Probiotics and prebiotics in intestinal health and disease: from biology to the clinic

An Author Correction to this article was published on 09 August 2019

This article has been updated

Abstract

Probiotics and prebiotics are microbiota-management tools for improving host health. They target gastrointestinal effects via the gut, although direct application to other sites such as the oral cavity, vaginal tract and skin is being explored. Here, we describe gut-derived effects in humans. In the past decade, research on the gut microbiome has rapidly accumulated and has been accompanied by increased interest in probiotics and prebiotics as a means to modulate the gut microbiota. Given the importance of these approaches for public health, it is timely to reiterate factual and supporting information on their clinical application and use. In this Review, we discuss scientific evidence on probiotics and prebiotics, including mechanistic insights into health effects. Strains of Lactobacillus, Bifidobacterium and Saccharomyces have a long history of safe and effective use as probiotics, but Roseburia spp., Akkermansia spp., Propionibacterium spp. and Faecalibacterium spp. show promise for the future. For prebiotics, glucans and fructans are well proven, and evidence is building on the prebiotic effects of other substances (for example, oligomers of mannose, glucose, xylose, pectin, starches, human milk and polyphenols).

Key points

  • The human gut microbiota is integral to health and is associated with a variety of diseases.

  • Therapeutic and prophylactic effects of some probiotics and prebiotics for a variety of gut-related disorders might be, at least in part, mediated through modification of the microbiota and/or its function.

  • Probiotic microorganisms act via a variety of means, including modulation of immune function, production of organic acids and antimicrobial compounds, interaction with resident microbiota, interfacing with the host, improving gut barrier integrity and enzyme formation.

  • Prebiotics are substrates that are selectively utilized by host microorganisms conferring a health benefit; prebiotic effects include defence against pathogens, immune modulation, mineral absorption, bowel function, metabolic effects and satiety.

  • Use of some probiotics and prebiotics is justified by robust assessments of efficacy, but not all products have been validated; the goal is evidence-based use by healthcare professionals.

Introduction

The request in 2000 by the Argentinian government that the Food and Agriculture Organization of the United Nations form an expert panel to evaluate the health and nutritional properties of probiotics in food precipitated the re-emergence of a concept long part of human history. International recognition of the concept of probiotics, and coalescence around a definition of probiotic offered by this expert consultation1, established an important consensus foundation. The definition of probiotic decided by the consultation retained the essence of historical definitions offered over previous decades. It was intentionally broad, to encompass a wide variety of microorganisms, hosts, benefits, target sites and product types. It has stood the test of time and was reaffirmed, but grammatically corrected, in 2014 to the consensus definition of probiotics, which is: “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”2.

There are many studies that have investigated how microorganisms are integrated into life processes and defined ways that beneficial microorganisms — both commensal and externally applied — affect physiological homeostasis and host function3. On the horizon is the promise of newly constructed recombinant strains and promising novel microbial species, which await testing in vivo. However, as these advances develop, we should recognize actionable evidence that is currently available. As is discussed in this Review, convincing evidence exists for some established probiotics, which should be incorporated into health management. This incorporation includes complementary use with pharmaceutical agents, foods and lifestyle. Education of consumers, practitioners and regulators will facilitate appropriate use and point out needs for further research, which will hopefully include exploration of how to reach the individuals at greatest need with affordable and reliable probiotic products4.

Prebiotics, first defined in 1995 (ref.5), have been used to manipulate microorganisms in the host to improve measurable health outcomes. An update to the definition of prebiotics published in 2017 as “a substrate that is selectively utilized by host microorganisms conferring a health benefit” was made necessary by the need to clarify what did and did not constitute a prebiotic substance in the face of scientific advances6. The desire to optimize, for improved health, the microbial world associated with humans has led to the development of compounds targeting an ever-expanding group of microorganisms and benefits that are derived through them. No longer are prebiotics seen simply as boosters of the growth of bifidobacteria and lactobacilli but are now recognized for their effects on system-wide metabolic and physiological readouts6. Although the intestine remains the gateway to most of these effects, it is not the exclusive gateway. The extent to which prebiotics can affect microbial communities of the urogenital tract, oral–nasal areas and skin is now the subject of intense exploration7.

This Review describes the current understanding of probiotic and prebiotic mechanisms of action, provides important examples of clinical studies on probiotic and prebiotic applications, and discusses current knowledge on mechanisms at the heart of these effects.

Human gut microbiome

The human gut is predominantly inoculated at birth. Microbial diversity develops as feeding and dietary patterns mature. By the age of 3–5 years the microbiota resembles that in the adult8. Because of variations in pH, substrate concentration, Eh (redox potential, activity of electrons) and transit time, microbial numbers vary between different anatomical regions of the gut9. The stomach harbours fewer microorganisms than the small and large intestines10. Studies using metagenomic approaches have highlighted the complex inter-relationship between human resident intestinal microbiota and mammalian metabolism11. Through the process of fermentation, anaerobic gut bacteria metabolize substrates to form end products such as organic acids and gases12. The main precursors for fermentation are dietary carbohydrates, proteins and lipids, as well as indigenous secretions such as mucin. This anaerobic metabolism contributes positively towards host daily energy requirements and homeostasis in the gut13. Ideally, the human host lives in harmony with its complex gut microbiota in a state that promotes physiological resilience14. However, dysbiosis can result from challenges such as medications, infections, ageing, lifestyle, surgery and poor nutrition14,15.

In humans, a range of acute and chronic disorders can be a consequence of perturbation of gut microbial communities16,17,18. On a chronic basis, inflammatory bowel disease (IBD), obesity and irritable bowel syndrome (IBS) have all been linked to intestinal bacteria and their activity10. This aspect opens up the possibility of influencing the microbiota to reduce disease risk, fortify homeostasis and, in some cases, improve therapeutic status. Diet is a principal driver of gut fermentation and therefore can greatly influence functionality of the indigenous microbiota19. Prebiotics are a popular dietary approach to the modification of the gut microbiota to improve host health6, as they are affordable, effective, safe and accessible.

Probiotics

As the concept of probiotics evolved over the past decades, the assumption was that their effects would be mediated through direct interaction with commensal microbiota. According to some early definitions, probiotics function “by contributing to [the host’s] intestinal microbial balance”20 or “by improving the properties of the indigenous microflora”21. However, in the current consensus definition of probiotics, the effects of probiotics are not considered to be only microbiota-mediated, and, indeed, other types of mechanism are known. This idea that probiotics function in ways that might act beyond affecting the colonizing microbiota opens the door to a wider range of probiotic possibilities, encouraging innovation in the field.

Much of our knowledge on probiotic mechanisms is based on research using in vitro, animal, cell culture or ex vivo human models. Figure 1 shows known mechanisms distributed among various probiotic strains. Not all mechanisms have been confirmed in humans nor do they exist in every probiotic strain. Although multiple mechanisms are probably co-expressed in a single probiotic, the importance of any given mechanism will depend on many factors. For example, in an inflamed intestine, the ability to downregulate inflammatory mediators and increase epithelial barrier function might be most important22,23, whereas the ability to increase short-chain fatty acids (SCFAs) and hydration in the colon could be more important to normalizing intestinal motility24.

Fig. 1: Probiotic mechanisms of action.
figure1

Diverse mechanisms are likely to drive probiotic benefits to host health. In some cases, such as production of antimicrobial products and cross-feeding other resident microorganisms, these mechanisms are driven directly by interactions with the resident microbiota. In other cases, such as direct interaction with immune cells, their effects might be direct via interaction with host cells. Overall, clinical benefits delivered by probiotics could result from the combined action of several mechanisms. GABA, gamma-aminobutyric acid.

Research elucidating mechanisms of probiotics has often relied on in vitro or animal studies. Probiotics are not unique in this regard. Animal studies have not always translated to humans25; notable examples are probiotics for Crohn’s disease and mental health function26,27. Furthermore, there are inherent differences among probiotic strains; for example, one probiotic (in this case in conjunction with a prebiotic) was found to markedly reduce sepsis in infants28, whereas a different formulation failed to prevent necrotizing enterocolitis in very preterm infants29.

The historic concept of ‘colonization resistance’30, the situation whereby native gut microbiota occupy host tissues to exclude infection by potential pathogens (resident or invading), is another mechanism attributed to probiotics31. Expression of colonization resistance is probably a sum outcome of the functioning of many of these different mechanisms in concert. Indeed, many host factors could affect the ultimate expression of health effects imparted by a probiotic, including properties of baseline microbiota. Although few data exist, one study showed that probiotic persistence in the gut is linked to the properties of the baseline microbiota. Persistence of Bifidobacterium longum subsp. longum AH1206 in the human gut was predicted by low abundance in the host of B. longum and low levels of microbial carbohydrate utilization genes32. No clinical end points were tracked in this study, but the property of long-term persistence could contribute to physiological benefits. However, the results of many different clinical trials that did not include stratification of study participants by baseline microbiota suggest that probiotic function is not necessarily predicated on a specific microbiota baseline33,34. There may well be compositional patterns of microbiota that do not respond well to incoming probiotic strains, just as there are for certain drugs35, but such profiles have not yet been fully defined.

Modulation of cell-mediated and humoral immune functions

Some probiotics have been shown to increase phagocytosis or natural killer cell activity and interact directly with dendritic cells (reviewed in ref.36). Some also demonstrate the ability to upregulate antibody secretion translating into improved defences against pathogens and augmenting vaccine responses37,38,39. Probiotic strains can increase levels of anti-inflammatory cytokines such as TNF with implications for abating colon cancer and colitis10,36. As discussed below, cell-surface architecture, such as fimbriae, capsule and surface structures expressed by certain probiotics, is a mechanistic driver for several of these activities.

Production of organic acids

Probiotic species belonging to the Lactobacillus and Bifidobacterium genera produce lactic and acetic acids as primary end products of carbohydrate metabolism. These organic acids when produced in situ can lower luminal pH and discourage growth of pathogens, as shown in various model systems40,41,42. Lactobacillus and Bifidobacterium do not produce butyrate but through cross-feeding other commensal microbiota (for example, Faecalibacterium), levels of butyrate and other SCFAs in the gut can increase, potentially influencing many aspects of physiology, including the cardiometabolic phenotype43. This phenotype can be derived from increased production of butyrate, correlating with improved insulin response, or abnormalities in propionate linked to type 2 diabetes mellitus44. Based upon analyses of weight, lifestyle, metabolic measurements and SCFA levels, the risk of an individual developing cardiometabolic diseases can be calculated45.

Interaction with gut microbiota

Probiotic strains can interact with the gut microbiota through competition for nutrients, antagonism, cross-feeding and support of microbiota stability46. Many probiotic strains are antagonistic toward other microorganisms, in part due to saccharolytic metabolism, which produces organic acids, but also by production of bacteriocins47. These antimicrobial compounds can be active against pathogens at many sites including the human urinary tract and the gut of humans and animals48,49. Bifidobacteria produce acetate and can cross-feed other members of the gut microbiota (reviewed in ref.50). Strains B. longum AH1206 and B. bifidum ATCC15696 have been shown to persist in the infant gut32,51, although in the latter case the concomitant decrease in pathogen abundance was not tested for a link to bacteriocin production. The ability of certain probiotic strains to improve eradication of Helicobacter pylori might involve some inhibition of the pathogen, but there is stronger evidence that probiotics in this context reduce the adverse effects of antibiotics used in treatment52.

Probiotic–host interactions

Interactions of probiotic strains with host tissues are mediated by cell surface macromolecules, including proteins (surface layer associated proteins, mucin-binding proteins, pili, and LPxTG-binding proteins) and non-protein components (lipoteichoic acid, peptidoglycan, exopolysaccharides)53. These structures have been shown to affect binding to intestinal and vaginal cells, mucin, and immune or dendritic cells, resulting in increased transit times and improved barrier integrity (reviewed in ref.53). An example of the different surface structures can be seen in the genome comparison of Lactobacillus rhamnosus GG that uses pili to interact with the intestine and L. rhamnosus GR-1 with a unique cluster of exopolysaccharides that aid vaginal activity54.

Improvement in barrier function

Primarily through studies in cell lines, several probiotic Lactobacillus and Bifidobacterium strains have been shown to increase expression of tight junction proteins (reviewed in ref.55). A study using human intestinal epithelial enteroids and colonoids showed that pretreatment with L. rhamnosus GG counters damage to tight junction zonula occludens 1 and occludin caused by IFNγ56. Another way in which probiotic strains might improve barrier function is through upregulating expression of mucus-secretion genes, thereby reducing pathogen binding to epithelial cells57,58. Downregulating inflammation is also regarded as a factor that improves barrier function53. Of note, although some probiotic strains have the capacity to improve barrier function, this process does not always occur in every cohort for reasons not yet fully understood59.

Manufacture of small molecules with local and non-local effects

Small molecules produced by certain probiotic strains with different effects on the host and its microbiota have been described58. Perhaps one of the more intriguing findings is the production of neurochemicals such as oxytocin, gamma-aminobutyric acid, serotonin, tryptamine, noradrenaline, dopamine and acetylcholine (reviewed in refs60,61,62) that are known to affect brain function. In a rat model of stress, L. helveticus NS8 feeding resulted in lower plasma corticosterone and adrenocorticotropic hormone levels and restored hippocampal serotonin and noradrenaline levels63.

Production of enzymes

Microbial enzymes such as β-galactosidase64 and bile salt hydrolase65, which are produced and delivered by some probiotic strains, improve lactose digestion and blood lipid profiles in humans, respectively. In the case of Streptococcus thermophilus in yogurt, which facilitates lactose digestion, its predisposition to be permeabilized by bile when entering the small intestine promotes the delivery of microbial β-galactosidase to the small intestine to break down lactose into digestible glucose and galactose64. This results in clinical benefit to individuals who are lactose intolerant. Indeed, the European Food Safety Authority considered evidence of this effect sufficient to authorize a health claim that S. thermophilus and L. bulgaricus as components of yogurt can alleviate symptoms of lactose maldigestion66.

Admittedly, cause-and-effect evidence of mechanisms in human hosts remains to be gathered, but technological advances in genome sequencing and microbiome analyses, and surgical advances that enable real-time sampling in vivo, should help acquire elucidating data over the next few years.

Prebiotics

If we are to understand how prebiotics work, and more importantly exploit them to manipulate the microbiota to propagate health, then we need to keep in mind that microorganisms live in complex functional ecosystems. Within these ecosystems, bacteria have a multitude of roles, including the conversion of incoming dietary carbohydrates, proteins and some fats into metabolites that can have either positive or negative effects upon host health67,68,69,70. Current prebiotics are predominantly carbohydrate-based, but other substances such as polyphenols and polyunsaturated fatty acids might exert prebiotic effects6. An example of polyphenols is water-insoluble cocoa fraction, which has been shown in a gut model to substantially increase bifidobacteria, lactobacilli and butyrate production71.

Low-molecular-weight carbohydrates are very efficiently metabolized by microorganisms such as bifidobacteria, which possess a range of cell-associated and extracellular glycosidases and specific transport systems enabling them to rapidly assimilate low-molecular-weight sugars72,73. Other microorganisms, such as members of the Bacteroides genus, are adept at breaking down high molecular weight polysaccharides74,75. Some bacteria might be regarded as keystone species in having the ability to initiate breakdown of particular substrates76; for example, Ruminococcus spp. can facilitate the degradation of resistant starch77. Liberated low-molecular-weight dextrins are then metabolized by the microbial community. The pathway from a polysaccharide to a SCFA is therefore a complex and indirect network of metabolism. Acetate and lactate, the main metabolic end products of bifidobacteria and lactic acid bacteria, are utilized by other microorganisms to produce, for example, propionate78 and butyrate50,79. Probable ecological networks involved in the metabolism of carbohydrates have been elucidated74,80,81, although the extent to which they operate in the gut is not clear at the present time.

A further complication in studies of the ecosystem response to carbohydrates is that it is heavily influenced by the microorganisms that are already present. It has become clear that individual microbiomes that are Prevotella-dominant can ferment carbohydrates more rapidly than can Bacteroides-dominant microbiomes82. Furthermore, when these distinct fecal inocula, dominated by Prevotella or Bacteroides, were incubated with prebiotic fructo-oligosaccharides (FOS) or with two different arabinoxylans, the profile of SCFA produced was distinctly different and correlated with the microbiome83. Cultures using Prevotella-dominant inocula produced substantially higher ratios of propionate to acetate and butyrate than the Bacteroides-dominant microbiotas. A similar influence of starting microbiome composition on carbohydrate fermentation has been seen using isomalto-oligosaccharides as a carbon source in an in vitro batch fermentation model with human microbiota84.

Microbiome studies based on 16S ribosomal DNA sequencing have given rise to an increased awareness of the richness of the gut microbial ecosystem85 and, in some cases, have revealed associations between certain microorganisms or microbiome profiles and disease states. These include IBD86, type 2 diabetes mellitus87,88,89, IBS90,91 and obesity92,93. These profiles have frequently been termed ‘dysbioses’, although it is not currently possible to define such a state as ‘normobiosis’ or a ‘normal’ microbiota. Such associations tend to be merely the starting point for investigation into the role of specific microorganisms in disease. Sequencing studies do not provide an understanding of the functional interactions between members of the gut microbiota, and it is imperative that this functional ecology is studied in more detail. It is becoming clear that although there might be a huge diversity of individual taxa in the gut microbiomes of individuals, there is a high level of functional redundancy, and specific ecological functions are provided by a range of bacteria across different individuals94,95.

Given that we have an imperfect understanding of the functional ecology of the gut microbiota, uncovering the mechanisms of action of prebiotics presents a challenge. Despite this issue, we can postulate probable mechanisms by which a prebiotic can lead to health benefits. These pathways are presented in Fig. 2 and discussed here. All of these postulated mechanisms have support from research carried out through in vitro or animal models, although in many cases, establishing that they actually occur within human gut microbiota is difficult.

Fig. 2: Identified mechanisms of action of prebiotics.
figure2

The premise is that prebiotics enter the gut and are selectively utilized. This step increases bacterial growth and functionality of specific genera or species. As a result of either or both of these effects, health benefits can accrue. Fecal bulking and improved bowel habits occur due to microbial growth. Immune regulation can be influenced by increased biomass and cell wall components of the bacteria. Metabolic products include organic acids, which lower intestinal pH and have concomitant effects upon microbial pathogens and mineral absorption. Metabolic products can also influence epithelial integrity and hormonal regulation. Bacteria that respond to prebiotic intake can influence the microbiota composition through elaboration of antimicrobial agents (for example, peptides) and competitive interactions, possibly reducing infections and bacteria containing lipopolysaccharide (LPS). GLP1, glucagon like peptide1; M cell, microfold cell; NK cell, natural killer cell; PYY, peptide YY; TGFβ, transforming growth factor-β; TH1 cell, type 1 T helper cell; TH2 cell, type 2 T helper cell; Treg cell, regulatory T cell; ZO1, zonula occludens 1.

Defence against pathogens

Although mechanistically challenging to establish in humans in vivo, pathogen defence can be investigated in vitro using model systems96,97. As noted for probiotics, production of organic acids through prebiotic administration and propagation of beneficial bacteria will result in a reduction in luminal pH, inhibiting growth of pathogens. Establishment of a stable population of commensal microorganisms will reduce nutrient availability for invading microorganisms, inhibiting colonization. In studies of elderly individuals, 10 weeks of daily galacto-oligosaccharide (GOS) consumption induced increases in immune function, notably enhanced phagocytic activity and activity of natural killer cells98,99.

Immune modulation

Although the exact mechanisms are unclear, there is evidence that prebiotic intervention can reduce type 2 T helper responses and therefore affect allergy. The most supportive data come from studies in infants. GOS and long-chain FOS in infant formula administered in a double-blind, randomized, placebo-controlled trial in 259 infants was associated with a reduction in incidence of atopic dermatitis, wheezing and urticaria to less than 50% of the incidence in non-prebiotic formula-fed infants100,101. In a prospective, double-blind, placebo-controlled fashion, not as yet replicated, healthy term infants at risk of atopy fed prebiotic-supplemented hypoallergenic formula for 6 months had a greater than fivefold reduction in prevalence of allergies 5 years after feeding102.

Increased mineral absorption

Since most absorption of minerals takes place by active transport mechanisms in the small intestine103, scavenging calcium could make a substantial positive contribution to health. As already discussed, fermentation of prebiotics leads to production of SCFA, which reduces luminal pH. This drop in pH can increase calcium solubility, thereby providing a greater driving force for passive uptake. A problem with proving this process is that many calcium salts in supplements and food have pH-dependent solubility and limited availability, and depending on the starting pH, the solubility of calcium can actually increase with increasing pH104.

Studies have shown that consumption by young adolescents of a mixture of FOS and inulin105,106 or GOS107 can result in marked increases in absorption and calcium mineralized into bone. Such early intervention could reduce the incidence of osteoporosis later in life. This hypothesis is supported by data from animal models108, but long-term studies in humans are lacking.

Improved bowel function

Improvements in bowel function have often been ascribed to simple fecal bulking by consumption of dietary fibre. However, animal studies have shown that SCFAs produced by fermentation of prebiotics can regulate gut hormones that in turn modulate the local motor responses of the gut109,110. The humectant water-binding capacity of prebiotic carbohydrates also has the effect of softening stools, making passage easier111,112.

There are surprisingly few studies on the effect of prebiotics on bowel function, although they have consistently led to improvements in stool consistency and defecation frequency in randomized trials113,114.

Metabolic effects

As discussed earlier, prebiotic intervention results in the elaboration of SCFAs that can act to improve barrier function in the gut, and prebiotic intervention with GOS has been shown to improve barrier function in vivo115. Impaired barrier function can allow translocation of inflammatory mediators such as bacterial lipopolysaccharide (LPS) from the gut into the systemic circulation, which has been termed metabolic endotoxaemia116 and has been suggested to be a causative factor in diabetes and obesity, although the evidence for this is from studies in mice117,118.

The metabolic effects of prebiotics have been the subject of several meta-analyses119,120,121,122 and although the results among studies vary, the general consensus is that prebiotic intervention has a positive effect on glucose homeostasis, inflammation and blood lipid profile in humans. Although interventions with GOS123 and inulin124 have been shown to improve inflammatory markers in individuals with obesity, these were relatively short-term studies over a few months, and the effect on metabolic health over a long period of consumption is yet to be established.

The hypothesis underlying much research on prebiotics and barrier function and inflammation is that fermentation products such as SCFA probably mediate the beneficial effects through mechanisms discussed earlier. However, it has been shown that, at least in vitro, GOS can directly stimulate the expression of tight junction proteins in intestinal epithelial cell lines and decrease transepithelial flux125,126. However, given that GOS is fermented in the gut, the extent to which such mechanisms act in vivo is unclear at present. It is possible that the effect of inulin in improving glycaemic response could be due to direct inhibition of the intestinal isomaltase–sucrase enzyme complex, but so far the evidence is only from mouse studies127. Identification of direct mechanisms from metabolic studies in humans is, however, extremely difficult.

Effect on satiety

SCFAs produced by fermentation in the gut can interact with specific fatty acid receptors, FFAR2 and FFAR3, and regulate lipolysis and release of the incretin glucagon-like peptide-1 (refs128,129). These receptors are found on many tissues and could be a key mechanistic link between prebiotic fermentation and systemic health benefits. SCFAs can regulate appetite via several mechanisms130, with studies showing that the interaction between SCFA and colonic L cells results in production of anorexigenic hormones such as PYY and GLP-1. Other examples are SCFAs surviving metabolism by colonic epithelial cells and reaching the liver via the hepatic portal vein where propionate stimulates gluconeogenesis that acts as a satiety signal131. SCFAs entering the circulation could also interact with FFAR2 and FFAR3 located on adipose tissue, resulting in leptin stimulation. According to a study in mice, acetate, the principal SCFA formed by prebiotic fermentation, can cross the blood–brain barrier and enter the hypothalamus, promoting anorectic signals132.

Translation to the clinic

Many clinical gastrointestinal indications could benefit from probiotic and prebiotic interventions. In the case of prebiotics, a link between the clinical benefit and microbiota function should be established. For probiotics, a clinical indication is needed. For both, robust product information is required133 (Box 1).

There are clinical indications for the use of certain probiotic strains supported by robust evidence. In paediatric and/or adult populations, the following have been suggested as indications for the use of probiotics: necrotizing enterocolitis134, antibiotic-associated diarrhoea and H. pylori infection135,136,137, defecation frequency138,139, infantile colic140, mild to moderate ulcerative colitis141, IBS142, acute diarrhoea143, prevention of Clostridium difficile-associated diarrhoea144 and neonatal sepsis28. A meta-analysis published in 2019 provided evidence that probiotic use has the potential to decrease antibiotic utilization in children145. Some clinical guidelines have been issued for probiotic use in children146,147. There is evidence that probiotics act systemically from the gut to reduce the incidence and duration of upper respiratory tract infections148,149. No official recommendations have been made for the use of probiotics in adults. Additional research clarifying the most effective strains and doses is needed for many clinical targets so far researched150,151,152. Although many clinical indications are promising, data are still emerging for end points including brain, metabolic and cardiovascular effects.

Generally, the strength of evidence for prebiotic interventions lags behind that for probiotics. Perhaps the strongest support for prebiotic use comes from prebiotic infant formulae. Such products are now routinely supplemented with mixtures of GOS and fructans153,154 and this blend of prebiotics in a 9:1 ratio has been shown to reduce respiratory tract infections to levels found in breast-fed infants101,155,156. There is less evidence that prebiotics can reduce infections in adults, although in one placebo-controlled, randomized, double-blind study in 159 healthy volunteers, GOS reduced the incidence of diarrhoea157.

Much of the research focus on prebiotics has been in the realm of functional food (improves well-being through benefit beyond its nutrient content) applications. The one example of a prebiotic food application recognized by European regulatory authorities is improvement in bowel function in healthy adults resulting from consumption of 12 g of chicory inulin per day158,159.

Prebiotic foods designed to increase satiety and reduce energy intake are a promising approach to augmenting compliance with weight-loss diets. Oligofructose-enriched inulin in overweight children has been shown to increase satiety, and reduce energy intake, BMI and body fat mass over 16 weeks (body weight decrease of 3.1% and percent body fat decrease of 2.4% compared with children given placebo (who showed increases of 0.5% and 0.05%, respectively)160,161. Oligofructose ingested daily by 29 adults for 12 weeks in a granola bar formulation reduced lean mass by 0.3 kg (standard deviation 1.2 kg) and waist circumference by 2.2 cm (standard deviation 3.6 cm), with a concomitant decrease in intake and an increase in satiety162. However, not all studies have indicated benefits. One study of 97 overweight or obese children given oligofructose for 12 weeks did not show a statistically significant change in BMI-for-age z-score versus placebo163. This study did not measure the effect of the prebiotic on the gut microbiota and its function, which would have provided mechanistic insights to better understand the null study results and enabled better design of future interventions.

The replacement of glycaemic carbohydrates in food products with non-glycaemic carbohydrates to reduce post-prandial glycaemic responses has already received a positive European Food Safety Authority opinion164. Prebiotic carbohydrates might be expected to bring additional benefits in terms of increasing satiety in such a replacement strategy. Promising results were observed from a double-blind, randomized, controlled crossover trial of 40–42 healthy adults who consumed a yogurt drink containing oligofructose. The intervention improved post-prandial glucose responses165.

There is now some evidence that the stool microbiota profiles of patients with inflammatory conditions, such as IBD, differ from those of heathy individuals166, but it is not clear at the present time why. It is unclear whether these differences are caused by the underlying medical condition, are a consequence of the disease pathology, or are due to confounding factors such as medications or altered dietary habits. Probiotic or prebiotic interventions hold promise for the mitigation of the disease or its symptoms through microbiota modulation. An understanding of the microbiome composition and function in the donor and recipient will help us understand the extent to which clinical success depends on these factors167. Indeed, some clinical trials have noted the importance of baseline microbiota composition among responders168,169,170. Microbiota patterns can be influenced by lifestyle, living conditions, diet, medications and stool consistency, among other transient variables. Advanced age is also thought to be a factor, but one study of Chinese individuals has shown that healthy centenarians have similar microbiota to healthy young people171, suggesting that factors other than age are more important drivers of microbiota composition. Furthermore, research methodologies and data management may lead to spurious interpretations of microbiota assessments, which has the potential to mislead172. Although clinical benefits have been observed with probiotic and prebiotic interventions, the onus is on researchers to clarify the role of the microbiome in these successes to optimize short- and long-term outcomes173,174,175,176,177.

Careful phenotypic and genotypic descriptions of study participants could also be important to the success of clinical trials targeting the microbiome. Host genetic studies could help, for example, in the microbiome-mediated disease of IBD, in which 163 loci have been identified as meeting genome-wide significance thresholds178. However, in the majority of patients with IBD, the disease is not the result of a single host gene defect179, complicating the development of clinical interventions based on host genetics. Another complication is that identified genes are risk factors, not causal determinants, for a disease, and therefore clinical strategies based on host genomics have not been forthcoming.

IBD comprises two main forms, Crohn’s disease and ulcerative colitis. In Crohn’s disease, there seem to be distinct molecular subclasses of genomic associations, further complicating development of effective management strategies180. This aspect might in part explain why the use of probiotic strains in the management of Crohn’s disease has generally failed to be effective181,182. It is not known why mild to moderate ulcerative colitis is somewhat improved by probiotic intervention183 but Crohn’s disease is not. The future success of microbiota manipulation to mitigate serious inflammatory conditions will require an understanding of the interactions between the microbiome and the human genetic risk factors, and will necessitate moving beyond microbial genomic sequencing to transcriptomic, metabolomic and proteomic investigations.

The promise of treating or curing disease with microbiota manipulation continues to be explored using probiotic species different from those traditionally employed184. Many probiotics in current use are from the genera Lactobacillus and Bifidobacterium. Although many of them were derived from the feces or intestinal mucosa of healthy individuals, researchers today are considering the utility of many newly explored human resident microorganisms, such as Akkermansia, Eubacterium, Propionibacterium, Faecalibacterium and Roseburia. This research will require going beyond laboratory animal experiments that have proliferated in the literature62,185.

Fecal microbial transplantation (FMT), which has been a reasonably successful treatment for recurrent C. difficile infection186,187,188, has shown mixed success in the treatment of other conditions189,190,191. Although FMT is not a probiotic application since it is not suitably defined microbiologically to meet the probiotic definition2, the approach is based on the concept that microorganisms derived from healthy donor feces can restore proper function to a dysbiotic microbial ecosystem. It is noteworthy that there have only been a few blinded, randomized controlled trials on FMT for treatment of recurring C. difficile infection, but these have been relatively small studies and we have little information on the long-term changes that such a broad, poorly defined and nonspecific treatment might induce in individuals. A well-defined reproducible probiotic intervention is more suitable for rigorous research investigation and could be safer long-term than FMT, as suggested by several researchers attempting to assemble a defined consortium of microorganisms for such purposes192. Whether these defined consortia, typically comprising many human commensal microbial species, can reach the same levels of cure as FMT remains to be seen.

The potential impact of gut microbiota manipulation on clinical medicine is promising. However, in the excitement over potential, stakeholders often forget that association does not mean causation. For example, blinded reviews of 34 oesophageal biopsy samples found that these microbiomes could be classified into two types. Type 1 is dominated by the genus Streptococcus and is phenotypically normal, but type 2, which demonstrates a greater proportion of Gram-negative anaerobes and/or microaerophiles, correlates with oesophagitis and Barrett’s oesophagus150. Like many other microbiome findings, this finding does not prove causation and there are numerous potential reasons why these associations might exist, including diet, drugs and lifestyle. One hypothesis might be that administering a safe, select Streptococcus could reduce oesophagitis and Barrett’s oesophagus, but this theory has not been tested. Microbiome differences do not necessarily mean that microbiota modification will lead to improved health.

The future

The gut microbiota might be central to the cause of many disorders and its modulation could hold the key to new effective therapies. So, what are the roles of probiotics and prebiotics? In a general sense, both interventions serve to increase the community of beneficial microorganisms and products of their growth and metabolism in the host. In this context, effects relayed systemically might exert influences in, for example, the cardiovascular system, urogenital tract, skin and brain193.

The field is poised for conceptual advances. Target microorganisms will expand beyond the typical Bifidobacterium spp. and Lactobacillus spp. (as mentioned earlier) to include other genera and perhaps more yeast species194,195,196,197. These microorganisms might be new probiotic candidates or further targets for prebiotic utilization. Improved precision, accuracy and repeatability of measures of microbial composition, which lead to genuine and not misleading interpretations, are needed in this field172. Improved assessments will lead to an expanded range of probiotic and prebiotic products. For example, propionate and butyrate are both considered to be beneficial gut microbial metabolites, but neither is produced by bifidobacteria or lactobacilli198,199. Therefore, an opportunity exists to define microorganisms with metabolic capabilities beyond those afforded by traditional probiotics. Another development could be anti-adhesive molecules and carbohydrates that attenuate microbial virulence. These factors would be adjuncts to current prebiotic approaches in that they are not selectively utilized substrates.

To have robust proof that gut microbiome alterations can reduce disease incidence or mitigate disease, more well-designed randomized controlled trials are needed. By randomly assigning individuals to intervention groups, most biases are reduced and the chances of useful results are improved. Owing to the easy availability and relatively low cost of high-throughput sequencing technology, microbiome analysis is becoming widespread and differences among disease states increasingly well publicized. The expertise and databases required for metabolomic analysis is also on an upward trend. This advance will be vital to optimize clinical translation, as a much greater awareness of the functional ecology of the gut is needed together with improved clarity of how this ecosystem influences systemic health. Microbiota and host transcriptomic studies are also important, but they are expensive and time-consuming, and require substantial bioinformatic support. Ultimately, the application of probiotic and prebiotic regimens has the potential to improve human health and contribute greatly to how patients are managed and/or disease risk is reduced.

Conclusions

Although certain commonalities allow us to group substances under the ‘probiotic’ or ‘prebiotic’ umbrellas, benefits to human health are tied to specific products, not the categories en masse. To the extent that a clinical outcome is associated with a specific mechanism of action, then it could be hypothesized that a similar strain or prebiotic expressing that mechanism might also be beneficial. However, it is important not to over-generalize conclusions about specific entities. In general, whether an intervention is effective or ineffective, it must be recognized that the results are tied to specific formulations, doses, clinical end points and target populations. It is incumbent upon responsible scientists to consider the totality of available information on specific interventions as a basis for overall conclusions on effectiveness. Furthermore, clinicians should scrutinize both positive and null studies for bias, as only in eliminating bias in research will we move the field toward truth, thereby realizing the potential of probiotics and prebiotics.

The body of research suggests that these interventions can not only improve symptomology, but also have a meaningful effect on reducing pathology and even saving lives. The prevention of sepsis and necrotizing enterocolitis in infants provides compelling examples. These findings demonstrate effective translation of human microbiome research. Such clinical impact has changed practices in many health-care environments; however, many constituencies have yet to embrace the concept through critically considering the strengths and weaknesses of existing data.

In developing countries, probiotics that are widely available in developed countries are either not accessible or affordable to most people. However, a programme has introduced inexpensive sachets containing a probiotic L. rhamnosus (GR-1 or Yoba 2012) plus S. thermophilus C106 that allow locals to produce different forms of fermented foods (yoghurt, millet, cereals, juices) that not only influence health but also empower poverty-stricken communities to improve social well-being4. With over 260,000 consumers being reached each week in East Africa, the potential is enormous to use these beneficial microorganisms and local food sources to impact communities (G.R. et al., unpublished observations).

Diseases and poor health often result from the interplay of microbiological and biological ecosystems along with societal issues including pollution, food shortages and poor medical care200,201. We encourage more research and translational efforts on probiotics and prebiotics to serve the people of developing countries, who might stand to benefit most from these interventions.

Change history

  • 09 August 2019

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Nature Reviews Gastroenterology & Hepatology thanks H. Szajewska, and the other, anonymous, reviewer(s), for their contribution to the peer review of this work.

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Correspondence to Glenn R. Gibson.

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M.E.S. declares personal fees related to probiotics from the following entities: California Dairy Research Foundation, Clorox, Danone, Danone USA, Dutch Mill, General Mills, JHeimbach, Kelley Drye & Warren, Kellogg, Kerry, Medscape, Nestle, New Chapter, Pepsico, Pfizer, Pharmavite, Probi, Procter & Gamble, Trouw Nutrition, Visalia Dairy Company, Williams Mullen, Winclove Probiotics and Yakult. D.J.M. declares personal fees for consulting for Bayer and Pharmavite. G.R. declares that he helped develop and commercialize probiotic strains GR-1 and RC-14, but has had no financial interest in them for over 10 years. He is Chief Scientific Officer for Seed, a company producing probiotic products. Over the past 3 years, he has consulted on probiotics with Acerus Pharmaceuticals, Altmann, Chr. Hansen, Danone, KGK Science, Kimberly-Clark, Metagenics and Seed. G.R.G. and R.A.R. declare no competing interests.

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Sanders, M.E., Merenstein, D.J., Reid, G. et al. Probiotics and prebiotics in intestinal health and disease: from biology to the clinic. Nat Rev Gastroenterol Hepatol 16, 605–616 (2019). https://doi.org/10.1038/s41575-019-0173-3

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