Gastrointestinal physiology and function is a cornerstone target for functional foods. This was the basis of the 1998 British Journal of Nutrition review titled ‘Functional food science and gastrointestinal physiology and function’(Reference Salminen, Bouley and Boutron-Ruault1). An output of an International Life Sciences Institute – Europe working group, this article covered the basics of gastrointestinal function in health and disease through the lens of developing novel functional foods for health (Fig. 1). The article focused on probiotics and prebiotics as target functional ingredients. Importantly, this review was written before the explosion of data characterising the human microbiome. As microbiome science evolved, probiotics, prebiotics, synbiotics and more recently postbiotics (together the ‘biotic’ substances) as well as fermented foods were seen as potential tools that could improve health by modifying colonising microbiota composition, function or the gut environment. Although evidence that health effects are causally linked to biotics-induced changes in the microbiome are often lacking, the field has continued to promulgate under this hypothesis. The potential of these substances was recognised by food and pharma companies alike, with a resultant increase in research and product development. There have been conceptual advances in understanding shared mechanisms that may drive health effects of probiotics, which may ultimately lead to assignment of benefits to taxonomic groups broader than individual strains and biotic substances(Reference Sanders, Benson and Lebeer2,Reference Hill, Guarner and Reid3) . Continued mechanistic research is needed to provide a rational basis for selecting probiotics and other biotics(Reference Vinderola, Gueimonde and Gomez-Gallego4), which may enable more effective design of human studies on functional foods required for demonstrating a health benefit. This commentary looks back at where we were at the time this article was published, where we are today and what the future may hold.
Quality and quantity of human interventions
Unfortunately, the zeal for the potential of biotic substances created an environment where too often marketing preceded the science. The review from 1998 acknowledges the paucity of well-designed human intervention studies for foods targeting the gut as a means of influencing health. Prior to 1999, there were only sixteen published (listed in PubMed) randomised controlled trials of probiotics in humans. Today, there are over 2500. For prebiotics, defined in 1995 by Gibson and Roberfroid(Reference Gibson and Roberfroid5), the respective numbers are zero and almost 700. Perhaps more important than the rise in numbers of publications is the overall improvement in the quality of human studies being published. In the 1990s, it was not uncommon to see studies on probiotics devoid of basic essential information, such as appropriate description of the intervention (strains and dose). Tracking and reporting of adverse events were uncommon, and trial reports often lacked clear descriptions of important study characteristics such as blinding, allocation concealment and compliance. However, today, trials of biotics are registered prior to recruitment (for example, at clinicaltrials.gov) and follow CONSORT guidelines for reporting(Reference Schulz, Altman and Moher6). A newer list of criteria for reporting microbiome-modulation studies, known as STORMS, is being promoted(Reference Mirzayi, Renson and Furlanello7). Together, these efforts reduce the risk of bias and increase the confidence in trial results.
Recent years have seen recommendations emerge for probiotics for some clinical conditions, even if some remain conditional and based on low-quality data. Recommendations for the use of probiotics to prevent necrotising enterocolitis(Reference Su, Ko and Bercik8), to treat colic in breast-fed infants(Reference Anabrees, Indrio and Paes9), to prevent antibiotic-associated diarrhoea in adults(Reference Hempel, Newberry and Maher10) and children(Reference Szajewska, Canani and Guarino11) and to prevent C. difficile-associated diarrhoea(Reference Su, Ko and Bercik8) have been published in recent years. Clinical recommendations for prebiotics, synbiotics or postbiotics are still lacking. Although there is still a great need for high-quality human studies to clarify the most effective interventions, doses and timing, progress has been made. There is also a great need to better understand likely responders to biotics interventions, taking into account differences in gut microbiota, diet, age and lifestyle.
The evolution and importance of definitions for scientific progress
An important development of the past decade has been the publication of definitions of the biotics family of terms (Table 1). These definitions were developed by consensus panels of experts convened by the International Scientific Association for Probiotics and Prebiotics(ISAPP). These panels applied several underlying principles in the development of the biotics definitions, including allowing for different mechanisms of action and not unduly limiting scope. Therefore, no definitions specify host, regulatory category or site of action. Since it was evident that these substances were intended to have utility as functional foods, functional ingredients or nutritional supplements, all definitions required a health benefit on a target host to be demonstrated. In addition, all definitions were limited to preparations that are administered and did not extend to substances produced by in situ activities, which would be adequately captured by the well-used term ‘microbe-derived metabolites’. Regarding metabolites produced in products prior to end-use, definitions do not exclude their inclusion in preparations of probiotics, prebiotics or postbiotics, and certainly they may contribute to overall measured health impact.
In addition to the biotics definitions, ISAPP also defined fermented foods. Fermented foods, which have been a part of human diets since the Neolithic revolution about 14 000 years ago, may theoretically encompass all the biotics substances, as they supply us with microbes at various stages along the live–dead continuum, predigested nutrients and bacterial metabolites, all of which may affect human gut microbiota and the gut-associated immune system. Unlike the definitions for the biotics, fermented foods are restricted to human use and do not require demonstration of a health benefit.
The intention with publishing these definitions was to achieve harmonisation of the use of these terms by scientists, regulators, press and product marketers. A generally accepted definition for each member of the biotic family will hopefully help in creating regulatory clarity and promote innovation and the development of new health-promoting products.
During the development of the definitions, some points are interesting to highlight. The ISAPP’s definition of probiotics came to endorse, with a slight linguistic adjustment, the WHO/FAO definition published by an expert consultation in 2001(Reference Hill, Guarner and Reid3). The 2017 definition of prebiotics updated the 1995 definition, making it more inclusive and more amenable to innovation. Whereas the 1995 definition focused on the promotion of a certain populations of gut microbes, more specifically lactobacilli and bifidobacteria, the 2017 definition was established to be included in the selective promotion of a wider range of microbes expected to promote health. For both definitions, the leading author was Prof. Glenn Gibson. For synbiotics, the 2020 definition updated the concept, clarifying the differences between a complementary and synergistic synbiotic(Reference Swanson, Gibson and Hutkins12). As for the definition of postbiotics, several definitions that had been previously proposed were considered, but the consensus panel deemed them to be insufficient(Reference Salminen, Collado and Endo13). The final decision on the most appropriate and useful definition will rest with the scientific community and regulatory authorities.
Regulatory pressure
Regulatory requirements in the European Union became more rigorous with the establishment of the European Food Safety Authority, which was tasked to conduct scientific assessments of the highest standard for evaluating the safety of novel foods and the efficacy and health claims for foods. Since the establishment of the novel foods Regulation (EC) No 258/97, two new novel microbes have been approved in Europe (Akkermansia muciniphila and Bacteroides xylanisolvens). No health claims for probiotics have been approved since Regulation (EC) No 1924/2006 was enacted. Further, the standing Committee on the Food Chain and Animal Health in the guidance document on health claims, noting the requirement for a health benefit in the definition of the terms probiotic and prebiotic, concluded that using these terms on food labels constituted a de facto health claim. They therefore determined that these terms could not be used on food labels in the absence of a health claim approved by European Food Safety Authority (—https://ec.europa.eu/food/system/files/2016–10/labelling_nutrition_claim_reg-2006–124_guidance_en.pdf). Similar logic will likely be applied to synbiotics and postbiotics. This approach has restricted information to consumers on biotics, while at the same time has allowed health claims, for example, for vitamins based on historical evidence rather than randomised controlled studies as is required for other health claims.
At the same time, an annually reviewed system of Qualitative Presumption of Safe assessment of microbes and biologicals approved in food has been established by EFSA(Reference Koutsoumanis, Allende and Alvarez-Ordóñez14). This highly regarded approach serves globally as a safety assessment standard.
The future
In 1998, the gut was seen as the target for the development of functional foods. Within 10 years, the gut microbiota became the attribute of the gut that drew the most attention. Since that time, and reflected in the ISAPP definitions, other applications such as the skin, the oral cavity, vaginal tract, metabolic health and brain function became targets of interest. For many years, probiotics were developed from few genera, such as Lactobacilliaceae, Bifidobacterium, Saccharomyces or Bacillus, but the future see expansion of next-generation probiotic species, such as Akkermancia muciniphila, Faecalibacterium prausnitzii, Prevotella copri and Christensenella minuta (Reference O’Toole, Marchesi and Hill15). Such developments may constitute an arsenal of probiotics, which in conjunction with traditional probiotics may enable more targeted use to likely responders. Biotic interventions have the potential to address challenges such as the increase of antibiotic-resistant pathogens or the microbiota disruptions caused by antibiotics and other medications resulting in the depletion of healthy microbiota. An important research question focuses on the extent biotics that may be able to improve the gut microbiota composition or function.
Acknowledgements
This commentary received no specific grant from any funding agency, commercial or not-for-profit sectors.
All authors contributed equally on the manuscript.
S. S. serves on the board of ISAPP and has been a speaker in meetings funded by Industry and Institute Danone. G. V. is a member of the Argentinian board of the Yoghurt in Nutrition Initiative (YINI, Argentina) and the board of ISAPP. M. E. S. is the executive science officer of ISAPP. M. E. S. has been compensated for consulting or service on advisory boards by Bayer, Bill and Melinda Gates Foundation, California Dairy Research Foundation, Church & Dwight, Georgetown University, Pepsico, Smith, Gambrell & Russell LLP, Cargill, Danone North America, Danone Research, Sanofi, Winclove Probiotics and Yakult. She has also been compensated for giving presentations for Kerry, Associated British Foods, Mead Johnson, Fairlife, GlaxoSmithKline, Trouw Nutrition, Omnibiotic/Allergosan, Probi, Sanofi and European Federation of the Associations of Dietitians. She has provided uncompensated service or been reimbursed for travel funding for non-profit organizations, USP, ILSI-NA/IAFNS and Nebraska Food for Health Center.
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Gastrointestinal physiology and function is a cornerstone target for functional foods. This was the basis of the 1998 British Journal of Nutrition review titled ‘Functional food science and gastrointestinal physiology and function’(Reference Salminen, Bouley and Boutron-Ruault1). An output of an International Life Sciences Institute – Europe working group, this article covered the basics of gastrointestinal function in health and disease through the lens of developing novel functional foods for health (Fig. 1). The article focused on probiotics and prebiotics as target functional ingredients. Importantly, this review was written before the explosion of data characterising the human microbiome. As microbiome science evolved, probiotics, prebiotics, synbiotics and more recently postbiotics (together the ‘biotic’ substances) as well as fermented foods were seen as potential tools that could improve health by modifying colonising microbiota composition, function or the gut environment. Although evidence that health effects are causally linked to biotics-induced changes in the microbiome are often lacking, the field has continued to promulgate under this hypothesis. The potential of these substances was recognised by food and pharma companies alike, with a resultant increase in research and product development. There have been conceptual advances in understanding shared mechanisms that may drive health effects of probiotics, which may ultimately lead to assignment of benefits to taxonomic groups broader than individual strains and biotic substances(Reference Sanders, Benson and Lebeer2,Reference Hill, Guarner and Reid3) . Continued mechanistic research is needed to provide a rational basis for selecting probiotics and other biotics(Reference Vinderola, Gueimonde and Gomez-Gallego4), which may enable more effective design of human studies on functional foods required for demonstrating a health benefit. This commentary looks back at where we were at the time this article was published, where we are today and what the future may hold.
Fig. 1. Screenshot of the abstract of the original highly cited paper(Reference Salminen, Bouley and Boutron-Ruault1).
Quality and quantity of human interventions
Unfortunately, the zeal for the potential of biotic substances created an environment where too often marketing preceded the science. The review from 1998 acknowledges the paucity of well-designed human intervention studies for foods targeting the gut as a means of influencing health. Prior to 1999, there were only sixteen published (listed in PubMed) randomised controlled trials of probiotics in humans. Today, there are over 2500. For prebiotics, defined in 1995 by Gibson and Roberfroid(Reference Gibson and Roberfroid5), the respective numbers are zero and almost 700. Perhaps more important than the rise in numbers of publications is the overall improvement in the quality of human studies being published. In the 1990s, it was not uncommon to see studies on probiotics devoid of basic essential information, such as appropriate description of the intervention (strains and dose). Tracking and reporting of adverse events were uncommon, and trial reports often lacked clear descriptions of important study characteristics such as blinding, allocation concealment and compliance. However, today, trials of biotics are registered prior to recruitment (for example, at clinicaltrials.gov) and follow CONSORT guidelines for reporting(Reference Schulz, Altman and Moher6). A newer list of criteria for reporting microbiome-modulation studies, known as STORMS, is being promoted(Reference Mirzayi, Renson and Furlanello7). Together, these efforts reduce the risk of bias and increase the confidence in trial results.
Recent years have seen recommendations emerge for probiotics for some clinical conditions, even if some remain conditional and based on low-quality data. Recommendations for the use of probiotics to prevent necrotising enterocolitis(Reference Su, Ko and Bercik8), to treat colic in breast-fed infants(Reference Anabrees, Indrio and Paes9), to prevent antibiotic-associated diarrhoea in adults(Reference Hempel, Newberry and Maher10) and children(Reference Szajewska, Canani and Guarino11) and to prevent C. difficile-associated diarrhoea(Reference Su, Ko and Bercik8) have been published in recent years. Clinical recommendations for prebiotics, synbiotics or postbiotics are still lacking. Although there is still a great need for high-quality human studies to clarify the most effective interventions, doses and timing, progress has been made. There is also a great need to better understand likely responders to biotics interventions, taking into account differences in gut microbiota, diet, age and lifestyle.
The evolution and importance of definitions for scientific progress
An important development of the past decade has been the publication of definitions of the biotics family of terms (Table 1). These definitions were developed by consensus panels of experts convened by the International Scientific Association for Probiotics and Prebiotics(ISAPP). These panels applied several underlying principles in the development of the biotics definitions, including allowing for different mechanisms of action and not unduly limiting scope. Therefore, no definitions specify host, regulatory category or site of action. Since it was evident that these substances were intended to have utility as functional foods, functional ingredients or nutritional supplements, all definitions required a health benefit on a target host to be demonstrated. In addition, all definitions were limited to preparations that are administered and did not extend to substances produced by in situ activities, which would be adequately captured by the well-used term ‘microbe-derived metabolites’. Regarding metabolites produced in products prior to end-use, definitions do not exclude their inclusion in preparations of probiotics, prebiotics or postbiotics, and certainly they may contribute to overall measured health impact.
Table 1. ISAPP consensus definitions for fermented food and biotics (probiotics, prebiotics, synbiotics and postbiotics). See https://isappscience.org/for-consumers/infographics/ for concise infographics describing all these substances
In addition to the biotics definitions, ISAPP also defined fermented foods. Fermented foods, which have been a part of human diets since the Neolithic revolution about 14 000 years ago, may theoretically encompass all the biotics substances, as they supply us with microbes at various stages along the live–dead continuum, predigested nutrients and bacterial metabolites, all of which may affect human gut microbiota and the gut-associated immune system. Unlike the definitions for the biotics, fermented foods are restricted to human use and do not require demonstration of a health benefit.
The intention with publishing these definitions was to achieve harmonisation of the use of these terms by scientists, regulators, press and product marketers. A generally accepted definition for each member of the biotic family will hopefully help in creating regulatory clarity and promote innovation and the development of new health-promoting products.
During the development of the definitions, some points are interesting to highlight. The ISAPP’s definition of probiotics came to endorse, with a slight linguistic adjustment, the WHO/FAO definition published by an expert consultation in 2001(Reference Hill, Guarner and Reid3). The 2017 definition of prebiotics updated the 1995 definition, making it more inclusive and more amenable to innovation. Whereas the 1995 definition focused on the promotion of a certain populations of gut microbes, more specifically lactobacilli and bifidobacteria, the 2017 definition was established to be included in the selective promotion of a wider range of microbes expected to promote health. For both definitions, the leading author was Prof. Glenn Gibson. For synbiotics, the 2020 definition updated the concept, clarifying the differences between a complementary and synergistic synbiotic(Reference Swanson, Gibson and Hutkins12). As for the definition of postbiotics, several definitions that had been previously proposed were considered, but the consensus panel deemed them to be insufficient(Reference Salminen, Collado and Endo13). The final decision on the most appropriate and useful definition will rest with the scientific community and regulatory authorities.
Regulatory pressure
Regulatory requirements in the European Union became more rigorous with the establishment of the European Food Safety Authority, which was tasked to conduct scientific assessments of the highest standard for evaluating the safety of novel foods and the efficacy and health claims for foods. Since the establishment of the novel foods Regulation (EC) No 258/97, two new novel microbes have been approved in Europe (Akkermansia muciniphila and Bacteroides xylanisolvens). No health claims for probiotics have been approved since Regulation (EC) No 1924/2006 was enacted. Further, the standing Committee on the Food Chain and Animal Health in the guidance document on health claims, noting the requirement for a health benefit in the definition of the terms probiotic and prebiotic, concluded that using these terms on food labels constituted a de facto health claim. They therefore determined that these terms could not be used on food labels in the absence of a health claim approved by European Food Safety Authority (—https://ec.europa.eu/food/system/files/2016–10/labelling_nutrition_claim_reg-2006–124_guidance_en.pdf). Similar logic will likely be applied to synbiotics and postbiotics. This approach has restricted information to consumers on biotics, while at the same time has allowed health claims, for example, for vitamins based on historical evidence rather than randomised controlled studies as is required for other health claims.
At the same time, an annually reviewed system of Qualitative Presumption of Safe assessment of microbes and biologicals approved in food has been established by EFSA(Reference Koutsoumanis, Allende and Alvarez-Ordóñez14). This highly regarded approach serves globally as a safety assessment standard.
The future
In 1998, the gut was seen as the target for the development of functional foods. Within 10 years, the gut microbiota became the attribute of the gut that drew the most attention. Since that time, and reflected in the ISAPP definitions, other applications such as the skin, the oral cavity, vaginal tract, metabolic health and brain function became targets of interest. For many years, probiotics were developed from few genera, such as Lactobacilliaceae, Bifidobacterium, Saccharomyces or Bacillus, but the future see expansion of next-generation probiotic species, such as Akkermancia muciniphila, Faecalibacterium prausnitzii, Prevotella copri and Christensenella minuta (Reference O’Toole, Marchesi and Hill15). Such developments may constitute an arsenal of probiotics, which in conjunction with traditional probiotics may enable more targeted use to likely responders. Biotic interventions have the potential to address challenges such as the increase of antibiotic-resistant pathogens or the microbiota disruptions caused by antibiotics and other medications resulting in the depletion of healthy microbiota. An important research question focuses on the extent biotics that may be able to improve the gut microbiota composition or function.
Acknowledgements
This commentary received no specific grant from any funding agency, commercial or not-for-profit sectors.
All authors contributed equally on the manuscript.
S. S. serves on the board of ISAPP and has been a speaker in meetings funded by Industry and Institute Danone. G. V. is a member of the Argentinian board of the Yoghurt in Nutrition Initiative (YINI, Argentina) and the board of ISAPP. M. E. S. is the executive science officer of ISAPP. M. E. S. has been compensated for consulting or service on advisory boards by Bayer, Bill and Melinda Gates Foundation, California Dairy Research Foundation, Church & Dwight, Georgetown University, Pepsico, Smith, Gambrell & Russell LLP, Cargill, Danone North America, Danone Research, Sanofi, Winclove Probiotics and Yakult. She has also been compensated for giving presentations for Kerry, Associated British Foods, Mead Johnson, Fairlife, GlaxoSmithKline, Trouw Nutrition, Omnibiotic/Allergosan, Probi, Sanofi and European Federation of the Associations of Dietitians. She has provided uncompensated service or been reimbursed for travel funding for non-profit organizations, USP, ILSI-NA/IAFNS and Nebraska Food for Health Center.