Probiotics: Promise, Evidence, and Hope

Abstract

Patients commonly ask physicians if they should take probiotics, and whether a specific brand is best for their individual problem. Many health care providers routinely encourage taking probiotics for various digestive diseases as well as some systemic illnesses.1Williams M.D. Ha C.Y. Ciorba M.A. Probiotics as therapy in gastroenterology: a study of physician opinions and recommendations.J Clin Gastroenterol. 2010; 44: 631-636PubMed Google Scholar Recommendations to take probiotics are often included in hospital discharge orders under the presumption that they can mitigate potential harms of antibiotics. Pharmacies and grocery stores brim with a multitude of probiotic products proclaiming an array of health benefits. In recent years, the public consumption of probiotic products may have also benefited from the steady gush of headlines about the importance of the microbiome in human health and its roles in many diseases. By 2023, the industry’s yearly global sales are projected to reach approximately US$70 billion.2Statista I. Estimated value of probiotics market worldwide from 2018 to 2023.https://www.statista.com/statistics/821259/global-probioticsl-market-value/Google Scholar Unfortunately, the public receives little help in distilling reliable information from the barrage of messages and promises. The current regulatory environment allows manufacturers to make vague and unsubstantiated claims for health benefits of these products. In fact, some of the regulatory requirements actually create barriers to the conduct of high-quality clinical studies to test them. In the meantime, health care providers do not have the background to critically evaluate the microbiome literature and are ill equipped to provide competent guidance to their patients. The massive overload of unfiltered information may be illustrative of the peculiar challenges of the modern age. Therefore, sorting out facts is more imperative than ever. The notions of “beneficial” microbes originated more than a century ago in the Pasteur Institute on the heels of the emergence of the germ theory of disease, which linked many of the most common maladies of the time to specific microbial pathogens. In 1899, Henry Tissier,3Tissier H. Traitement des infections intestinales par la methode de la flore bacterienne de l’intestin.CR Soc Biol. 1906; 60: 359-361Google Scholar a pediatrician working at the Institute, isolated irregular Y-shaped, “bifid,” bacteria from the feces of healthy human infants, now known as Bifidobacterium, and suggested their potential in treatment of diarrhea. Concurrently, Ilya Mechnikov,4Metchnikoff E. The prolongation of life: optimistic studies. GP Putnam’s Sons, New York1908Google Scholar a major force at the Institute and winner of the 1908 Nobel Prize for pioneering work in immunology, focused his research on the biological problem of aging. He speculated that the aging process was driven by toxins produced by intestinal bacteria and that “intestinal putrefaction” could be halted by bacteria in soured milk, much as they protected milk from spoiling. Compelling support for this notion could be found in sensationalist stories of the time of extreme longevity among villagers in Southern Europe, where yogurt and other fermented milk products were dietary staples. Although Mechnikov4Metchnikoff E. The prolongation of life: optimistic studies. GP Putnam’s Sons, New York1908Google Scholar tried to be circumspect and urged continued scientific research, the allure of a cheap “elixir of youth” proved inescapable. Doctors, pharmacies, spas, and manufacturers capitalized on milk-souring bacteria, which rapidly grew in sales in the form of fermented food products, tablets, powders, and liquid concoctions. These products became the precursors to the modern probiotics industry. Belief in beneficial microbes persisted without much scientific support over the ensuing decades. However, over the past 25 years increased understanding of mucosal immunology and epithelial biology has opened new avenues of research into the presumed benefits of the main bacterial genera used in probiotics (eg, Lactobacillus sp, Bifidobacterium sp, Streptococcus sp). In model systems, probiotics have been shown to modulate the immune system, provide resistance to invasion by pathogens, improve intestinal barrier function, lower the pH of the gut, and modulate intestinal motility and pain perception.5Kleerebezem M. Binda S. Bron P.A. et al.Understanding mode of action can drive the translational pipeline towards more reliable health benefits for probiotics.Curr Opin Biotechnol. 2019; 56: 55-60Crossref PubMed Scopus (36) Google Scholar,6Theodorou V. Ait Belgnaoui A. Agostini S. et al.Effect of commensals and probiotics on visceral sensitivity and pain in irritable bowel syndrome.Gut Microbes. 2014; 5: 430-436Crossref PubMed Scopus (52) Google Scholar Yet, despite a number of animal studies showing how probiotic bacteria can alleviate diseases ranging from autism to osteoporosis, translation of these findings into human clinical trials that has efficacy has been slow to emerge. The most likely reasons for lack of progress include scant high-quality human clinical trials, scientific misconceptions, and absence of appropriate regulation of probiotics. One critical fact that has muddled the field is the lack of recognition that many functions of bacteria are specific to the strain, not the species. Clinicians know this about pathogens. For example, most strains of Escherichia coli are harmless inhabitants of the mammalian gut that likely play important roles in the overall structure and functionality of the intestinal microbial communities. However, some strains (eg, shiga-toxin producing E coli, enterotoxigenic E coli, enteropathogenic E coli, enteroinvasive E coli) are clearly pathogenic, whereas the E coli strain Nissle 1917 (EcN) makes the short list of currently accepted probiotic bacteria. Yet, clinical researchers may be constrained by logistic considerations in obtaining a product for their trials, rather than choosing specific strains based on mechanistic hypotheses. Similarly, investigators conducting systematic reviews may be forced to group trials conducted with different microbial strains simply because of their “probiotic” designation. A common notion that probiotics “balance” the intestinal microbial composition is almost certainly wrong.7Mercer M. Brinich M.A. Geller G. et al.How patients view probiotics: findings from a multicenter study of patients with inflammatory bowel disease and irritable bowel syndrome.J Clin Gastroenterol. 2012; 46: 138-144Crossref PubMed Scopus (40) Google Scholar The intestinal microbiota is made up of assemblages of highly specialized microbes that are well adapted to the host environment and interconnected with each other through complex functional networks. Although these communities are dynamic, they are also intrinsically stable and resilient to invasion. In fact, colonization resistance against pathogens is one of the key benefits provided by the indigenous microbiota to the host. Notably, most of the probiotic strains available on the market today are not adapted to the environment of the human intestine. Most probiotic strains were derived from fermented foods, and even microbes of intestinal origin, such as EcN, have long adjusted to the conditions of their in vitro cultivation. This is one of the reasons why probiotics are generally considered to be safe. Companies may also prefer strains that do not colonize the intestine to strengthen the rationale for daily administration. Even if the intestinal microbiota is not the direct therapeutic target of probiotics, their effects are likely affected by the indigenous microbiota, which is highly heterogeneous among individuals. The problem was illustrated by Elinav and colleagues in a series of experiments with a commercial probiotic preparation (Bio-25) containing 11 species of common probiotic bacteria.8Zmora N. Zilberman-Schapira G. Suez J. et al.Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features.Cell. 2018; 174: 1388-1405.e21Abstract Full Text Full Text PDF PubMed Scopus (684) Google Scholar,9Suez J. Zmora N. Zilberman-Schapira G. et al.Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT.Cell. 2018; 174: 1406-1423.e16Abstract Full Text Full Text PDF PubMed Scopus (518) Google Scholar Transient colonization of the colonic mucosa could be demonstrated only in a fraction of healthy individuals. Pretreatment of study participants with antibiotics markedly increased colonic colonization, but large interindividual differences persisted. Perhaps most alarmingly, given that a common rationale for recommending probiotics to patients is to reverse antibiotic injury to gut microbes, treatment with this preparation of probiotics actually delayed recovery of normal intestinal microbial community structure. Probiotics are regulated by the Food and Drug Administration (FDA) and the Federal Trade Commission (FTC). The FDA, unlike the FTC, regulates products by category (eg, foods, drugs, dietary supplements, medical devices, and cosmetics). Whether a product is considered a food or dietary supplement (a subcategory of foods) or a drug is of significant import to product manufacturers. Foods and dietary supplements, unlike drugs, do not require FDA premarket approval. By law, probiotic foods and dietary supplements must be safe. However, food manufacturers are permitted to make a self-determination of whether their product meets the “generally recognized as safe” (GRAS) designation, typically based on history of prior use.10US Food and Drug AdministrationGenerally Recognized as Safe (GRAS).https://www.fda.gov/food/food-ingredients-packaging/generally-recognized-safe-grasGoogle Scholar For dietary supplements, there is a limited exception to proceeding to market without prior approval. If the probiotic is considered a “new dietary ingredient” (NDI), that is, one that was not marketed before October 15, 1994,11Code U. Title 21. FOOD and DRUGS. Chapter 9. Federal food, drug, and cosmetic act. Subchapter IV. Food. Section 350b. New dietary ingredients.Google Scholar the manufacturer must notify the FDA 75 days before marketing the product and include evidence that the NDI is reasonably expected to be safe under its labeled conditions of use. Otherwise, for supplements, regulation is limited to adverse event reporting post marketing.12Code U. Title 21. FOOD and DRUGS. Chapter 9. Federal food, drug, and cosmetic act. Subchapter VII. General authority. Part H. Serious Adverse Event Reports. Section 379aa-1.Google Scholar Probiotic food and dietary supplement manufacturers do not have to specify on their product labels the strains they use in probiotic products or specify the number of live microbes of each strain that the product delivers through the end of its shelf life; and, although they are required to have validation of label claims, they are not required to submit it to the FDA.13Hoffmann D.E. Fraser C.M. Palumbo F. et al.Probiotics: achieving a better regulatory fit.Food Drug Law J. 2014; 69 (ii): 237-272PubMed Google Scholar In contrast, manufacturers wanting to claim that their product may be used to diagnose, treat, mitigate, cure, or prevent disease will be treated by FDA as drug or biologic producers. The assignment to the drug/biologic category triggers a lengthy and costly approval process which requires submission to the FDA of an investigational new drug (IND) application and includes a description of the characterization of the drug substance. For live biotherapeutic products, the subcategory for probiotic drugs, entails a detailed summary of the strain genotype and biological activity, as well as rigorous analytical methods used to ensure the identity, strength, quality, and purity of the drug substance. In addition to submitting characterization information, a manufacturer is required to submit pharmacokinetic and pharmacodynamic analyses of the drug substance, a description of how the company manufactures, processes, and packages the substance, and results of studies as to how the drug performs in animal models. Finally, the drug producer must submit the results of several phases of clinical trials in human subjects. On average, the process costs more than $2 billion and takes more than 10 years to complete.14DiMasi J.A. Grabowski H.G. Hansen R.W. Innovation in the pharmaceutical industry: New estimates of R&D costs.J Health Econ. 2016; 47: 20-33Crossref PubMed Scopus (1624) Google Scholar If the product is approved, a drug manufacturer will receive a new drug approval, whereas a biologic manufacturer will receive a biologics license. Once a product is marketed, if the FDA receives serious adverse event reports or other information that a product is unsafe, it may take steps to have the manufacturer remove it from the market. It is hardly surprising that there is no probiotic strain that is FDA approved to treat any disease on the market today. For a manufacturer, the contrast between the 2 paths toward commercialization could not be more stark. It is far easier to take the path of dietary supplements and engage in creative marketing that skirts the legal boundaries of what can be said without triggering a rebuke from the regulators. Dietary supplements can make structure/function claims, even though they cannot claim to treat any specific disease. These claims can sound very promising and consumers may be hard pressed to distinguish between a statement that a product “improves digestion,” a structure/function claim that is so vague that it is literally untestable, from a statement that a product may help symptoms of irritable bowel syndrome. Unfortunately, current law and FDA practices create additional barriers for food and dietary supplement manufacturers to conduct research on the therapeutic benefits of their products without crossing over into the drug category. For example, a provision of the Food, Drug & Cosmetic Act (referred to as the “lock-in” provision) prohibits the marketing of a food or dietary supplement where the substance has not been marketed as a food or dietary supplement and is first studied under an IND, even if the study is ultimately intended to support a food or dietary supplement use, rather than a drug use. The FDA has also required clinical trialists to obtain an IND if they are conducting research based on disease endpoints, even if the manufacturer is content with making only structure/function claims and markets its products as a food or dietary supplement.13Hoffmann D.E. Fraser C.M. Palumbo F. et al.Probiotics: achieving a better regulatory fit.Food Drug Law J. 2014; 69 (ii): 237-272PubMed Google Scholar An investigator wishing to pursue such research would be compelled to request chemistry, manufacturing, and control (CMC) information from the supplier for the IND application, which can constitute proprietary information that the manufacturer may not care to share. The American Gastroenterological Association Institute review on the role of probiotics in management of a limited set of common gastrointestinal disorders, published in this issue of Gastroenterology, is a valiant attempt at sorting through the voluminous probiotics literature on the chosen conditions.15Preidis G.A. Weizman A.V. Kashyap P.C. et al.AGA technical review on the role of probiotics in the management of gastrointestinal disorders.Gastroenterology. 2020; 159: 708-738Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar The investigators took care not to group disparate microbial strains under a generic umbrella of “probiotics”; they included only randomized, placebo-controlled trials in updating existing high-quality reviews; and, they used the GRADE approach in their analysis, which considers the risk of bias, inconsistency (or heterogeneity), indirectness, imprecision, and/or publication bias when assessing the certainty of evidence. Despite these strengths, they still faced serious challenges, such as different dosing regimens, preparations of heterogeneous potency, varying patient populations, and clinical endpoints, mainly single-center studies, and lack of systematic capturing of potential adverse events that would be otherwise routine in clinical trials. It is actually remarkable that the review yielded 2 important conclusions that clinicians can take away. First, the Institute found moderate evidence that probiotics do not reduce the duration or severity of diarrhea in children with acute infectious gastroenteritis. It is ironic that diarrhea in children was one of the original indications for potential therapy using probiotics more than 100 years ago. However, only a minority of the studies tested strains of Bifidobacteria suggested by Tissier.3Tissier H. Traitement des infections intestinales par la methode de la flore bacterienne de l’intestin.CR Soc Biol. 1906; 60: 359-361Google Scholar In contrast, there was moderate to high level of evidence that probiotics containing different strains of Lactobacillus and Bifidobacterium genera were beneficial in preventing necrotizing enterocolitis, the most frequent and devastating gastrointestinal disease in preterm, low birthweight newborns and mitigating its complications. These results suggest that there is value in additional rigorous reviews of the probiotics literature for indications not yet tackled in a similar way; however, we should view these undertakings as a bookend on the past century of probiotics research. Further meaningful progress is not likely unless we fundamentally change how we view probiotics and adjust our regulatory framework to require more specific description of benefits and rigorous demonstration of safety and efficacy in human consumers. Unfortunately, without congressional action, it is doubtful that the regulatory agencies, will be able to make the necessary changes. Moreover, agency underfunding, more urgent priorities, and pressures from the industry and advocacy groups, will substantially hinder any change to the current rules or their enforcement. However, it is imperative that health care providers not fall prey to seductive advertising and meaningless structure/function claims. They should be informed guides to their patients. Although probiotic foods and dietary supplements may be of limited therapeutic value, microbial therapeutics targeting disease conditions are becoming a reality. Fecal microbiota transplants (FMT) have proven to be remarkably successful in treating recurrent Clostridioides difficile infections. Stooll products for FMTs are classified as drugs and biologics by the FDA and are being developed in a variety of formulations, including encapsulated, freeze-dried microbiota for oral administration.16Staley C. Hamilton M.J. Vaughn B.P. et al.Successful resolution of recurrent Clostridium difficile infection using freeze-dried, encapsulated fecal microbiota; pragmatic cohort study.Am J Gastroenterol. 2017; 112: 940-947Crossref PubMed Scopus (121) Google Scholar,17Jiang Z.D. Jenq R.R. Ajami N.J. et al.Safety and preliminary efficacy of orally administered lyophilized fecal microbiota product compared with frozen product given by enema for recurrent Clostridium difficile infection: a randomized clinical trial.PLoS One. 2018; 13e0205064Crossref PubMed Scopus (60) Google Scholar Rational selection of donor microbiota should be possible based on microbiome-based diagnostics, as well as in vitro technologies that interrogate the functional potential of complex microbial communities. There are parallel, intensive efforts to develop defined microbial communities. A common theme among these different approaches is deployment of complex assemblages of microorganisms rather than single strains. Such complex consortia are likely to have more consistent and predictable effects. The high-throughput nucleic acid sequencing and computational technologies have enabled investigators to study microbial communities rather than restrict their focus to individual microbes. The new technologies have enabled a paradigm shift in our understanding of microbe-host interactions and the germ theory of disease is undergoing an adjustment. We now recognize that entire microbial communities, not just individual microbial pathogens, may drive pathogenesis of a many common disorders.18Relman D.A. The human microbiome: ecosystem resilience and health.Nutr Rev. 2012; 70: S2-S9Crossref PubMed Scopus (219) Google Scholar Similarly, we need to understand specific microbial community functionalities that can provide benefits to the host. Development of novel technologies to assess functional capabilities of microbial consortia will be essential for scientists and regulatory agencies to assess new products as they emerge into the market. Personalized medicine is likely to be critical for many indications, and we will need methods to choose the best therapeutics for specific indications and individual patterns of dysbiosis; however, some indications may be amenable to very targeted mechanism-based therapeutics, some of which may not even be formulated with live microorganisms. For example, consistent with the benefits observed with a variety of probiotic preparations, bacterial DNA alone could be effective against necrotizing enterocolitis in experimental animal models through differential activation of mucosal Toll-like receptors.19Good M. Sodhi C.P. Ozolek J.A. et al.Lactobacillus rhamnosus HN001 decreases the severity of necrotizing enterocolitis in neonatal mice and preterm piglets: evidence in mice for a role of TLR9.Am J Physiol Gastrointest Liver Physiol. 2014; 306: G1021-G1032Crossref PubMed Scopus (89) Google Scholar The emergence of microbial therapeutics requires development of a new branch of pharmacology. The challenges of formulation, pharmacokinetics, and pharmacodynamics are very distinct from those of small molecule therapeutics or protein biologics. Systematic pharmacologic investigations will need to be top priorities for developers of these new therapeutics. The regulators will also have to keep up with the rapidly developing microbiome science and be fluent in subjects not traditionally associated with medicine, including microbial ecology and computational biology. Rigorous clinical trials with capture of adverse events will also aid in understanding potential toxicities and interactions of microbial therapeutics with other drugs. It is important to appreciate that all therapeutics, including probiotics, regardless of how they are defined, have potential risks.20DeFilipp Z. Bloom P.P. Torres Soto M. et al.Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant.N Engl J Med. 2019; 381: 2043-2050Crossref PubMed Scopus (514) Google Scholar, 21Yelin I. Flett K.B. Merakou C. et al.Genomic and epidemiological evidence of bacterial transmission from probiotic capsule to blood in ICU patients.Nat Med. 2019; 25: 1728-1732Crossref PubMed Scopus (116) Google Scholar, 22US Food and Drug AdministrationFecal microbiota for transplantation: safety alert - risk of serious adverse events likely due to transmission of pathogenic organisms.https://www.fda.gov/safety/medical-product-safety-information/fecal-microbiota-transplantation-safety-alert-risk-serious-adverse-events-likely-due-transmission. 2020Google Scholar As effective microbial therapeutics emerge, we might see a retreat of traditional probiotics products. Alternatively, we may see some of the traditional probiotic strains to be incorporated into next-generation microbial therapeutics; however, their inclusion will be based on mechanistic understanding and careful formulation, followed by rigorous testing of pharmacologic metrics and clinical outcomes. The pioneering scientists at the turn of the 20th century recognized the importance of host interactions with its microbiota, but were limited by the technologies of their day. The recent rediscovery of the microbiome leaves little question that these interactions have profound implications for health and disease. The emergence of the probiotics industry in the past 30 years, along with the regulatory designation treating probiotics as dietary supplements, has led to the clinical situation we are now faced with: many products with unsubstantiated or vague claims and confused physicians and consumers. How can we move forward to better provide all of the various stakeholders with products that are properly vetted to have a bona fide impact on human health and disease? With next-generation sequencing technologies, germ-free animal platforms, novel genetic tools, and methods for assaying the functions of communities of microbes, we now have the appropriate technology to provide a scientific basis for probiotic selection. These next-generation probiotics will need to be tested for safety and efficacy in well-designed and properly powered clinical trials. Progress may depend on the ability of lawmakers and the regulatory agencies to develop updated paradigms to evaluate these new products. The rules need to be based on the most up-to-date science, ensure patient access to safe and effective treatments, while encouraging further innovation. Despite the many pitfalls, we expect that next-generation probiotics have an important role in the future of human health and prevention of disease.