Prebiotics and Probiotics in Digestive Health

As the importance of the gut microbiota in health and disease is increasingly recognized interest in interventions that can modulate the microbiota and its interactions with its host has soared. Apart from diet, prebiotics and probiotics represent the most commonly used substances taken in an effort to sustain a healthy microbiome or restore balance when it is believed bacterial homeostasis has been disturbed in disease. While a considerable volume of basic science attests to the ability of various prebiotic molecules and probiotic strains to beneficially influence host immune responses, metabolic processes and neuro-endocrine pathways, the evidence base from human studies leaves much to be desired. This translational gap owes much to the manner in which this sector is regulated but also speaks to the challenges that confront the investigator who seeks to explore microbiota modulation in either healthy populations or those who suffer from common digestive ailments. For many products marketed as probiotics, some of the most fundamental issues relating to quality control, such as characterization, formulation, viability safety are scarcely addressed. As the importance of the gut microbiota in health and disease is increasingly recognized interest in interventions that can modulate the microbiota and its interactions with its host has soared. Apart from diet, prebiotics and probiotics represent the most commonly used substances taken in an effort to sustain a healthy microbiome or restore balance when it is believed bacterial homeostasis has been disturbed in disease. While a considerable volume of basic science attests to the ability of various prebiotic molecules and probiotic strains to beneficially influence host immune responses, metabolic processes and neuro-endocrine pathways, the evidence base from human studies leaves much to be desired. This translational gap owes much to the manner in which this sector is regulated but also speaks to the challenges that confront the investigator who seeks to explore microbiota modulation in either healthy populations or those who suffer from common digestive ailments. For many products marketed as probiotics, some of the most fundamental issues relating to quality control, such as characterization, formulation, viability safety are scarcely addressed. Given the intimate relationships that are known to exist between what happens in the lumen of the gastrointestinal tract and various homeostatic phenomena, both locally in the gut and throughout the organism, it should come as no surprise that considerable interest has been kindled in the modulation of 1 critical component of the enteric microenvironment—the gut microbiota.1Barbara G. Feinle-Bisset C. 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Gut microbiota and the neuroendocrine system.Neurotherapeutics. 2018; 15: 5-22Crossref PubMed Scopus (4) Google Scholar immune,2Thaiss C.A. Zmora N. Levy M. Elinav E. The microbiome and innate immunity.Nature. 2016; 535: 65-74Crossref PubMed Scopus (341) Google Scholar and metabolic functions,21Quigley E.M. Abu-Shanab A. Murphy E.F. Stanton C. Monsour Jr., H.P. The Metabolic role of the microbiome: implications for NAFLD and the metabolic syndrome.Semin Liver Dis. 2016; 36: 312-316Crossref PubMed Scopus (3) Google Scholar a role for the microbiota has been invoked in disorders as diverse as arthritis22Taneja V. Arthritis susceptibility and the gut microbiome.FEBS Lett. 2014; 588: 4244-4249Crossref PubMed Scopus (0) Google Scholar and liver disease.21Quigley E.M. Abu-Shanab A. Murphy E.F. Stanton C. Monsour Jr., H.P. The Metabolic role of the microbiome: implications for NAFLD and the metabolic syndrome.Semin Liver Dis. 2016; 36: 312-316Crossref PubMed Scopus (3) Google Scholar The recent proposal that interactions between microbiota and gut could extend all the way to the central nervous system via what is referred to as the microbiota-gut-brain axis6Dinan T.G. Cryan J.F. The microbiome-gut-brain axis in health and disease.Gastroenterol Clin North Am. 2017; 46: 77-89Abstract Full Text Full Text PDF PubMed Google Scholar now provides a framework for the incrimination of gut microbes in neurological disorders such as Parkinson’s disease.13Quigley E.M.M. Microbiota-brain-gut axis and neurodegenerative diseases.Curr Neurol Neurosci Rep. 2017; 17: 94Crossref PubMed Scopus (37) Google Scholar The list of maladies in which the microbiome has been implicated, albeit with varying levels of evidence, continues to expand and now includes autism, Alzheimer’s disease, atherosclerosis, obesity, metabolic syndrome, diabetes, colon cancer, depression, and anxiety.12Flemer B. Warren R.D. Barrett M.P. et al.The oral microbiota in colorectal cancer is distinctive and predictive.Gut. 2018; 67: 1454-1463Crossref PubMed Scopus (44) Google Scholar, 13Quigley E.M.M. Microbiota-brain-gut axis and neurodegenerative diseases.Curr Neurol Neurosci Rep. 2017; 17: 94Crossref PubMed Scopus (37) Google Scholar, 21Quigley E.M. Abu-Shanab A. Murphy E.F. Stanton C. Monsour Jr., H.P. The Metabolic role of the microbiome: implications for NAFLD and the metabolic syndrome.Semin Liver Dis. 2016; 36: 312-316Crossref PubMed Scopus (3) Google Scholar This is the context in which all interventions, including prebiotics and probiotics, that seek to modulate the microbiota must now be viewed. It is likely that foods and supplements that may well have exhibited prebiotic or probiotic properties have been around for centuries, if not millennia, and used empirically in health maintenance as well as in the management of gastrointestinal symptoms and disorders. Now, this unregulated and over-the-counter market in products that claim prebiotic and probiotic properties has begun to attract the scrutiny of the scientific community and the regulatory authorities. The biological effects of these substances are being investigated, plausible hypotheses for their use in health or disease developed and, albeit too slowly, rigorous clinical studies of their impact in humans are beginning to emerge. Whether prodded by regulators or demanded by prescribers and consumers, prebiotics and probiotics are emerging from the dark and into the light of scientific scrutiny. This review will focus on recent developments in their definition, biology and clinical effects. Comments will be limited to issues pertinent to the gastrointestinal tract and its related organs. The most widely quoted definition of a prebiotic is that provided by Gibson and Roberfroid23Gibson G.R. Roberfroid M.B. Dietary modulation of the human colonic microbiota. Introducing the concept of prebiotics.J Nutr. 1995; 125: 1401-1412Crossref PubMed Google Scholar in 1995 as “a non-digestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon.” A panel of experts convened by the International Scientific Association for Probiotics and Prebiotics (ISAPP) in 2016 modified this to “a substrate that is selectively utilized by host microorganisms conferring health benefit.”24Gibson G.R. Hutkins R. Sanders M.E. et al.The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics.Nat Rev Gastroenterol Hepatol. 2017; 14: 491-502Crossref PubMed Scopus (0) Google Scholar Selectivity is regarded as central to the prebiotic concept; in contrast to fibers, such as cellulose, pectins, and xylans, which promote the growth of many microorganisms in the gut, prebiotics such as fructo-oligosaccharides and galacto-oligosaccharides primarily stimulate the proliferation of Lactobacillus and Bifidobacterium. This has clinically important ramifications as selectivity mitigates against the promotion of potential pathogens, or of gas-producing organisms, such as Clostridium, that might induce unwanted side effects. An insistence on selectivity does not, as pointed out by Gibson et al24Gibson G.R. Hutkins R. Sanders M.E. et al.The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics.Nat Rev Gastroenterol Hepatol. 2017; 14: 491-502Crossref PubMed Scopus (0) Google Scholar, exclude effects on species or strains other than Lactobacillus and Bifidobacterium. Relationships between fibers and prebiotics can be the source of some confusion—depending on the fiber and the host that ingests it, some fibers can exert prebiotic effects whereas others, as already mentioned, do not. As prebiotics are typically “carbohydrate polymers that are neither digested nor absorbed in the human small intestine,”25Codex Alimentarius CommitteeGuidelines on nutrition labelling CAC/GL 2-1985 as last amended 2010.in: Joint FAO/WHO Food Standards Programme, Secretariat of the Codex Alimentarius Commission. FAO, Rome, Italy2010Google Scholar most prebiotics, in contrast, can be classified as fibers.26Holscher H.D. Dietary fiber and prebiotics and gastrointestinal microbiota.Gut Microbes. 2017; 8: 172-184Crossref PubMed Scopus (0) Google Scholar Molecules classically regarded as prebiotics include human milk oligosaccharides, inulin, fructo-oligosaccharides, and galacto-oligosaccharides. The concept of selectivity has been challenged. Bindels et al27Bindels L.B. Delzenne N.M. Cani P.D. Walter J. Towards a more comprehensive concept for prebiotics.Nat Rev Gastroenterol Hepatol. 2015; 12: 303-310Crossref PubMed Scopus (231) Google Scholar proposed an alternative definition of a prebiotic as “a nondigestible compound that, through its metabolization by microorganisms in the gut, modulates composition and/or activity of the gut microbiota thus conferring a beneficial physiologic effect on the host.” In so doing, they ditched the requirement for selectivity and specificity and expanded metabolism beyond fermentation. In support of the latter, they draw attention to the demonstration of potentially beneficial effects of prebiotics which are not dependent on fermentation.27Bindels L.B. Delzenne N.M. Cani P.D. Walter J. Towards a more comprehensive concept for prebiotics.Nat Rev Gastroenterol Hepatol. 2015; 12: 303-310Crossref PubMed Scopus (231) Google Scholar They also proposed that noncarbohydrates may act as prebiotics and added the following candidate prebiotics to the usual list: “resistant starch, pectin, arabinoxylan, whole grains, various dietary fibers, and noncarbohydrates that exert their action through a modulation of the gut microbiota.”27Bindels L.B. Delzenne N.M. Cani P.D. Walter J. Towards a more comprehensive concept for prebiotics.Nat Rev Gastroenterol Hepatol. 2015; 12: 303-310Crossref PubMed Scopus (231) Google Scholar For now, however, the concept of selectivity prevails but may well be refined as research progresses. Indeed, recent studies support the concept of selectivity. Thus, when Vandeputte et al28Vandeputte D. Falony G. Vieira-Ailva S. et al.Prebiotic inulin-type fructans induce specific changes in the human gut microbiota.Gut. 2017; 66: 1968-1974Crossref PubMed Scopus (53) Google Scholar examined the impact of inulin-type fructans on the fecal microbiota of healthy adults with mild constipation, they found, as expected, increased relative abundance of Bifidobacterium spp., but also noted increases in Anaerostipes spp. and a decrease in the population of Bilophila; the latter effect correlating with a change in stool consistency. Though probably in existence for centuries, probiotics were first defined by Lilly and Stillwell29Lilly D.M. Stillwell R.H. Probiotics. Growth promoting factors produced by micro-organisms.Science. 1965; 147: 747-748Crossref PubMed Google Scholar in 1965 as “substances secreted by one microorganism which stimulate (in contrast to antibiotics) the growth of another.” This definition of a probiotic was subsequently expanded to “a preparation of, or a product containing viable, defined microorganisms in sufficient numbers, which alter the microflora (by implantation or colonization) in a compartment of the host and by that exert beneficial health effects on the host.”30Schrezenmeir J. de Vrese M. Probiotics, prebiotics, and synbiotics—approaching a definition.Am J Clin Nutr. 2001; 73: 361S-364SCrossref PubMed Google Scholar The widely quoted Food and Agricultural Organization of the World Health Organization is more succinct in defining a probiotic as being “live microorganisms which when administered in adequate amounts confer a health benefit on the host.”31Food and Agriculture Organization of the United Nations and World Health Organization. Health and nutritional properties of probiotics in food including powder milk with live lactic acid bacteria. World Health Organization. 2001. Available at: http://www.who.int/foodsafety/publications/fs_management/en/probiotics.pdf. Accessed October 29, 2018.Google Scholar Another ISAPP panel recently revisited the term probiotic and came out in support of the retention of the Food and Agricultural Organization of the World Health Organization definition.32Hill C. Guarner F. Reid G. et al.Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic.Nat Rev Gastroenterol Hepatol. 2014; 11: 506-514Crossref PubMed Scopus (1217) Google Scholar They listed 4 categories of compounds or products that contain live microorganisms and are intended for human use and addressed their regulatory implications:1.Live or active culturesThese products, such as yogurts, simply claim that they contain live and active cultures but, unless evidence is provided that they confer a health benefit (which some do), this descriptor should not be taken to imply probiotic activity.2.Probiotic in food or supplement without a health claimSuch products state that they “contain probiotics.” They should be safe and provide evidence of a general health benefit in humans. In some jurisdictions, the use of the term “probiotic” has been regarded as an implied health claim (based on the aforementioned definitions of a probiotic) and, therefore, forbidden in the absence of acceptable evidence of a health benefit.33Food Safety Authority of IrelandProbiotic health claims.http://www.fsai.ie/faq/probiotic_health_claims.htmlGoogle Scholar Definitions do matter!3.Probiotic in food or supplement with a specific health claimThis category requires that the product has demonstrated convincing evidence of a specific health claim such as “reinforces the body’s natural defenses.” For example, in Europe, the European Food Safety Authority requires the following evidence to support a health claim34Salminen S. van Loveren H. Probiotics and prebiotics: health claim substantiation.Microb Ecol Health Dis. 2012; 23: 40-42Google Scholar, 35van Loveren H. Sanz Y. Salminen S. Health claims in Europe: probiotics and prebiotics as case examples.Annu Rev Food Sci Technol. 2012; 3: 247-261Crossref PubMed Scopus (41) Google Scholar:a.Characterization of the strain or each of the strains in a probiotic mix or combinationb.Identification of the health relationship that is considered as a beneficial physiological effect to the target population (ie, the general population or a defined part of it)c.Demonstration of health effects in a normal healthy population.Few probiotics have met these requirements.4.Probiotic drugHere the probiotic is used to treat or prevent a specific disease. In the United States, and elsewhere, this is now categorized as a drug (defined as an article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease) and must satisfy all the 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 a drug, it is regulated in the United States under the Dietary Supplement Health and Education Act of 1994 and is regarded as a food. Dietary supplements do not require approval by the Food and Drug Administration before being marketed but, according to Dietary Supplement Health and Education Act of 1994, must provide evidence of safety and follow Current Good Manufacturing Practice requirements for dietary supplements. Serious adverse events must be reported to the Food and Drug Administration.36Venugopalan V. Shriner K.A. Wong-Beringer A. Regulatory oversight and safety of probiotic use.Emerging Inf Dis. 2010; 16: 1661-1665Crossref PubMed Scopus (0) Google Scholar The regulatory approach in other jurisdictions varies considerably from treating nonfood probiotics as drugs or biological agents to classifying them as functional foods. In others, there is minimal oversight.37Arora M. Baldi A. Regulatory categories of probiotics across the globe: a review representing existing and recommended categorization.Indian J Med Microbiol. 2015; 33: 2-10PubMed Google Scholar The current definition of a probiotic has further ramifications. Two issues deserve special emphasis: the focus on “live” organisms and the insistence on conferring “a health benefit on the host.” Firstly, while it is readily acknowledged that studies in a number of animal models have demonstrated efficacy for killed bacteria, or even bacterial products or components,38Rachmilewitz D. Kayatura Karmeli F. et al.Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis.Gastroenterology. 2004; 126: 520-528Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar, 39Jijon H. Backer J. Diaz H. et al.DNA from probiotic bacteria modulates murine and human epithelial and immune function.Gastroenterology. 2004; 126: 1358-1373Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 40Kamiya T. Wang L. Forsythe P. et al.Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats.Gut. 2006; 55: 191-196Crossref PubMed Scopus (0) Google Scholar in generating a number of anti-inflammatory and anti-infective effects, this strategy has not, as yet, been explored or validated in humans. It seems improbable that effects of probiotics in humans will be confined to live organisms so this aspect of the definition will ultimately have to be refined or the term abandoned completely. The term pharmabiotic has been proposed to encompass all biological active moieties derived from the microbiota. Second, it is obvious from the latter part of the definition that clinical claims in humans, be they in the augmentation of health or in the treatment of disease, must be supported by credible clinical trial data. As its name suggests, a synbiotic refers to the combination of a prebiotic with a probiotic. The intent is to amplify the benefits of the probiotic as well as stimulate the growth of indigenous beneficial microbes. The tersely worded legalize of the documents which typify the seemingly esoteric promulgations of the various regulatory bodies do have significant practical implications. In the United States, for example, where, in comparison with drugs, prebiotics, probiotics and synbiotics appear relatively unregulated, the consumer is confronted with products and formulations all claiming to be (or contain) probiotics whose range seems to be limited only by the imagination of the manufacturer. Claims deftly skirt around preventing or treating disease by the use of vague terms such as “immune boosting” or “restoring digestive balance” yet are seldom supported by any clinical data. How is the hapless consumer to differentiate between high quality products with supportive data and those which have none in an environment of such “light touch” regulation? It seems inevitable that regulatory oversight must increase. A change in the regulatory climate may also demand a more rigorous approach to clinical trials. This will pose challenges for potential investigators; specifically, who will fund the trials which will be required to satisfy the new demands of regulatory authorities—requirements that are already beginning to emerge in Europe?41Gibson G.R. Brummer R.J. Isolauri E. et al.The design of probiotic studies to substantiate health claims.Gut Microbes. 2011; 2: 299-305Crossref PubMed Scopus (17) Google Scholar, 42Binnendijk K.H. Rijkers G.T. What is a health benefit? An evaluation of EFSA opinions on health benefits with reference to probiotics.Benef Microbes. 2013; 4: 223-230Crossref PubMed Scopus (22) Google Scholar If it is decided that a given probiotic product is to be regarded as a food, profit margins will be slim and the target population will, by definition, be the healthy population. Such trials will by virtue of their endpoints require very large numbers of participants and be very expensive. Within the food category one acceptable endpoint would be the demonstration of a reduction in risk for a given entity in the general population. This requires a validated biomarker of risk, of which there are few (eg, cholesterol for heart disease), not a biomarker of early disease (which immediately moves the product into the drug category). Both issues, the size of study population and need for validated biomarkers of risk pose huge problems for the food industry, which does not have a tradition of funding such trials. In other words, it may be cheaper to study probiotics as drugs for narrow indications within the pharmaceutical sector (paradoxically lower costs and higher margins on licensable product) unless new microbial biomarkers of risk emerge. Any prebiotic that is recommended for use in humans should be thoroughly characterized in terms of its structural biochemistry and it should be resistant to the effects of gastric acid, bile, and digestive enzymes so that it arrives at its proposed site of action (usually the colon) intact. Dose ranging studies should be performed to ensure that an effective dose is delivered without causing adverse effects.24Gibson G.R. Hutkins R. Sanders M.E. et al.The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics.Nat Rev Gastroenterol Hepatol. 2017; 14: 491-502Crossref PubMed Scopus (0) Google Scholar Needless to say, any and all health claims should be supported by clinical evidence and every effort should be made to establish a cause-and-effect relationship between the administration of the prebiotic, changes in microbial populations and their metabolism and the health benefit. For probiotics (and synbiotics) the guidelines for the evaluation of probiotics in food proposed in 2001 still form a reasonable basis for quality control36Venugopalan V. Shriner K.A. Wong-Beringer A. Regulatory oversight and safety of probiotic use.Emerging Inf Dis. 2010; 16: 1661-1665Crossref PubMed Scopus (0) Google Scholar, 43Joint Food and Agriculture Organization of the United Nations/World Health Organization Working Group. 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