, Moayyedi P, Chey WD, et al. ACG Task Forceon Management of Irritable Bowel Syndrome. AmericanCollege of Gastroenterology monograph on management ofirritable bowel syndrome. Am J Gastroenterol 2018;113(Suppl 2):1–18.
133. Singh S, Stroud AM, Holubar SD, Sandborn WJ, Pardi DS.Treatment and prevention of pouchitis after ileal pouch-analanastomosis for chronic ulcerative colitis. Cochrane DatabaseSyst Rev 2015;CD001176.
134. Newlove-Delgado TV, Martin AE, Abbott RA, et al. Dietary in-terventions for recurrent abdominal pain in childhood. CochraneDatabase Syst Rev 2017;3:CD010972.
135. Pinos Y, Castro-Gutiérrez V, Rada G. Are probiotics effective toprevent traveler’s diarrhea? Medwave 2016;16:e6807.
136. Hiippala K, Jouhten H, Ronkainen A, et al. The potential of gutcommensals in reinforcing intestinal barrier function and allevi-ating inflammation. Nutrients 2018;10:E988.
Reprint requestsAddress requests for reprints to: Eamonn M.M. Quigley, MD, Division ofGastroenterology and Hepatology, Houston Methodist Hospital, 6550 FanninSt, SM 1201, Houston, Texas 77030. e-mail: [email protected].
Conflicts of interestThe author discloses no conflicts.
FundingSupported, in part, by an endowment from the Hughes-Sterling Foundation.