By Bruno Pot, PhD, Vrije Universiteit Brussel and Mary Ellen Sanders, PhD, Executive Science Officer, ISAPP
On July 2nd, the European Food Safety Authority (EFSA) published the 12th update of the qualified presumption of safety (QPS) list, a list of safe biological agents, recommended for intentional addition to food or feed, covering notifications from October 2019-March 2020. It was good news to all stakeholders to see that EFSA discussed the recent taxonomic changes within the genus Lactobacillus (see ISAPP blog here) as well as addressed some microbes being considered as potential, novel probiotics.
What is QPS?
In 2005 EFSA established a generic approach to the safety assessment of microorganisms used in food and feed, prepared by a working group of the former Scientific Committee on Animal Nutrition, the Scientific Committee on Food and the Scientific Committee on Plants of the European Commission. This group introduced the concept of “Qualified Presumption of Safety” (QPS), which described the general safety profile of selected microorganisms. The QPS process was mainly developed to provide a generic pre‐evaluation procedure harmonized across the EU to support safety risk assessments of biological agents performed by EFSA’s scientific panels and units. A QPS assessment is performed by EFSA following a market authorisation request of a regulated product requiring a safety assessment. Importantly, in the QPS concept, a safety assessment of a defined taxonomic unit is performed independently of the legal framework under which the application is made in the course of an authorisation process.
QPS status is granted to a taxonomic unit (most commonly a species), based on reasonable evidence. A microorganism must meet the following four criteria:
1. Its taxonomic identity must be well defined.
2. The available body of knowledge must be sufficient to establish its safety.
3. The lack of pathogenic properties must be established and substantiated (safety).
4. Its intended use must be clearly described.
Any safety issues, noted as ‘qualifications’, that are identified for a species assessed under QPS must be addressed at the strain or product level. Microorganisms that are not well defined, for which some safety concerns are identified or for which it is not possible to conclude whether they pose a safety concern to humans, animals or the environment, are not considered suitable for QPS status and must undergo a full safety assessment. One generic qualification for all QPS bacterial taxonomic units is the need to establish the absence of acquired genes conferring resistance to clinically relevant antimicrobials (EFSA, 2008).
If an assessment concludes that a species does not raise safety concerns, it is granted “QPS status”. Once EFSA grants a microorganism QPS status, it is included on the “QPS list” and no microorganism belonging to that group needs to undergo a full safety assessment in the European Union.
The QPS list is re‐evaluated every 6 months by the EFSA Panel on Biological Hazards based on three “Terms of Reference” (ToR)*. This evaluation is based on an extensive literature survey covering the four criteria mentioned above.
What happened to the genus Lactobacillus?
In April 2020, based on a polyphasic approach involving whole genome sequencing of more than 260 species of the former genus Lactobacillus, the genus was reclassified into 25 genera including the emended genus Lactobacillus, which includes host-adapted organisms that have been referred to as the L. delbrueckii group, the earlier described genus Paralactobacillus as well as 23 novel genera, named Acetilactobacillus, Agrilactobacillus, Amylolactobacillus, Apilactobacillus, Bombilactobacillus, Companilactobacillus, Dellaglioa, Fructilactobacillus, Furfurilactobacillus, Holzapfelia, Lacticaseibacillus, Lactiplantibacillus, Lapidilactobacillus, Latilactobacillus, Lentilactobacillus, Levilactobacillus, Ligilactobacillus, Limosilactobacillus, Liquorilactobacillus, Loigolactobacilus, Paucilactobacillus, Schleiferilactobacillus, and Secundilactobacillus. Read more in the original paper here or on the ISAPP blog here).
These name changes could have considerable economic, scientific and regulatory consequences, as discussed during an expert workshop organised by the Lactic Acid Bacteria Industrial Platform (LABIP). One of the points discussed during this workshop was the possible implication of the name change on the QPS list in Europe and the FDA’s GRAS list in the USA.
What did EFSA do?
In a 42-page document, which can be found here, amongst others, the species of the former genus Lactobacillus that were already listed on the QPS list, have been formally renamed at the genus level. The species names remained the same, as the taxonomic revision from April 2020 only affected the genus name. As a result, the genus names of 37 former Lactobacillus species on the QPS were updated, and now span 13 different genera. Table 1 delineates these nomenclature updates.
Table 1: Taxonomic revision of the 37 species formerly of the Lactobacillus genus present on the QPS list (published here).
Earlier denomination |
Updated denomination |
Lactobacillus acidophilus |
Lactobacillus acidophilus |
Lactobacillus alimentarius |
Companilactobacillus alimentarius |
Lactobacillus amylolyticus |
Lactobacillus amylolyticus |
Lactobacillus amylovorus |
Lactobacillus amylovorous |
Lactobacillus animalis |
Ligilactobacillus animalis |
Lactobacillus aviarius |
Ligilactobacillus aviarius |
Lactobacillus brevis |
Levilactobacillus brevis |
Lactobacillus buchneri |
Lentilactobacillus buchneri |
Lactobacillus casei |
Lacticaseibacillus casei |
Lactobacillus collinoides |
Secundilactobacillus collinoides |
Lactobacillus coryniformis |
Loigolactobacillus coryniformis |
Lactobacillus crispatus |
Lactobacillus crispatus |
Lactobacillus curvatus |
Latilactobacillus curvatus |
Lactobacillus delbrueckii |
Lactobacillus delbrueckii |
Lactobacillus dextrinicus |
Lapidilactobacillus dextrinicus |
Lactobacillus diolivorans |
Lentilactobacillus dioliovorans |
Lactobacillus farciminis |
Companilactobacillus farciminis |
Lactobacillus fermentum |
Limosilactobacillus fermentum |
Lactobacillus gallinarum |
Lactobacillus gallinarum |
Lactobacillus gasseri |
Lactobacillus gasseri |
Lactobacillus helveticus |
Lactobacillus helveticus |
Lactobacillus hilgardii |
Lentilactobacillus hilgardii |
Lactobacillus johnsonii |
Lactobacillus johnsonii |
Lactobacillus kefiranofaciens |
Lactobacillus kefiranofaciens |
Lactobacillus kefiri |
Lentilactobacillus kefiri |
Lactobacillus mucosae |
Limosilactobacillus mucosae |
Lactobacillus panis |
Limosilactobacillus panis |
Lactobacillus paracasei |
Lacticaseibacillus paracasei |
Lactobacillus paraplantarum |
Lactiplantibacillus paraplantarum |
Lactobacillus pentosus |
Lactiplantibacillus pentosus |
Lactobacillus plantarum |
Lactiplantibacillus plantarum |
Lactobacillus pontis |
Limosilactobacillus pontis |
Lactobacillus reuteri |
Limosilactobacillus reuteri |
Lactobacillus rhamnosus |
Lacticaseibacillus rhamnosus |
Lactobacillus sakei |
Latilactobacillus sakei |
Lactobacillus salivarius |
Ligilactobacillus salivarius |
Lactobacillus sanfranciscensis |
Fructilactobacillus sanfranciscensis |
EFSA further specifies that “To maintain continuity within the QPS list, all the strains belonging to a previous designed Lactobacillus species will be transferred to the new species. Both the previous and new names will be retained”. (Emphasis added.)
Impact of the QPS update on the probiotic field
The probiotic field can also take note of this current update for its review of two ‘next generation’ probiotic species evaluated for possible QPS status, Akkermansia muciniphila and Clostridium butyricum. Akkermansia muciniphila has been actively researched as a probiotic to help manage metabolic syndrome (Depommier et al. 2019). A probiotic preparation containing both Akkermansia muciniphila and Clostridium butyricum has been studied in a randomized controlled trial for postprandial glucose control in subjects with type 2 diabetes (Perraudeau et al 2020). The committee’s decisions:
- Akkermansia muciniphila is not recommended for QPS status due to safety concerns;
- Clostridium butyricum is not recommended for QPS status because some strains contain pathogenicity factors; this species is excluded for further QPS evaluation.
The publication of the next scientific opinion updating the QPS list is planned for December 2020, based on the 6-month assessments carried out by the BIOHAZ Panel.
Conclusion
Due to its scientific rigor and continuous updates, the EFSA QPS efforts provide useful perspective for the global scientific community on safety of candidate microbes for use in foods. Their embrace of the new taxonomic status of lactobacilli signals to other stakeholders that it is time to start the process of doing the same. Further, their assessment of species being proposed and studies as ‘next generation’ probiotics is an important reminder that a microbe’s status as a human commensal is not a guarantee of its safety for use in foods.
*QPS Terms of Reference (ToR) (quoted from here):
ToR 1: Keep updated the list of biological agents being notified in the context of a technical dossier to EFSA Units such as Feed, Pesticides, Food Ingredients and Packaging (FIP) and Nutrition, for intentional use directly or as sources of food and feed additives, food enzymes and plant protection products for safety assessment.
ToR 2: Review taxonomic units previously recommended for the QPS list and their qualifications when new information has become available. The latter is based on a review of the updated literature aiming at verifying if any new safety concern has arisen that could require the removal of the taxonomic unit from the list, and to verify if the qualifications still efficiently exclude safety concerns.
ToR 3: (Re)assess the suitability of new taxonomic units notified to EFSA for their inclusion in the QPS list. These microbiological agents are notified to EFSA and requested by the Feed Unit, the FIP Unit, the Nutrition Unit or by the Pesticides Unit.
New ISAPP-led paper calls for investigation of evidence for links between live dietary microbes and health
/in ISAPP Science Blog, Consumer Blog /by KCThe past two decades have brought a massive increase in knowledge about the human gut microbiota and its links to human health through diet. And although many people perceive that regular consumption of safe, live microbes will benefit their health, the scientific evidence to date has not been sufficiently developed to justify adding a daily recommended intake of live microbes to food guides for different populations.
Recently, a group of seven scientists, including six ISAPP board members, published their perspective about the value of establishing the link between live dietary microbes and health. They conclude that although the scientific community has a long way to go to build the evidence base, efforts to do this are worthwhile.
The collaboration on this review was rooted in an ISAPP expert discussion group held at the 2019 annual meeting in Antwerp, Belgium. During the discussion, various experts presented evidence from their fields—addressing the potential health benefits of live microbes in general, rather than the narrow group of microbial strains that qualify as probiotics.
Below, the authors of this new review answer questions about their efforts to quantify the relationship between greater consumption of live microbes and human health.
Why is it interesting to look at the potential importance of live microbes in nutrition?
Prof. Joanne Slavin, PhD, RD, University of Minnesota
Humans need proper nutrition to survive, and a lack of certain nutrients creates a ‘deficiency state’. Is this the case for live microbes?
Dr. Mary Ellen Sanders, PhD, ISAPP Executive Science Officer
Why think about intake of ‘live microbes’ in general, rather than intake of probiotic & fermented foods specifically?
Prof. Maria Marco, PhD, University of California Davis
What are dietary sources of live microbes? And do we get microbes in foods besides fermented & probiotic foods?
Prof. Bob Hutkins, PhD, University of Nebraska Lincoln
What’s the evidence that a greater intake of live microbes may lead to health benefits?
Prof. Dan Merenstein, MD, Georgetown University
Why is it difficult to interpret past data on people’s intake of live microbes and their health?
Prof. Colin Hill, PhD, University College Cork
Databases of dietary information have data on people’s intake of live microbes, but what are the limitations of our available datasets?
Prof. Dan Tancredi, PhD, University of California Davis
See ISAPP’s press release on this paper here.
Update on harmonized guidelines for probiotics being developed by the Codex Alimentarius
/in ISAPP Science Blog, News /by KCBy Prof. Gabriel Vinderola, PhD, Associate Professor of Microbiology at the Faculty of Chemical Engineering from the National University of Litoral and Principal Researcher from CONICET at Dairy Products Institute (CONICET-UNL), Santa Fe, Argentina
In December 2017, at the 39th session of the Codex Committee on Nutrition and Foods for Special Dietary Uses (CCNFSDU) in Berlin, members of the Committee agreed to include in the agenda a discussion of harmonized guidelines on probiotics for use in foods and food supplements. Argentina supported this initiative and proposed itself to lead the work, building a guideline based on the present Argentinian framework on probiotics.
The first draft of the document was presented in 2018. Some countries supported the work to develop harmonized guidelines with a definition and minimum requirements for characterization, quality, and labeling, while other countries did not support the initiative, arguing that there was no perceived need to start this new work, it was not a priority for the Committee at that moment, and the document should be revised to provide more clarity on the need to start work on this topic.
Early in 2019, Argentina convened a panel of local experts to contribute to the discussion of the paper based on the issues raised in the first round of revision. I participated in that panel.
In November 2019, at the 41th meeting of the CCNFSDU, an updated version of the paper was presented. This revision clarified that the goal of the work was to produce a regulatory framework for the use of probiotics in food and food supplements. This objective is in line with the purpose of the Codex Alimentarius to guarantee safe and quality food and to ensure equity in international food trade.
In the course of the debate, some delegations favored the topic, stressing the value of regulatory harmonization within the Codex. They pointed out that framework could be based on the existing probiotic definition and guidelines of FAO and WHO, providing clear guidance and principles focused on the use of probiotics as ingredients. Delegations that opposed the new work noted that the Codex had already adopted principles and guidelines of a similar (horizontal) nature on issues such as labeling, claims, contaminants, safety and hygiene covering all foods, including food supplements, and that probiotic-specific regulations were not needed. FAO and WHO had also conducted work in this area.
After the debate, the Committee considered that the document presented needed further clarification, especially with regard to the scope and the issues raised in the discussion. Finally, it was agreed that Argentina and Malaysia would revise the document to be presented at the next plenary meeting of the Committee (42th meeting), to be held in November 2020. It was agreed that in order to assess the need to work on this topic, the new proposal should include a justification for additional probiotic-specific criteria in accordance with the mechanism for assigning Committee priorities.
Due to the COVID-19 pandemic, the 42th meeting has been postponed until November 2021, and a deadline of March 2021 was set for submitting the revised paper to the CCNFSDU.
The information reported in this post was kindly provided by Andrea Moser, Argentinian representative at the Codex Committee on Nutrition and Foods For Special Dietary Uses.
Locally produced probiotic yogurt for better nutrition and health in Uganda
/in Consumer Blog, News /by KCBy Prof. Seppo Salminen, Director of Functional Foods Forum, University of Turku, Turku, Finland
Can locally produced probiotic yogurt be a way to increase the health and wealth of people in resource-poor areas of Uganda? Recently Dr. Nieke Westerik, a researcher from the Netherlands, partnered with a local Ugandan team to explore a yogurt production and distribution program similar to one that had previously proved successful in low-income areas of Argentina.
Since 2008, “Yogurito Social Program” has been operating in Argentina and now some 350,000 schoolchildren in less developed provinces enjoy the benefits of daily probiotic yogurt developed locally. Dr. Westerik (Free University of Amsterdam and Yoba 4 Life Foundation), with support from former ISAPP board member Prof. Gregor Reid, has now helped adapt the program to local needs in Uganda, making use of a well-known probiotic (Lacticaseibacillus rhamnosus GG) plus a yogurt starter (produced by the Yoba 4 Life Foundation) for production of the yogurt. The probiotic’s health effects have been demonstrated in human intervention studies.
The team worked on technical training and quality control of the locally produced yogurt, developing a production protocol suitable for Ugandan small-scale manufacture of probiotic fermented foods. Dr. Westerik’s team then conducted two clinical studies that demonstrated that the consumption of this probiotic product improved natural defenses and prevented respiratory infections (e.g. the common cold) and intestinal infections, which are the infectious conditions of greatest relevance in childhood in Uganda.
Yogurt is a new tool for individuals in developing areas of Uganda to achieve better health through diet, with potentially significant social and economic implications. Both the Ugandan and Argentinian experiences illustrate the power of microbes to positively impact the lives of women, men, and children. Given the positive results from these two different contexts, such activities could be replicated in other geographical areas—with either dairy, vegetable, or grain fermentations used locally with defined, well-studied starter cultures.
Further reading:
Julio Villena, Susana Salva, Martha Núñez, Josefina Corzo, René Tolaba, Julio Faedda, Graciela Font and Susana Alvarez. Probiotics for Everyone! The Novel Immunobiotic Lactobacillus rhamnosus CRL1505 and the Beginning of Social Probiotic Programs in Argentina. International Journal of Biotechnology for Wellness Industries, 2012, 1, 189-198.
Westerik N. 2020. Locally produce probiotic yoghurt for better nutrition and increased incomes in Uganda. PhD thesis, Free University of Amsterdam, The Netherlands.
Reid G, Kort R, Alvarez S, Bourdet- Sicard R, Benoit V, Cunningham M, Saulnier DM, van Hylckama Vlieg JET, Verstraelen H, Sybesma W. Expanding the reach of probiotics through social enterprises. Beneficial Microbes, 9 (5): 707-715.
YOGURITO –the Argentinian social program with a special yogurt
Probiotics to Prevent Necrotizing Enterocolitis: Moving to Evidence-Based Use
/in ISAPP Science Blog /by KCBy Ravi Mangal Patel, MD, Msc, Associate Professor of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta. rmpatel@nullemory.edu Twitter: @ravimpatelmd
Necrotizing enterocolitis (NEC) is one of the most lethal neonatal diseases, yet most people have never heard about it. The disease primarily affects preterm infants and is characterized by the development of intestinal inflammation. Clinically, the disease often manifests with an infant developing feeding intolerance or abnormal abdominal exam findings. The diagnosis is confirmed by abdominal x-ray or ultrasound. One of the key diagnostic radiographic findings is pneumatosis, which is air in the lumen of the bowel caused by gas-producing bacteria.
Dr Ravi Mangal Patel
NEC accounts for 1 out of every 10 deaths in US neonatal intensive care units. Among extremely preterm infants (those born at 22-28 weeks’ gestation) in the US, NEC is the most common single cause of death between 2 weeks and 2 months of age. Many infants with NEC undergo surgery to remove diseased bowel and those who recover and survive are at risk for long-term neurodevelopmental impairment and short bowel syndrome.
Decades of research into NEC have identified several key risk factors, including formula feeding, inconsistent feeding, abnormal intestinal oxygenation and [gut microbiota] dysbiosis. Studies have shown that dysbiosis, or abnormal intestinal colonization, is an important antecedent risk factor for the development of NEC. These studies have found that infants who develop NEC have an increase or bloom in the relative abundance of proteobacteria, compared to those who do not develop NEC. These proteobacteria, which contain a lipopolysaccharide coating, may lead to inflammation through their interaction with Toll-like receptor 4.
Given the role of dysbiosis in NEC, efforts to intervene by provision of probiotics to prevent NEC is a rational and extensively studied intervention, with over 63 randomized trials enrolling ~15,000 infants to date. The aforementioned meta-analysis, along with several others (Table 1), show probiotic supplementation results in large magnitude reductions in the risks of NEC and death and more modest reductions in the risks of late-onset sepsis. However, there is more limited data on extremely preterm infants and the quality or certainty of evidence for probiotics for the prevention of NEC was low in a recent Cochrane review.
Source: https://doi.org/10.1053/j.sempedsurg.2017.11.008
In the United States, an increasing number of centers have begun to routinely provide probiotics, with the greatest increase in use beginning in 2015. Observational studies evaluating routine probiotic use show benefits that are similar in magnitude to those from randomized trials, supporting the external validity of the results from the trials. This includes a large recent evaluation of probiotic use in the United States. Around the world, probiotic use is highly variable, from 100% of NICUs in New Zealand, 68% of NICUs in Germany, to 12% in the UK, 21% in Canada and 14% in the United States. Some of the variability in clinical use may be related to the uncertainty regarding the quality of commercially available probiotic products and need for clarity regarding strain-specificity of effects. There are many considerations both for and against routine use of probiotics to prevent NEC (Table 2). Current probiotic dietary supplements do not undergo FDA’s premarket review and approval requirements for safety and effectiveness or have to meet manufacturing and testing standards for drugs, and the potential risks were highlighted by a case of an infant death from a contaminated supplement. There is currently no FDA-approved live biotherapeutic product to prevent NEC.
Source: doi: 10.1016/j.earlhumdev.2019.05.009
Recent recommendations and guidance from ESPHGAN and the AGA also demonstrate that some medical organizations recognize the strength of the data in support of probiotic use to prevent NEC. It has been over two decades since the first study demonstrating the benefit of probiotic supplementation to prevent NEC in preterm infants. Now, more than ever, the evidence continues to accumulate regarding the beneficial effects of probiotic use in preterm infants as a compelling strategy to reduce the risks of both NEC and death. Therefore, considering the balance of potential risks and benefits including data from both randomized trials and routine implementation studies, my opinion is that the cumulative evidence to date supports routine probiotic use to prevent NEC and death in preterm infants.
As important is considering the parent voice regarding probiotic use. The NEC Society is a non-profit focused on NEC that has worked to incorporate the voice of the patient-family in clinical decisions.
Disclosures: Dr. Patel serves on the data-safety monitoring board of the Connection Study, which is a trial examining the use of an investigational probiotic to decrease the risk of NEC.
For further information, see this seminar by Dr. Patel: Practical Consideration for Probiotics in the NICU
ISAPP board member Prof. Colin Hill receives Career Achievement Research Award from University College Cork
/in News /by KCThis month, ISAPP board member and former president Professor Colin Hill received a prestigious award from University College Cork (Ireland), where he has worked since 1992: The UCC Career Achievement Research Award. The prize honours leading researchers whose influential work has been recognized globally.
Hill’s research interests lie in molecular microbiology—specifically, issues around infection. His team was the first to discover lacticin 3147 and thuricin CD, two examples of a class of anti-microbials produced by bacteria that kill bacteria. He is also a leading scientist exploring the human virome: his team developed tools for gut virome analysis, performed phage therapy in vivo, and increased the number of known phage genomes by tens of thousands. Hill is the inventor on 23 patents, has published over 570 research articles, and to date, has secured over €25 million worth of research funding. His publications and citations put him in the top 1% of researchers worldwide.
Hill has served on the ISAPP board of directors since 2009, and was president from 2012-2015. He has supported ISAPP’s efforts to advance the science of probiotics through his scientific insights and leadership: he was lead author on the landmark ISAPP consensus paper on probiotics, participated in the recent ISAPP consensus panel on postbiotics, led numerous ISAPP discussion groups during the ISAPP annual meetings, and co-authored 10 ISAPP publications.
Prof. Todd Klaenhammer, who is a founding ISAPP board member, a member of the US National Academy of Sciences, and a retired professor from North Carolina State University, says of the award, “This is fantastic and a huge honor for Colin, one that is very well deserved. He has distinguished himself as a leading scientist, with some of the most brilliant work I have seen from anyone who has successfully crossed disciplines—as he has with his work on phage, probiotics, listeria, among others.”
ISAPP’s Executive Science Officer, Dr. May Ellen Sanders, says, “Colin is a rare combination of great scientist, effective leader and engaging person. During his tenure as president, ISAPP really made it onto the global map. It was a productive and really fun three years with him at ISAPP’s helm.”
Hill’s ISAPP colleagues know him for his exceptional curiosity and willingness to push boundaries, and wish him the best of success as he continues his groundbreaking scientific work.
New Spanish-language e-book about fermented foods now available for download
/in News, Consumer Blog /by KCBy Dr. Gabriel Vinderola, PhD, Associate Professor of Microbiology at the Faculty of Chemical Engineering from the National University of Litoral and Principal Researcher from CONICET at Dairy Products Institute (CONICET-UNL), Santa Fe, Argentina
Fermented foods and beverages such as yogurt, wine, beer, kefir, kombucha, kimchi, and miso are created with the help of microbes. After more than 10,000 years of practice around the globe, fermentation has finally caught massive attention from a general public interested in knowing more about the fascinating, invisible world of microbes. In essence, the act of fermentation places food in a unique place between raw and cooked. The flavours, tastes, textures and potential health benefits of fermented foods, made possible through the presence of viable or non-viable microbes and their metabolites, are achieved through this set of ancestral food processing techniques. Today’s science allows us to see the functions of fermentation microbes that can make certain nutrients more bioavailable in foods. Fermentation can also reduce certain anti-nutrients and generate a large number of potentially beneficial microorganisms.
To help people learn about fermented foods, I was pleased to collaborate on an e-book with Ricardo Weill, an Argentinian dairy industry expert who first introduced Lactobacillus rhamnosus GG in Argentinian fermented milks in the 1990s, and Alejandro Ferrari, a biologist and scientific communications expert. The book is titled ‘Fermented Foods: microbiology, nutrition, health and culture’, and is currently available only in Spanish.
The book aimed to reach the general public, with scientific concepts but in easy-to-follow language for people with little or no previous knowledge of microbiology, nutrition or food technology. It tells the stories of many types of fermented foods around the world and adds a scientific perspective on their health benefits. The book brings together information from 38 authors from Argentina, Colombia, Japan, Spain and Finland, including ISAPP President Prof. Seppo Salminen, and Martin Russo, a professional chef in Argentina who specializes in fermentation. The book includes the following sections:
Fermentation: An anthropological view
Variety of fermented foods in Japan and other East Asian countries, and the microorganisms involved in their fermentation
Introduction to the intestinal microbiota: its role in health and the disease
Consumption of probiotic fermented milk and its impact on the immune system
Fermented milks, yogurts and probiotics
Kefir and artisanal fermented foods
Fermented meat sausages: Contribution of lactic bacteria in global quality
Lactic fermentation of cereals and Andean ancestral grains
Fermented vegetables and legumes
Fermentation of fruit drinks and drinks
Yeasts in beer and baked goods
Role of fermented foods in diet
Role of lactic acid in the beneficial effects of fermented foods
Microbiological safety of fermented foods
Fermented foods and chronic non-communicable diseases: A narrative review of the literature
Fermentation and gastronomy: A cook among scientists, a scientist among cooks
This e-book initiative started in October 2019, when a symposium about fermented food was organized by the Danone Institute of the Southern Cone (DISC).
The Danone Institute of the Southern Cone (DISC) was founded in 2008, and it is the local chapter for Argentina, Chile and Uruguay of the Danone Institute International network, which gathers 14 Danone Institutes (13 local Institutes and 1 International) in 15 countries. All Danone Institutes are non-profit organizations, dedicated to non-commercial activities and promotion of science.
Since its foundation, the DISC has collaborated with more than 200 experts taking part in different projects, and has served as a collaborative meeting place to reflect with their peers—all of them remarkable scientists coming from different and complementary specialties, focusing on key aspects of public health linked to food.
See the link to our book here:
Fermented Food: Microbiology, Nutrition, Health & Culture. (2020)
See the ISAPP press release about this book in English and en español.
Some previously-produced nutrition books that are freely available in Spanish on the DISC website are:
Opportunity for research grants to help understand evidence linking live dietary microbes and health
/in News, ISAPP Science Blog /by KCFor thousands of years, cultures across the globe have been consuming fermented foods, many of which contain diverse and numerous live microbes. Yet scientists are still puzzling over whether a greater intake of live microbes results in measurably better health. As part of long-term efforts to understand evidence for the health benefits of live dietary microbes and identify research gaps, ILSI North America is presenting a grant opportunity for researchers to help assess current scientific evidence for these links.
Researchers are invited to submit grant proposals, which should include the research approach along with anticipated challenges, resources, timeline, and key deliverables. The ILSI North America Gut Microbiome Committee also requests the inclusion of a suggested publication plan for the work. Budgets in the range of $100-150K will be considered. The deadline to submit the proposal is October 30, 2020 at 11:59PM EST. See here for more details.
ISAPP is supporting long-term efforts in this topic area. Its latest effort is the publication of a review paper (in press) on the links between dietary live microbes and health, called Should there be a recommended daily intake of microbes? The paper is authored by ISAPP board members Prof. Maria Marco, Prof. Colin Hill, Prof. Bob Hutkins, Prof. Dan Tancredi, Prof. Dan Merenstein, and Dr. Mary Ellen Sanders along with well-known nutrition researcher, Prof. Joanne Slavin.
ILSI North America is a non-profit scientific organization whose mission is to advance food safety and nutrition science for the benefit of public health. The organization engages academic, government, and industry experts by conducting research projects, workshops, seminars, and publications.
Current status of research on probiotic and prebiotic mechanisms of action
/in ISAPP Science Blog /by KCBy Mary Ellen Sanders, PhD, ISAPP Executive Science Officer
Human intervention studies in the fields of probiotics and prebiotics assess the health effects of these ingredients, whether it’s improving specific symptoms or preventing the occurrence of a health condition. Yet scientists in the field recognize the importance of learning the ‘chain of events’ by which probiotics and prebiotics are able to confer health benefits. Such mechanistic insights allow better probiotic selection and development of therapeutic approaches, as well as more precise dosing.
Mechanisms of action for probiotics and prebiotics are complex and often difficult to pinpoint, especially since any given health benefit may derive from multiple co-functioning mechanisms. However, scientists have made incremental gains in understanding these mechanisms. This scientific progress was covered in a recent webinar co-presented by ISAPP and ILSI-Europe, titled Understanding Prebiotic and Probiotic Mechanisms that Drive Health Benefits. Speakers for the webinar were:
The webinar was held live on September 17, 2020. Of the 499 webinar registrants, 357 attended the webinar live from 57 countries, from Australia to the US. ISAPP and ILSI-Europe hope the webinar will serve as a resource for people who want a rapid overview about mechanisms of action.
Watch the full webinar here, and read further for a summary of key points from these experts.
Prebiotic benefits and mechanisms of action
Prebiotics are defined as substrates that are “selectively utilized by host microorganisms conferring a health benefit”. ‘Utilization’ in the gut may involve crossfeeding, which means products produced by the first microbes degrading the prebiotic can then be used by different members of the host microbiota – so it may take a series of complex steps to get to a final health outcome. However, selective utilization and health benefit are always required for a substance to meet the definition of a prebiotic.
The health benefit of a prebiotic can be local (in the gut) or systemic. Locally, prebiotics can act via fecal bulking, as they are typically types of fiber. In addition, they can produce short-chain fatty acids (SCFAs), which reduce gut pH and thereby can discourage pathogenic and toxigenic activity of gut microbes, increase calcium ion absorption and provide energy for gut epithelial cells.
Systemic functions of prebiotic metabolism include them being used as substrates for microbes that produce or interact with host cells to produce molecules with neurochemical, metabolic or immune activity. Further, SCFAs can end up in the blood and can reach the liver, muscles and the brain. The SCFAs interact with specific host receptors and can lead to the release of satiety hormones or interact with receptors in the liver, adipose tissue and muscle tissue, leading to reduced inflammation. Prebiotics can also interact directly with immune cells.
Probiotic health effects and mechanisms of action
Health and disease are the end results of complex interactions on a molecular scale within a human or animal host. Host molecules also interact with microbial molecules, including those molecules introduced with or produced by probiotics. Designing studies to discover probiotic mechanisms in human research is extremely challenging because both host and probiotic are very complex systems that most probably engage with one another on multiple levels. Probiotic molecules can have direct effects and downstream effects, and we are aware of only a few cases where a health effect can be tied to one specific probiotic molecule.
Probiotics can interact directly with the host, but also can act indirectly by influencing the microbiome. There may be many different mechanisms by which a given probiotic interacts with the host.
It is interesting to note that probiotics use some of the same types of mechanisms (pili, small molecule production, etc.) that are used by pathogens, microbes that have a detrimental effect on the host. But these shared mechanisms are usually connected to surviving or colonising strategies, not those that cause damage to the host.
L. rhamnosus GG is a well-researched model probiotic, for which many mechanisms have been identified, including pili, immune modulators and lactic acid production, some mechanisms shared with other probiotic strains and species. Other studies have identified mechanisms for novel types of probiotics. For example, in mice and humans taking a strain of Akkermansia, heat killed cells had the same or even better effect on markers of metabolic health, which implies that the molecules (perhaps proteins in the bacteria, unaffected by heat treatment) are mediating the effect in this case.
See here to watch the webinar in full.
Citizen scientists step up for a research project on women’s health
/in ISAPP Science Blog /by KCBy Prof. Sarah Lebeer, Research Professor in Microbiology and Molecular Biology, Department of Bioscience Engineering, University of Antwerp, Belgium
Lactobacilli are a very important group of bacteria that live on the human body and in many other environments on Earth. They have been linked to human health for more than 100 years already, but mainly in the context of digestive health and dairy-based fermented foods. Knowledge about other habitats and applications of lactobacilli is lagging behind, and surprisingly, we know little about where lactobacilli come from in the life of an individual or even in the evolution of humans. Studying the genetic capabilities of lactobacilli and their interactions with the host will give us a clearer picture of how these bacteria help us stay healthy.
This knowledge gap inspired me to apply for a European Research Council (ERC) grant. Last year I was awarded with this prestigious grant, which provides funding to explore novel aspects about the ecology and evolutionary history of lactobacilli.
Lactobacilli are dominant colonizers of the human vagina, where they play a key role in women’s health. Among the lactobacilli, I consider the vaginal lactobacilli as ‘mother lactobacilli’. As you might have noticed from our recent reclassification of the Lactobacillus genus complex, the vaginal type strains Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus jensenii and Lactobacillus iners all belong to the Lactobacillus genus strictu sensu, because they are closely related to the first Lactobacillus species ever described: Lactobacillus delbrueckii subsp. bulgaricus, originating from yogurt. So, the study of vaginal lactobacilli could also be seen as a study on the basics of the genus Lactobacillus and what makes this group so important for human health.
At present, it is not well understood why lactobacilli dominate the human vagina under healthy conditions. Interestingly, this appears to be the case only in humans and not in other mammals. We speculate that it is because lactobacilli have beneficial functions and, when transmitted from mother to infant in early life, have a peculiar capacity to inhibit dangerous pathogens for our offspring, including group B streptococci, Enterobacteriaceae, fungi and various viruses. Lactobacilli also have interesting immune modulatory capacities. A rather unique feature in humans is the menstrual cycle and the estrogen-stimulated production of glycogen being a major sugar source for the lactobacilli in the vagina, resulting in high production of lactic acid, an excellent antimicrobial molecule against numerous pathogens. But the short answer is that we have no really clear answer to these fundamental questions of human biology.
Because the ERC funding allows us to be a bit more aspirational than in our usual research endeavors, we decided to address some of these questions by engaging women as citizen scientists. So we launched an ambitious citizen science project on vaginal lactobacilli and women’s health, named the Isala Project (see www.isala.be — it’s only in Dutch, but easily translatable with Google Translate 😊). The project is named after Isala Van Diest (1842-1916), the very first female physician in Belgium.
Our initial ambition was to ask 200 healthy women at different points in their menstrual cycle to provide vaginal swabs for microbiome sequencing and culture of lactobacilli. Our plan was to launch the call for volunteers on International Women’s Day (March 8, 2020), but COVID-19 made us revise our plans. We postponed our call until March 24, realizing that most women were at home during the lockdown. We assumed that since the national news was dominated by the SARS-CoV-2 virus, it was going to be difficult to reach out with traditional news channels. However, within two weeks, more than 5500 women registered for Isala on our website and we even had to restrict sign-ups!
We thought many women would still drop out if they found out they had to fill in an extensive questionnaire with intimate and lifestyle-related questions, but this was not the case. Almost 4700 women filled out the extensive questionnaire, demonstrating strong enthusiasm, commitment, and engagement. We decided to send a self-sampling kit to all the women who had filled in the entire questionnaire and supplied their postal address. Over the summer, we sent 4100 self-sampling kits, and of these, 80% of the women have already sent back their swabs to us. Our lab members are overjoyed with the citizen science enthusiasm!
Even though managing the logistics of the postal packages was a huge administrative challenge, we managed to keep everything straight. Thanks to an amazing team of dedicated and super-organized PhD students, lab techs, postdocs, master students, clinicians, bio-informaticians, statisticians, and communication partners, we can now say that we are around halfway through the project. We have been able to process all swabs that arrived to DNA extracts (for microbiome sequencing) and glycerol stocks (for the lactobacilli biobank and metabolomics later). Within the next months, these samples will be run on our MiSeq for 16S rRNA amplicon sequencing; the functional, genetic, and metabolomic characterization will of course take much more time. Making vaginal microbiome profiles for all these citizen scientists by next spring is now our priority, as we want to send all participants a personal update by then.
With this project, we are also changing up the traditional publication timeline: we are communicating about the process while not having all the results yet. We will inform the participants about their microbiome profiles before we submit or publish the related peer-reviewed manuscripts. This is because we want to actively communicate with our participants, opening discussions on the topic — and empowering women, without delay, to think about their vaginal health. We even have suggested conversation starters on our website and in the sampling boxes.
Time will tell whether these efforts will pay off for women’s health! Citizen Science can sometimes be surprising, but so far, we are very happy with the contact we’ve made with our committed and enthusiastic participants. We even have a hashtag, ‘#LetsSwab for the future’. I highly encourage my fellow scientists to consider organizing citizen science projects on topics related to the human microbiome, probiotics and prebiotics, because it is a unique way to get inspired and to do research on a large scale.
Precision approaches to microbiota modulation: Using specific fiber structures to direct the gut microbial ecosystem for better health
/in ISAPP Science Blog, News /by KCBy now, hundreds of scientific articles show the differences in gut microbiota composition and function between states of health and disease, leading to the idea that gut microbiota modulation is a promising way to achieve better health. But in practice, changing the complex community of microbes in the gut has proved challenging—the gut microbiota of the average adult is remarkably stable.
When it comes to diet, non-digestible carbohydrates are the main way to provide nutritional support to microbial populations and to modulate these communities, either in composition or in function. Can these dietary fibers be used to modulate the gut microbiota in a precise manner, with the aim of inducing certain health effects?
Prof. Jens Walter of APC Microbiome Ireland addressed this topic in a plenary lecture at the ISAPP 2020 annual meeting, titled: Precision microbiome modulation through discrete chemical carbohydrate structures.
Walter sees the gut microbiota as an complex ecological community of interacting microbes that is remarkably stable in healthy adults (albeit with a high degree of inter-individual variation). In order to precisely modulate gut microbiomes through diet, scientists must consider the ecological principles that shape these communities and determine how they function.
In the lecture, Walter introduced a perspective for using discrete fiber substrates to precisely modulate gut microbiota – a framework first articulated in a 2014 paper by Hamaker and Tuncil. According to this framework, gut microbiomes can be precisely manipulated, whether to achieve a certain microbiota composition or the production of health-relevant metabolites, through the use of specific fiber structures that are aligned with microbes that have the ability to utilize them. Walter explains some of the main challenges of the framework, which relate to the vast inter-individual differences in the gut microbes that are present, and their response to fiber; and discovering the exact dose of a fiber required for reliable changes in a person’s gut microbiota.
At the core of the presentation is a study by the Walter Lab that systematically tested the framework through a human dose-response trial using resistant starches with slight differences in their chemical structure. The findings of the study, which were published this year, illustrate how this ecological concept can be successfully applied. This shows the colonic microbiota can be successfully shaped in a desired manner with discrete dietary fiber structures.
See Prof. Walter’s presentation in full here.
New publication co-authored by ISAPP board members gives an overview of probiotics, prebiotics, synbiotics, and postbiotics in infant formula
/in News, ISAPP Science Blog /by KCFor meeting the nutritional needs of infants and supporting early development, human milk is the ideal food—and this is reflected in breastfeeding guidelines around the world, including the World Health Organization’s recommendation that babies receive human milk exclusively for the first six months of life and that breastfeeding be continued, along with complementary foods, up to two years of age or beyond. In certain cases, however, breastfeeding is challenging or may not even be an option. Then, parents rely on alternatives for feeding their infants.
A group of scientists, including three ISAPP board members, recently co-authored an article in the journal Nutrients entitled Infant Formula Supplemented with Biotics: Current Knowledge and Future Perspectives. In the review, they aimed to highlight the new technologies and ingredients that are allowing infant formula to better approximate the composition of human milk. They focused on four types of ingredients: probiotics, prebiotics, synbiotics, and postbiotics.
Co-author Gabriel Vinderola, Associate Professor of Microbiology at the Faculty of Chemical Engineering from the National University of Litoral and Principal Researcher from CONICET at Dairy Products Institute (CONICET-UNL) in Santa Fe, Argentina says, “Modern technologies have allowed the production of specific microbes, subtrates selectively used by the host microbes, and even non-viable microbes and their metabolites and cell fragments—for which scientific evidence is available on their effects on infant health, when administered in adequate amounts. Thus, this current set of gut modulators can be delivered by infant formula when breastfeeding is limited or when it is not an option.”
The authors say a well-functioning gut microbiota is essential for the overall health and proper development of the infant, and components of human milk support the development of this microbiota. They list important human milk components and the novel ingredients that aim to mimic the functions of these components in infant formulas:
HMOs are specialized complex carbohydrates found in human milk, which are digested in the infant colon and serve as substrates for beneficial microbes, mainly bifidobacteria, residing there. In recent years, prebiotic mixtures of oligosaccharides (e.g. short-chain GOS and long-chain FOS) have been added to infant formula to recapitulate the effects of HMOs. But now that it’s possible to produce several types of HMOs synthetically, some infant formulas are enriched with purified HMOs: 2’-fucosyllactose (2’FL) or lacto-N-neotetraose (LNnT). Even 3′-galactosyllactose (3′-GL) can be naturally produced by a fermentation process in certain infant formulas.
Human milk has a complex microbiota, which is an important source of beneficial bacteria to the infant. Studies support the notion that the human milk microbiota delivers bioactive components that support the development of the infant’s immune system. Probiotic strains are sometimes added to infant formula in order to substitute for important members of the milk microbiota.
Human milk also contains metabolic byproducts of bacteria called “metabolites” in addition to the bacteria themselves. These components have not been fully studied to date, but bacterial metabolites such as butyrate and other short-chain fatty acids may have important health effects for the overall development of the infant. A future area of nutritional research is likely to be the addition of ‘postbiotics’ — non-viable cells, their metabolites and cell components that, when administered in adequate amounts, promote health and well-being — to infant formulas. (ISAPP convened a scientific consensus panel on the definition of postbiotics, with publication of this definition expected by the end of 2020.)
The precise short- and long-term health benefits of adding the above ingredients to infant formula are still under study. One pediatric society (the ESPGHAN Committee on Nutrition) examined the data in 2011 and at that time did not recommend the routine use of infant formulas with added probiotic and/or prebiotic components until further trials were conducted. A systematic review concluded that evidence for the health benefits of fermented infant formula (compared with standard infant formula) are unclear, although improvements in infant gastrointestinal symptoms cannot be ruled out. Although infant formulas are undoubtedly improving, review co-author Hania Szajewska, MD, Professor of Paediatrics at The Medical University of Warsaw, Poland, says, “Matching human milk is challenging. Any alternative should not only match human milk composition, but should also match breastfeeding performance, including how it affects infant growth rate and other functions, such as the immune response.”
Can the microbiota help protect against viral infections? Summary of an ISAPP discussion group
/in ISAPP Science Blog /by KCBy Drs. Karen Scott, University of Aberdeen, and Sarah Lebeer, University of Antwerp
As part of the ISAPP virtual annual meeting 2020, around 85 members of the ISAPP community joined us in a Zoom discussion forum to discuss the topic: “Do our resident microbes help protect against viral infections?” A scientific perspective on this topic is especially important during the COVID-19 pandemic, when many members of the general public are wondering about actions (if any) they can take to protect themselves before a SARS-CoV-2 vaccine becomes widely available.
We introduced the topic and were joined by several invited experts, who also gave short presentations:
The ensuing conversation, open to all participants, was wide-ranging, starting with the gut microbiota and expanding to include the microbiota at other body sites, and the effects of the gut microbiota around the body gut via transport of metabolites. Here are some of the main take-home messages from this discussion.
Components of the microbiota (bacteria, fungi, archaea, viruses and others) at a body site interact with each other. Although scientists often study one component of the (gut) microbiota at a time, members of the microbiota from different kingdoms interact with each other in ways that can be positive or negative for the host. In particular, specific activities of bacteria can be widespread, frequent or rare among members of the microbiota – and it is often the rare activities that have important impacts on the course of a disease: e.g. specific antimicrobial agents produced by some bacteria prevent Salmonella infections in pigs and cure mastitis in cows.
Mechanistic work shows bacteria in the microbiota can prevent, eliminate or promote viral infections. Studies have shown some microbes can prevent attachment of viruses to cell surfaces by offering alternative receptors. In contrast, virus particles can utilise other bacterial cells to “mask” them and facilitate entry into host cells. Other bacteria can stimulate the immune system to promote elimination of a viral infection, while under specific circumstances this same immune activation may promote viral infection. When it comes to the microbiota of the respiratory tract, studies have shown its bacterial members play a crucial defensive role. Probiotics that are already shown to be effective against other viral upper respiratory tract infections may have promise for COVID-19 (either for preventing infection or enhancing recovery), and currently studies are underway to investigate these.
Probiotics or prebiotics could be useful adjuncts to vaccination, but they are not likely to become a reality for COVID-19. Scientists are perennially interested in the topic of vaccine efficacy, and some probiotics have been shown to increase efficacy for widely available vaccines in certain populations. But in the current pandemic, developing a safe and effective vaccine (or vaccines) is the primary concern. Testing the possibility of probiotic or prebiotic combination therapies would be secondary, since the necessary testing would take longer in order to evaluate the adjuvant potential of different probiotic strains. Because the expression of cell surface molecules that can mediate adjuvant activity is strain-dependent, screening and selecting the best strains would probably take too long to become a reality for COVID-19. Certainly, participants agreed that introduction of a safe, effective vaccine was the priority, without any delays to test out ‘extras’.
A scientific rationale exists for maintaining gut microbiota diversity in order to reduce the development of diseases which, as “underlying health conditions”, may result in more severe COVID-19 outcomes. It is clear that individuals with certain underlying health conditions—related to the central nervous system and gastrointestinal system, and to metabolic and immunological dysfunction—tend to experience a more severe disease, with worse outcomes, following SARS-CoV-2 infection. Many of these conditions are also associated with a gut microbiota that is different from that of healthy controls. Research consistently shows that individuals with metabolic disease, for example, have a less diverse, lower ‘richness’ microbiota, which is often linked to increased intestinal permeability, higher gut inflammation and more oxidative stress throughout the body. This increased oxidative stress then exacerbates the microbial dysbiosis, causing more inflammation and increased intestinal permeability – creating a vicious cycle effect. This cycle is linked with obesity and metabolic disorders. In healthy individuals who are at risk of developing such conditions, the diversity of the existing resident microbiota may be increased by the application of prebiotics or synbiotics, included within a healthy, diverse, high-fibre diet. These approaches may improve bacterial fermentation in the large intestine, resulting in increased production of important bacterial metabolites that help regulate host metabolism, including short-chain fatty acids.
Until a SARS-CoV-2 vaccine is available, supporting a diverse and complex gut microbiota through diet may contribute to maintaining health in at-risk populations. Despite the intense worldwide scientific efforts and collaborations, it is unlikely that an effective vaccine against COVID-19 will be widely available soon. In the meantime, we have to protect ourselves and our local ‘at-risk’ populations as best we can. We are learning more and more about the mechanisms of dietary fibre’s health effects, in which gut bacteria play a major role. Evidence suggests that keeping our gut microbiota as complex and diverse as possible by consuming a high-fibre diet (supplemented by fermented foods, probiotics and prebiotics) might help mitigate susceptibility to infections in general.
New synbiotic definition lays the groundwork for continued scientific progress
/in ISAPP Science Blog /by KCBy Karen Scott, Mary Ellen Sanders, Kelly Swanson, Glenn Gibson, and Bob Hutkins
When Glenn Gibson and Marcel Roberfroid first introduced the prebiotic concept in 1995, they also conceived that prebiotics could be combined with probiotics to form synbiotics. In 2011, Gibson and Kolida described additional criteria for defining synbiotics and proposed that synbiotics could have either complementary or synergistic activities.
In the past decade, nearly 200 clinical studies on synbiotics have been reported in the literature. Nonetheless, the term itself has been open to interpretation, and the existing definition – a probiotic plus a prebiotic – was inadequate to account for the synbiotic formulations described in the literature or available in the marketplace.
To provide clarity on the definition and lay the groundwork for progress in the years ahead, scientists working on probiotics, prebiotics, and gut health came together in an expert panel. The outcome of this panel, the ISAPP consensus definition and scope of the word synbiotic, has now been published in Nature Reviews Gastroenterology & Hepatology.
A diverse panel of experts
The panel of experts who met to discuss the definition of synbiotics in May, 2019, consisted of eleven interdisciplinary scientists in the fields of microbiology and microbial ecology, gastrointestinal physiology, immunology, food science, nutritional biochemistry, and host metabolism. The panel’s range of experience was important in order to ensure the definition made sense from different scientific perspectives. The panel met under the auspices of ISAPP and was led by Prof. Kelly Swanson.
An inclusive definition
Initially, it seemed logical that synbiotic could be defined as a combination of a probiotic and a prebiotic, with each component needing to meet the criteria for either probiotic or prebiotic according to the previous scientific consensus definitions (Hill, 2014; Gibson, 2017). However, as the group discussed different scenarios and combinations, it became clear that this narrow characterization of a synbiotic could place undue emphasis on the individual components of a synbiotic rather than the combination of these components. For example, the original definition would not include a combination of inulin (a prebiotic) with live microorganisms that did not have probiotic status, even if live microbes in the host selectively utilized inulin and the combination was shown to confer a health benefit.
The definition of synbiotic agreed upon by the panel is: “A mixture, comprising live microorganisms and substrate(s) selectively utilized by host microorganisms, that confers a health benefit on the host.”
The panel discussed exactly which microorganisms must be targeted by the substrate in a synbiotic and decided that the targeted ‘host microorganisms’ can include either autochthonous microbes (those already present in the host) or allochthonous microbes (those that are co-administered).
Further, the panel defined two distinct types of synbiotics: complementary and synergistic. In a ‘synergistic synbiotic’, the substrate is designed to be selectively utilized by the co-administered microorganism(s)—and do not necessarily have to be individual probiotics or prebiotics, as long as the synbiotic itself is health promoting. In a ‘complementary synbiotic’, an established probiotic is combined with an established prebiotic designed to target autochthonous microorganisms— therefore each component of a complementary synbiotic must meet the minimum criteria for a probiotic or a prebiotic.
The definition is purposefully inclusive, so a synbiotic could be established for different hosts, e.g. humans, companion animals, or agricultural animals. Even subsets of these hosts (those of a certain age or living situation) could be targeted by synbiotic products. Moreover, products may be called synbiotics if they target areas of the host’s body outside of the gut (e.g. the skin).
Implications for study design
According to the new definition, different types of studies must be designed for synergistic synbiotics versus complementary synbiotics. For the former, a single study must demonstrate both selective utilization of the substrate and a health benefit. For complementary synbiotics, however, it is only necessary to show a health benefit of the combined ingredients; it is not necessary to show selective utilization of the prebiotic substrate, since selective utilization should have already been established.
The panel remained open to different scientifically valid approaches to demonstrate selective utilization of the substrate. Further, the nature of the ‘health benefit’ was not prescribed, but to the extent biomarkers or symptoms are used, they must be validated.
Continuing scientific progress
The field of synbiotics is evolving – some studies exist to show human health benefits deriving from synbiotic ingredients. While the studies on individual components (probiotics and prebiotics separately) may guide those in the field, there is the possibility that we will find novel uses and applications for synbiotics in the years ahead.
Causality is an important issue that scientists will need to address in this field. The definition of synbiotics rests on an important concept originally advanced in the definition of prebiotics: evidence of health benefit plus selective utilization of the substrate by microbes must be demonstrated. More investigations of causal links between these two things will have to be explored; this is closely connected with ongoing work to uncover probiotic and prebiotic mechanisms of action.
This definition is a first step—and it is fully expected that the field will evolve in the years ahead as more data are generated on the benefits of synbiotics for human and animal hosts.
Find the ISAPP press release on this publication here.
See here for a previous ISAPP blog post on the synbiotic definition.
See below for ISAPP’s new infographic explaining the concept of synbiotics.
New Probiotic and Prebiotic Society Among Ibero-American Countries
/in News /by KCBy Prof. Gabriel Vinderola PhD, Associate Professor of Microbiology at the Faculty of Chemical Engineering from the National University of Litoral and Principal Researcher from CONICET at Dairy Products Institute (CONICET-UNL), Santa Fe, Argentina
On February 8, 2019, within the framework of the X Workshop of the Spanish Society for Microbiota, Probiotics and Prebiotics (SEMiPyP), the Ibero-American Society for Microbiota, Probiotics and Prebiotics (SIAMPyP) was established, with the aim of enhancing communication among researchers and clinicians from Spain, Portugal, Mexico and several South American countries.
SIAMPyP will build on 10 years of collaboration among experts from both sides of the Atlantic, who have come together as SEMiPyP with a common interest in the potential of the microbiome in human health and disease, in promoting and disseminating scientific discovery, in rigor of scientific evidence, and facilitating future research to the benefit of Ibero-America and the globe.
Currently, the plan is for SIAMPyP to convene biennial meetings, the first being planned for March 2021 (dependent on the state of the pandemic) in Madrid and subsequently in 2023 in Mexico City. Academic sessions of basic and clinical science will be presented in this context, taking advantage of common languages (Spanish and Portuguese) to establish synergies in Latin American countries and the Iberian Peninsula.
The SIAMPyP has fostered connections with other international academic and scientific societies with knowledge in microbiota, probiotics and prebiotics in the pediatric, gastroenterology and neurogastroenterology fields of various Spanish and Portuguese speaking countries, as well as with ISAPP. Likewise, it has the support of research-oriented pharmaceutical and food industries that seek to modulate the microbiota to benefit human health in various clinical settings with probiotics, prebiotics and postbiotics.
The current board of directors of SIAMPYP is chaired and represented by doctors from both continents, including the well-known scientists Dr. Francisco Guarner (former ISAPP board member, from Spain), Dr. Guiilermo Alvarez-Calatayud (Spain), Dr. Luis Peña (Spain), as well as Dr. Aldo Maruy (Peru), Dr. Christian Boggio (Argentina) and Dr. Ana Teresa Abreu (Mexico), in addition to members and consultants who support and strengthen it, divided by region, with Latin America being a region with several countries.
SIAMPyP welcomes scientific partners from all Ibero-American countries, at no cost. See www.siampyp.org for further information.
Hear from ISAPP board members in webinar covering probiotic and prebiotic mechanisms of action
/in Consumer Blog, News /by KCThis webinar is now complete — see the recorded version here.
New probiotic and prebiotic trials are published all the time – but when they show a health benefit, what do we know about the basic science behind it?
To provide insight into this topic, ISAPP has partnered with the International Life Sciences Institute (ILSI) Europe on a free webinar titled Understanding Prebiotic and Probiotic Mechanisms that Drive Health Benefits. This webinar helps scientists, members of the public, and media take a deep dive into what we know about the mechanisms of action of probiotics and prebiotics.
The live webinar is scheduled for Thursday, September 17, 2020 from 3 – 4:15pm Central European Time.
Short, 10-minute perspectives will be provided by the following top experts:
The presentations will be followed by a 35-minute live Q&A session, enabling participants to probe deeper into the science behind mechanisms of probiotics and prebiotics.
ILSI Europe is a non-profit organization that aims to improve public health and well-being from a science-based approach.
To learn more about probiotic mechanisms of action in advance of the webinar, see ISAPP’s blog post here.
¿Cómo permanecen vivos los probióticos hasta el momento de ser consumidos?
/in Consumer Blog /by KCPor Gabriel Vinderola, Dr. en Química, Investigador Principal del Consejo Nacional de Investigaciones Científicos y Técnicas (CONICET) en el Instituto de Lactología Industrial (INLAIN, CONICET-UNL) y Profesor Asociado de la Facultad de Ingeniería Química de la Universidad Nacional del Litoral.
Como docente-investigador, la mayor parte del tiempo se comparte con personas del ambito académico y científico. Pero a través de las actividades de divulgación, tengo también la posibilidad de interactuar con personas que no tienen formación en ciencias, pero que tienen curiosidad por el mundo científico. Una pregunta que me hacen a menudo es: “¿Es posible que los probióticos sigan vivos cuando están deshidratados y en una cápsula?” La respuesta es sí. Permítanme proporcionar algo de información básica sobre los probióticos y explicar mi respuesta.
La idea de consumir microbios vivos para promover la salud no es nueva. En 1907, Élie Metchnikoff, discípulo de Louis Pasteur, el padre de la microbiología, asoció el consumo de leches fermentadas que contenían lactobacilos vivos, con una vida prolongada y saludable en campesinos búlgaros (see here). Esta idea fue retomada más tarde por el concepto de probióticos: microorganismos vivos que, cuando se administran en cantidades adecuadas, confieren un beneficio para la salud del huésped (Hill et al. 2014). Son cuatro criterios sencillos y pragmáticos los permiten concluir si determinadas cepas de microorganismos reúnen las condiciones para ser consideradas probióticos. Los probióticos deben: i) estar correctamente identificados (género, especie, cepa); ii) ser seguros para el uso previsto; iii) estar respaldados por al menos un ensayo clínico en humanos que demuestre su eficacia; y iv) estar vivos en el producto, y en cantidades suficientes para ser eficaces, durante todo el período de conservación (Binda et al. 2020). Estar viables en el momento del consumo es una de las características clave de los probióticos.
La vida es la condición que distingue a los animales y las plantas de la materia inorgánica. La vida implica actividad metabólica y la capacidad de crecer y reproducirse. Para que la vida sea posible, deben darse ciertas condiciones ambientales, las cuales difieren para los distintos organismos. Para los microorganismos en general, la disponibilidad de agua y nutrientes, la temperatura adecuado y la ausencia de inhibidores de crecimiento (como la acidez o los antibióticos) son condiciones esenciales para su desarrollo. Sin embargo, es posible manipular ciertas condiciones para lograr un estado en el que el crecimiento puede ponerse en “stand-by”, pero el microorganismo seguirá vivo. Nosotros los humanos no podemos imaginarnos en una condición “en modo de espera”, en la que estemos vivos aún sin ninguna actividad metabólica, pero para los microbios esto sí es posible. Los probióticos pueden estar en alimentos (ciertos yogures, jugos de fruta, barras de cereales) o en suplementos alimenticios (cápsulas, píldoras, sachets) en un estado de “hibernación”, caracterizado por la ausencia de crecimiento, de reproducción, en espera a que se den las condiciones adecuadas para retomar la actividad metabólica. Esto último ocurre cuando los probióticos llegan al intestino, donde encuentran la temperatura adecuada, los nutrientes necesarios, la ausencia de inhibidores y el agua necesaria para retomar su actividad metabólica. Por lo tanto, en el caso de los microorganismos, hay una disociación de la vida y la actividad metabólica. Incluso sin tener ninguna actividad metabólica, pueden seguir vivos, pero en un estado de latencia.
Al abrir un suplemento alimenticio que contenga probióticos, probablemente encontraremos un polvo seco blanco. Así es como los microorganismos pueden estar en un estado de latencia, debido a un proceso tecnológico llamado liofilización. La liofilización es un proceso de dos etapas en el que las células primero se congelan rápidamente a temperaturas muy bajas (de -40 a -70°C, o menos, utilizando nitrógeno líquido, por ejemplo). Luego, el agua congelada se elimina mediante un proceso de evaporación a baja presión y baja temperatura, llamado sublimación. Este proceso elimina la mayor parte del agua de las células, dejando a los microorganismos en un estado de inactividad o latencia. La actividad de agua es la forma en que los científicos miden la disponibilidad de agua para los probióticos. Esta medida tecnológica oscila entre 0 (sin disponibilidad de agua) y 1 (con total disponibilidad agua). Una actividad de agua cercana a 0 impide el crecimiento. En los suplementos dietarios, la liofilización deja la actividad de agua en un valor menor a 0,2, lo que asegura que no se produzca actividad metabólica durante la vida útil del producto.
Células de un probiótico constituido por bifidobacterias liofilizadas (indicadas por un círculo rojo). Esta es una imagen de microscopía electrónica de barrido amplificada 10.000 veces. Las células están incrustadas en una matriz de polidextrosa deshidratada, sin agua.
Así es que sí, los probióticos en los suplementos alimenticios están vivos, a su manera. Este es el caso también de los probióticos incluidos en ciertos alimentos como barras de cereales. En el caso de alimentos con actividades de agua más cercanas a 1, como los yogures, las leches fermentadas, los quesos o los jugos de fruta que contienen probióticos, el factor que limita la actividad metabólica es la baja temperatura a la que se conservan estos productos, combinada en ciertos casos (como los yogures y jugos de fruta) con el bajo pH (o alta acidez) de estos productos. La combinación de baja temperatura y acidez es eficaz para mantener a las células probióticas en un estado de latencia, lo que impide la actividad metabólica que pueda provocar estrés celular y muerte a lo largo de la vida útil del producto. Sin embargo, aunque se controlen estrictamente los factores que impiden la actividad metabólica durante la conservación, puede producirse cierta pérdida de viabilidad celular durante la vida útil de los probióticos en los productos que los contienen. En este caso, se agregan cantidades adicionales de probióticos para que la concentración de células viables necesaria para proporcionar un efecto benéfico sea la adecuada hasta el final de la vida útil del producto.
En los alimentos y suplementos probióticos, el número de células viables se expresa comúnmente como un número de unidades formadoras de colonias, abreviado “UFC”. Como los probióticos están presentes en altas concentraciones, el número de células viables suele alcanzar los miles de millones dentro de una cápsula o en una porción de yogur. Para poder contar un número tan grande de células, los microbiólogos deben hacer diluciones sucesivas del producto probiótico. Luego, pondrán una pequeña gota de las mayores diluciones en la superficie de una placa de Petri que contiene un medio de cultivo en el que crecerán los probióticos. Cada célula probiótica (o grupo de células) es una unidad formadora de colonias, que crecerá en su lugar y formará una colonia visible que puede ser observada a simple vista, y contada.
Placa de medio de cultivo que contiene colonias de una bacteria probiótica. Las células depositadas en la superficie del medio de cultivo se duplicaron varias veces hasta formar una cantidad visible de células: una colonia.
En síntesis, los probióticos están presentes en los alimentos y suplementos como cultivos vivos, pero en un estado de vida diferente al de los organismos superiores. Durante la vida útil de los probióticos, la actividad metabólica se detiene mediante la liofilización (en el caso de suplementos alimenticios) o mediante una combinación de baja temperatura y acidez (en el caso de yogures y jugos de fruta con probióticos, por ejemplo). El crecimiento activo de los probióticos suceso otra vez cuando estos microorganismos entran en el intestino y encuentran las condiciones adecuadas de nutrientes, temperatura, acidez y agua para estar activos y producir sus efectos benéficos sobre la salud.
How do probiotics stay alive until they are consumed?
/in Consumer Blog, ISAPP Science Blog /by KCBy Prof. Gabriel Vinderola PhD, Associate Professor of Microbiology at the Faculty of Chemical Engineering from the National University of Litoral and Principal Researcher from CONICET at Dairy Products Institute (CONICET-UNL), Santa Fe, Argentina
See the Spanish version of this blog post here.
As a professor, most of my days are spent with people from the academic and scientific world. But through some outreach activities, I am also fortunate to interact with many people who are not scientists by training, but have curious, scientific minds. One question I am often asked is, “Is it really possible for probiotics to still be alive when they are dried and in a capsule?” The answer is yes. Let me provide some basic background on probiotics and explain my response.
The idea of consuming live microbes to promote health is not new. Back in 1907, Élie Metchnikoff, a disciple of Louis Pasteur, the father of microbiology, associated the intake of fermented milks containing live lactobacilli, with a prolonged and healthy life in Bulgarian peasants (see here). This idea was later captured by the concept of probiotics: live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (Hill et al. 2014). Four simple and pragmatic criteria allow one to conclude if specific strains of microorganisms qualify as a probiotic for use in foods and dietary supplements. Probiotic strains must be (i) sufficiently characterized; (ii) safe for the intended use; (iii) supported by at least one human clinical trial showing they are effective; and (iv) alive in the product at an efficacious dose throughout shelf life (Binda et al. 2020). Being alive at the moment of consumption is one of the key characteristics of probiotics.
Life is the condition that distinguishes animals and plants from inorganic matter. Life includes the capacity for growth, for reproduction and for metabolic activity. In order to sustain life, certain environmental conditions must be met, but these differ for different organisms. For microbes, the availability of water and nutrients, adequate temperature and pH (acidity), and the absence of growth inhibitors are essential conditions. However, it is possible to manipulate certain conditions to bring about a state where growth may be put in “stand-by mode”, yet the microbe remains alive. We cannot imagine ourselves in a condition where life is preserved even without any metabolic activity, but for microbes it is possible. Probiotics can be in foods (yoghurts, fermented milks, fruit juices, cereal bars) or in food supplements (capsules, compressed pills) in a “hibernation” state, characterized by no growth, no reproduction and no metabolic activity, waiting for the proper conditions to come back to full metabolic life. This occurs when the microbes reach the gut, which has proper temperature, nutrient availability, lack of inhibitors, adequate acidity and water. Thus, in case of microbes, there is an uncoupling of life and metabolic activity. Even without having any metabolic activity, they can still be alive, but in a dormant state.
Open a food supplement containing probiotics and you will probably find a white dry powder. This is what the microbes may look like in their dormant state, due to a technological process called freeze-drying or lyophilization. Freeze-drying is a two-stage process where cells are first quickly frozen at very low temperatures (-40 to -70°C, or less, using liquid nitrogen for example). Then, frozen water is removed by a gentle process of evaporation at low pressure and temperature, called sublimation. This process removes most of the water from around and inside the cells, leaving the microbes in a dormant state. Water activity is scientists’ way of measuring water availability for the microbes. This technological measure ranges from 0 (no water) to 1 (pure water). A water activity close to 0 impairs growth. In food supplements, freeze-drying leaves water activities less to 0.2, ensuring that no metabolic activity will take place during the shelf life of the product.
Bifidobacteria cells (circled in red) freeze-dried in a probiotic powder. This is a scanning electron microscopy image amplified 10,000 times. Cells are embedded in dry polydextrose.
So yes, probiotics in food supplements are alive in their own way. This is the case also for probiotics included in certain foods such as cereal bars. In case of food products with water activities closer to 1, such as yogurts, fermented milks, cheeses or fruit juices containing probiotics, the factor that limits metabolic activity is the low temperature at which these products are stored, combined in certain cases (yogurts, fermented milks, fruit juices) with the low pH (or high acidity) of these products. The combination of low temperature and acidity is effective in maintaining probiotic cells in a dormant state, impairing any metabolic activity that may lead to cell stress and cell death along the shelf life of the product. Yet, even while tightly controlling factors that impair metabolic activity, some cell death may occur during the shelf life of probiotics in the products that deliver them. In this case, responsible manufacturers are sure to add extra probiotic cells so that the necessary amount of viable cells needed to deliver a health effect are present through the end of the shelf life of the product.
In both probiotic foods and food supplements, the number of viable cells is commonly expressed as a certain number of colony forming units, or by the abbreviation “CFU”. As probiotics are present in high concentrations, the number of viable cells often reaches into the billions within a capsule or in a serving of yogurt. To be able to count such enormous numbers of cells, microbiologists must make serial dilutions of the probiotic product. Then, they will put a small drop of a dilution on the surface of a Petri dish containing a culture medium on which probiotics will grow. Each probiotic cell (or clump of cells) will grow in place and form a visible colony that can be observed to the naked eye, and counted.
Agar plate containing colonies of a probiotic bacteria. Cells deposited on the surface of the agar plate duplicated several times until forming a visible amount of cells: a colony.
In brief, live probiotics are present in food and supplements, but in a state of life different to that of higher organisms where metabolic activity is taking place at all times. During shelf life, the metabolic activity of probiotics is stopped by freeze-drying them (food supplements) or by a combination of low temperature and acidity (yogurts and fruit juices, for example). Active growth returns when these microbes enter out gut and find the proper conditions of nutrients, temperature, acidity and water to be active and deliver their health effects.
EFSA’s QPS committee issues latest updates
/in ISAPP Science Blog /by KCBy Bruno Pot, PhD, Vrije Universiteit Brussel and Mary Ellen Sanders, PhD, Executive Science Officer, ISAPP
On July 2nd, the European Food Safety Authority (EFSA) published the 12th update of the qualified presumption of safety (QPS) list, a list of safe biological agents, recommended for intentional addition to food or feed, covering notifications from October 2019-March 2020. It was good news to all stakeholders to see that EFSA discussed the recent taxonomic changes within the genus Lactobacillus (see ISAPP blog here) as well as addressed some microbes being considered as potential, novel probiotics.
What is QPS?
In 2005 EFSA established a generic approach to the safety assessment of microorganisms used in food and feed, prepared by a working group of the former Scientific Committee on Animal Nutrition, the Scientific Committee on Food and the Scientific Committee on Plants of the European Commission. This group introduced the concept of “Qualified Presumption of Safety” (QPS), which described the general safety profile of selected microorganisms. The QPS process was mainly developed to provide a generic pre‐evaluation procedure harmonized across the EU to support safety risk assessments of biological agents performed by EFSA’s scientific panels and units. A QPS assessment is performed by EFSA following a market authorisation request of a regulated product requiring a safety assessment. Importantly, in the QPS concept, a safety assessment of a defined taxonomic unit is performed independently of the legal framework under which the application is made in the course of an authorisation process.
QPS status is granted to a taxonomic unit (most commonly a species), based on reasonable evidence. A microorganism must meet the following four criteria:
1. Its taxonomic identity must be well defined.
2. The available body of knowledge must be sufficient to establish its safety.
3. The lack of pathogenic properties must be established and substantiated (safety).
4. Its intended use must be clearly described.
Any safety issues, noted as ‘qualifications’, that are identified for a species assessed under QPS must be addressed at the strain or product level. Microorganisms that are not well defined, for which some safety concerns are identified or for which it is not possible to conclude whether they pose a safety concern to humans, animals or the environment, are not considered suitable for QPS status and must undergo a full safety assessment. One generic qualification for all QPS bacterial taxonomic units is the need to establish the absence of acquired genes conferring resistance to clinically relevant antimicrobials (EFSA, 2008).
If an assessment concludes that a species does not raise safety concerns, it is granted “QPS status”. Once EFSA grants a microorganism QPS status, it is included on the “QPS list” and no microorganism belonging to that group needs to undergo a full safety assessment in the European Union.
The QPS list is re‐evaluated every 6 months by the EFSA Panel on Biological Hazards based on three “Terms of Reference” (ToR)*. This evaluation is based on an extensive literature survey covering the four criteria mentioned above.
What happened to the genus Lactobacillus?
In April 2020, based on a polyphasic approach involving whole genome sequencing of more than 260 species of the former genus Lactobacillus, the genus was reclassified into 25 genera including the emended genus Lactobacillus, which includes host-adapted organisms that have been referred to as the L. delbrueckii group, the earlier described genus Paralactobacillus as well as 23 novel genera, named Acetilactobacillus, Agrilactobacillus, Amylolactobacillus, Apilactobacillus, Bombilactobacillus, Companilactobacillus, Dellaglioa, Fructilactobacillus, Furfurilactobacillus, Holzapfelia, Lacticaseibacillus, Lactiplantibacillus, Lapidilactobacillus, Latilactobacillus, Lentilactobacillus, Levilactobacillus, Ligilactobacillus, Limosilactobacillus, Liquorilactobacillus, Loigolactobacilus, Paucilactobacillus, Schleiferilactobacillus, and Secundilactobacillus. Read more in the original paper here or on the ISAPP blog here).
These name changes could have considerable economic, scientific and regulatory consequences, as discussed during an expert workshop organised by the Lactic Acid Bacteria Industrial Platform (LABIP). One of the points discussed during this workshop was the possible implication of the name change on the QPS list in Europe and the FDA’s GRAS list in the USA.
What did EFSA do?
In a 42-page document, which can be found here, amongst others, the species of the former genus Lactobacillus that were already listed on the QPS list, have been formally renamed at the genus level. The species names remained the same, as the taxonomic revision from April 2020 only affected the genus name. As a result, the genus names of 37 former Lactobacillus species on the QPS were updated, and now span 13 different genera. Table 1 delineates these nomenclature updates.
Table 1: Taxonomic revision of the 37 species formerly of the Lactobacillus genus present on the QPS list (published here).
EFSA further specifies that “To maintain continuity within the QPS list, all the strains belonging to a previous designed Lactobacillus species will be transferred to the new species. Both the previous and new names will be retained”. (Emphasis added.)
Impact of the QPS update on the probiotic field
The probiotic field can also take note of this current update for its review of two ‘next generation’ probiotic species evaluated for possible QPS status, Akkermansia muciniphila and Clostridium butyricum. Akkermansia muciniphila has been actively researched as a probiotic to help manage metabolic syndrome (Depommier et al. 2019). A probiotic preparation containing both Akkermansia muciniphila and Clostridium butyricum has been studied in a randomized controlled trial for postprandial glucose control in subjects with type 2 diabetes (Perraudeau et al 2020). The committee’s decisions:
The publication of the next scientific opinion updating the QPS list is planned for December 2020, based on the 6-month assessments carried out by the BIOHAZ Panel.
Conclusion
Due to its scientific rigor and continuous updates, the EFSA QPS efforts provide useful perspective for the global scientific community on safety of candidate microbes for use in foods. Their embrace of the new taxonomic status of lactobacilli signals to other stakeholders that it is time to start the process of doing the same. Further, their assessment of species being proposed and studies as ‘next generation’ probiotics is an important reminder that a microbe’s status as a human commensal is not a guarantee of its safety for use in foods.
*QPS Terms of Reference (ToR) (quoted from here):
ToR 1: Keep updated the list of biological agents being notified in the context of a technical dossier to EFSA Units such as Feed, Pesticides, Food Ingredients and Packaging (FIP) and Nutrition, for intentional use directly or as sources of food and feed additives, food enzymes and plant protection products for safety assessment.
ToR 2: Review taxonomic units previously recommended for the QPS list and their qualifications when new information has become available. The latter is based on a review of the updated literature aiming at verifying if any new safety concern has arisen that could require the removal of the taxonomic unit from the list, and to verify if the qualifications still efficiently exclude safety concerns.
ToR 3: (Re)assess the suitability of new taxonomic units notified to EFSA for their inclusion in the QPS list. These microbiological agents are notified to EFSA and requested by the Feed Unit, the FIP Unit, the Nutrition Unit or by the Pesticides Unit.
New publication addresses the question: Which bacteria truly qualify as probiotics?
/in News, ISAPP Science Blog /by KCAlthough the international scientific consensus definition of probiotics, published in 2014, is well known—”live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”—the word is often used incorrectly in practice.
A recent article published in Frontiers in Microbiology builds on this definition and describes four criteria for accurate use of the word ‘probiotic’. Eight scientists co-authored the paper, including two ISAPP board members. The project was initiated by industry scientists affiliated with IPA Europe.
The authors explain why it’s important for scientists and companies to be sure the four identified criteria apply before using the term ‘probiotic’. Given the many misuses of the term that are evident today, however, consumers need to scrutinize ‘probiotic’ products to be sure they are legitimate.
Read the ISAPP press release on this publication here.
See an infographic summary of this publication here.
GG + BB-12 don’t reduce antibiotic use in an elderly, institutionalized population
/in Consumer Blog, ISAPP Science Blog /by KCBy Mary Ellen Sanders, PhD, ISAPP Executive Science Officer
Close to two years ago, a team convened by ISAPP conducted a meta-analysis showing that probiotics may reduce number of antibiotic prescriptions, with evidence primarily in children (ISAPP-initiated systematic review and meta-analysis shows the association of probiotic consumption with reduced antibiotic prescriptions). A recent study suggests that this outcome likely does not extend to elderly care home residents.
A newly published randomized, placebo-controlled trial tested a combination product comprising two well-studied probiotic strains, Lacticaseibacillus (formerly known as Lactobacillus) rhamnosus GG and Bifidobacterium animalis subsp lactis BB-12, administered at ~1.5 × 1010 per day to institutionalized residents 65 years of age or older to test if this treatment reduced antibiotic administration. The study showed no reduction in antibiotic use compared to the control. Further, the probiotic was not associated with improvement in secondary endpoints, which included many that probiotics are hypothesized to mitigate, including incidence of common infections, duration of infections, C. difficile infection, antibiotic associated diarrhea, hospitalizations, or presence of antibiotic resistant microbes in fecal samples.
Other endpoints suggested that the probiotic group fared worse than the placebo group. Statistically significant differences were found between the probiotic and placebo groups for antibiotics administered for lower respiratory tract infections and well-being scores at 3 months.
This was a well-controlled, comprehensively reported study. Some factors to consider in interpreting these results: The population was elderly (mean age = 85.3 years) and infirmed (66% lacked capacity to consent and 63 of 310 randomized subjects died prior to conclusion of the study). Stool culture at 3 months showed L. rhamnosus present in 84% of intervention group compared to 37% of placebo group, although the groups were matched for this factor at baseline. This suggests some cross-contamination between the placebo and intervention groups may have occurred. As the authors state, exposure of the placebo group to the probiotic “would dilute any between-group differences in outcomes.” A higher number of C. diff positive subjects were assigned to the probiotic group than the placebo group (7.2% vs 0%, respectively).
Overall, this study provides evidence that L. rhamnosus GG + B. lactis BB-12 are not effective prophylactically in a population of elderly care home residents.
Bulgarian yogurt: An old tradition, alive and well
/in Consumer Blog, ISAPP Science Blog /by KCBy Mariya Petrova, PhD, Microbiome insights and Probiotics Consultancy, Karlovo, Bulgaria
Family and family traditions are very important to me. Some of you may have seen my previous blog post on fermented food and my father’s tradition of making fermented cabbage and vegetables every autumn. Of course, this is not limited to my family – in Bulgaria, it is our culture and our country’s tradition. But despite the fact that I wrote about fermented vegetables first, Bulgarians are much more proud of another fermented product – yogurt.
I still remember waking up every morning when I was a kid and having a healthy homemade yogurt to start the day. I still do when I am back at home, because my father continues to make yogurt at home. Here, I’ll take you on a new adventure and tell you all about Bulgarian yogurt, an old tradition still alive in every home.
Élie Metchnikoff and his work are well familiar to anyone involved in probiotic research. In short, Metchnikoff observed in 1907 that Bulgarian peasants lived longer lives and he attributed this to their daily consumption of yogurt.
We are so proud of our yogurt that many Bulgarians will tell you that ancient Bulgarian tribes were the ones who discovered yogurt by accident. Since Bulgarian tribes were nomadic, they carried the milk in animal skins, which created an environment for bacteria to grow and produce yogurt. This is indeed the way people learned to make yogurt, but it most likely happened in many places independently. Of course, I know many countries make yogurt but I remain proud of all the discoveries that happened in my country (I am saying this because at times I have been judged when I tried to say how important we find the yogurt in Bulgaria and how proud we are).
Yogurt is a tradition in Bulgaria. I don’t know a Bulgarian who does not eat yogurt on a daily basis, up to a few pots per day. And I am not talking about those sweet yogurt products that are made by adding jam or vanilla. I am talking about real, natural yogurt, slightly sourer than most of the products that can be found in the Western world. We add yogurt to almost everything, it is just the perfect addition. It is even the basis of a traditional Bulgarian cold summer soup called “tarator,” made of yogurt, water, cucumber, garlic, and dill. We also make a salad with it called “snezhanka”, and it contains yogurt, cucumbers, garlic, and walnuts. (Recipes can be found below if you want to try something new during the lockdown.) In fact, I am so “addicted” to our yogurt that in every country I go to, the first thing I have do is to find a good yogurt. It took me years to find a good one in Belgium when I lived there (even though one product was labelled ‘Bulgarian yogurt’, it was not the same for sure). In Canada, it was somehow easier. After trying a few different products, it was even faster to find something that I like in the Netherlands, but they have many kinds of milk products. Yet none of them are truly comparable with what you can find in Bulgarian shops. Even the smallest shops have at least 3 to 4 different types because we have a lot of yogurt factories. Every product is different, it has a unique taste and can be made of different kinds of milk.
How to make it, you may ask?
So you need fresh milk, which my family in Bulgaria currently gets from a local farm. The milk is carefully boiled, and while it is still warm, transferred to a preferable container where you want to make the yogurt. We use old yogurt jars that were very popular before. For some time, my father also used Tupperware, so you can choose anything that you find handy. Before transferring the milk, my father also separates the cream from the milk in a separate jar and uses it to make homemade butter by constantly shaking the jar for around 10 minutes (it is an intensive workout, I tried it a few times!). The biggest problem these days is having a good starter culture so you can begin the milk fermentation. As a starter culture, most of the people, including my father, use a spoon or two of the previous batch of yogurt. So my father never finishes all the yogurt; he always makes sure that there are some leftovers so he can start a new fermentation. He usually adds one tablespoon of the old yogurt to 500 ml warm milk (around 45 C). Of course if the milk is too hot, the bacteria present in the starter culture will die, and nothing will happen. There is also the case that the milk is too cold, and then it will most likely still ferment, but it will have a strange consistency, something between milk and yogurt. If my father is out of old yogurt to start a new fermentation, he usually buys his favorite yogurt from the shop and uses this as starter. Once the jars are filled, he packs blankets all around them to keep the environment warm so the fermentation will begin. From here, you need around 4h to 5h to have a nice homemade yogurt. Simple and straightforward. The next morning you can have a great family breakfast, remembering the old traditions, talking about old memories, passing on the torch to the new generation, and enjoying a healthy start to the day.
The next time you have yogurt, I hope you enjoy it and remember the Bulgarian traditions!
Tarator soup recipe:
What you need: 1 cucumber, 250 -300 g yogurt, 1-2 cloves crushed garlic, salt, oil, water, fresh chopped dill. (Most of the ingredients depend on your taste so feel free to add more or less of certain ingredients. Some people also add parsley and walnuts, but it is up to your taste.)
How to make it: Peel and cut the cucumbers into cubes and put them in a preferred bowl; add the crushed garlic, and the minced dill. Beat the yogurt until it turns to liquid and mix it with the rest of the ingredients. Add salt and oil to taste. Add water to make the soup as liquid as you like. Put into the refrigerator to cool it. You can also make it with cold yogurt and cold water. It is perfect for the hot summer days.
Snezhanka (which means “Snow White” in Bulgarian) salad recipe:
What you need: 1 cucumber, 500 g yogurt, 1-2 cloves crushed garlic, 2-3 spoons ground walnuts, salt, oil, fresh chopped dill. (Again, it depends on your taste, if you like more cucumber or yogurt just add more.)
How to make it: First strain the yogurt for a couple of hours, so that all unnecessary water is drained away. Peel and cut the cucumbers into cubes and put them in the bowl. Add the strained yogurt. Add the fresh dill, salt and oil to taste. Sprinkle the walnuts on top of the salad. Perfect for all seasons. If you don’t have a fresh cucumber, you can also use pickles — the final result is also very delicious.
Early career researchers discuss the future of probiotics and prebiotics in the first ISAPP-SFA paper
/in News, ISAPP Science Blog /by KCBy Irina Spacova, ISAPP-SFA 2019 President and postdoctoral fellow at the University of Antwerp, Belgium
Early career scientists play a vital and dynamic role in research, especially in environments supporting their enthusiasm and drive for innovation. ISAPP has long been promoting young researchers through its Students and Fellows Association (ISAPP-SFA), which is a student-led branch of ISAPP established in 2009. The SFA was championed and guided from its inception through June 2020 by Prof. Gregor Reid. Together with ISAPP, the organization encourages diversity and participation through free memberships and ISAPP meeting travel grants open to all students and fellows working in research institutions. Currently, ISAPP-SFA includes 450 members from 50 countries in Asia, Africa, North and South America, Europe, and Australia.
The 2019 ISAPP meeting in Antwerp, Belgium was a milestone for ISAPP-SFA participation with 48 early career attendees from 19 countries. Facilitated by discussion clubs and poster sessions, the Antwerp meeting created an exceptional ‘melting pot’ of ideas. It was clear that young researchers had a lot to say, and the lingering idea of creating the first ISAPP-SFA paper finally took shape during the ISAPP 2019 dinner cruise of the Antwerp Harbor.
Less than a year later, the paper “Future of probiotics and prebiotics and the implications for early career researchers” was accepted in Frontiers in Microbiology, just in time for the 2020 ISAPP meeting. This initiative was driven by the ISAPP-SFA 2019 executive committee members Irina Spacova, Hemraj Dodiya, Anna-Ursula Happel, Conall Strain, Dieter Vandenheuvel, and Xuedan Wang. The core of the paper reflects what we as early career researchers believe are the biggest opportunities and challenges in advancing probiotic and prebiotic science, and summarizes a wide array of promising in vitro, in vivo and in silico tools. We emphasize the important goal of using probiotics and prebiotics to ameliorate global issues, and give examples of current initiatives in developing countries, such as Westernheadseast.ca and Yoba4Life.org. Our advice for early career researchers is to form inter-connected teams and implement the diverse toolsets to further advance the probiotics and prebiotics field.
We had a lot of fun with this paper, but also several challenges. It was not trivial to produce a concise paper with many opinions, techniques and references that would be useful to both young and established researchers. This intercontinental endeavor between young scientists working in Belgium, Japan, Ireland, South Africa, USA, and UK required a lot of early-morning and late-night meetings. Many interactions and discussions were necessary to deliver a novel perspective to add to the many excellent reviews on probiotics and prebiotics already published. Accessibility of the publication was a decisive factor, and one of the reasons why we chose to publish open access in Frontiers in Microbiology. Of course, this publication would not be possible without ISAPP, and we are especially grateful for the input and encouragement from Gregor Reid and Mary Ellen Sanders.
60 Minutes’ 13 minutes on probiotics
/in ISAPP Science Blog /by KCBy Mary Ellen Sanders, PhD, ISAPP Executive Science Officer
On June 28, 60 Minutes aired a 13-minute segment about probiotics titled, “Do Probiotics Actually Do Anything?” Unfortunately the media segment did not provide listeners with a nuanced perspective.
‘Probiotics’ were treated as if they were one entity, ignoring the best approach to addressing the topic of what probiotics do: evaluate the evidence for specific strains, doses and endpoints, and then make a conclusion based on the totality of the evidence. They would have found that many experts agree that actionable evidence exists for certain probiotics to prevent antibiotic associated diarrhea (here, here), prevent upper respiratory tract infections (here), prevent morbidity and mortality associated with necrotizing enterocolitis (here,), treat colic (here), and treat acute pediatric gastroenteritis (here). (For an overall view of evidence, see here.)
Importantly, not all retail probiotics have evidence (at least evidence that is readily retrievable, see here and here). But that does not mean that none do.
The 60 Minutes segment also highlighted questions about probiotic safety. No intervention is without risk, and no one claims as much for probiotics. Prof. Dan Merenstein, MD, just one clinical investigator of probiotics, has collected over 20,000 pediatric clinical patient days’ worth of safety data over the past eight years of clinical investigation, with no indication of safety concerns. In fact, participants in the placebo group generally have more adverse events than in the probiotic groups. But importantly, the safety standard for probiotics was mischaracterized by 60 Minutes. According to Dr. James Heimbach, a food safety expert (not interviewed in the segment) who has conducted 41 GRAS determinations on probiotics, over 25 of them notified to the FDA, he objects to the statement that GRAS is a lower safety bar than a drug. He clarifies:
Finally, the story implied that benefits people claim for themselves when using probiotics are due to a placebo effect. This ignores the many properly controlled studies directly comparing the effects of specific probiotics to placebos. A positive trial on probiotics, such as observed in this recent trial on irritable bowel syndrome symptoms (here) and in most trials included in Cochrane meta-analyses on prevention of C. difficile-associated diarrhea (here), means that positive effects were observed beyond any placebo effect. The placebo effect is real, equally applicable to probiotics and drugs, but as with all clinically evaluated substances, properly controlled trials control for this effect.
The probiotic field has come a long way over the past 20 years with regard to number and quality of clinical trials. In that time, well-done systematic reviews of the evidence have found benefits for specific probiotics for specific conditions, while also finding a lack of evidence for beneficial effects in other contexts. There are of course well-conducted clinical trials that have failed to demonstrate benefit (here, here, here). This should not be equated to mean that probiotics do not do anything.
Many challenges remain for improving the quality of the evidence across the wide range of different strains, doses, endpoints and populations. More clinical research needs to be conducted in a manner that minimizes bias and is reported according to established standards. Confidence in the quality of commercial products could be improved by industry adopting third party verification (here), and the quality of products targeting compromised populations need to be fit for purpose (here). Companies should stop using the term ‘probiotic’ on products that have no evidence warranting that description. We need to understand much better how a person’s individual situation, such as diet, microbiome, use of medications and fitness, impact the ability of a probiotic to promote health. Much remains to be learned in this evolving and exciting field. As Dr. Merenstein says, “The key question is not, ‘Do probiotics actually do anything?’, as that is easily answered ‘yes’ when you look at robust placebo-controlled trials of specific probiotics. Better questions are ‘Which probiotics do anything, and for what?’”
Further reading:
Misleading press about probiotics: ISAPP responses
ISAPP take-home points from American Gastroenterological Association guidelines on probiotic use for gastrointestinal disorders
New publication gives a rundown on probiotics for primary care physicians
Safety and efficacy of probiotics: Perspectives on JAMA viewpoint
Are prebiotics good for dogs and cats? An animal gut health expert explains
/in Consumer Blog, ISAPP Science Blog /by KCBy Kelly S. Swanson, PhD, The Kraft Heinz Company Endowed Professor in Human Nutrition, University of Illinois at Urbana-Champaign, USA
Pet dogs and cats are cherished companions. In developed countries, many households with pets treat them like family members. Similarly to humans, a high level of nutrition and veterinary care promotes health and longevity. As people become more aware of what they feed themselves and their human family, they make the same considerations for their canine and feline companions. Pet food trends have closely followed those of the human food industry over the last couple decades, with high-quality natural and organic foods gaining popularity.
One way pet food companies have enhanced their products is by incorporating functional ingredients into their formulas. Functional ingredients provide benefits beyond that of their nutrient content. One of the most popular target areas for functional ingredients is pet gastrointestinal health, with structure/function claims of “supporting digestive health”, or something similar, being quite common. Loose stools, constipation, and various gastrointestinal disorders and diseases such as inflammatory bowel diseases and irritable bowel syndrome are common in pets. The task of “poop scooping” after the dog in the park or cleaning out the cat’s litterbox provides owners with an opportunity for daily assessment of stool quality and serves as a reminder of how important diet is to gut health.
Benefits of prebiotics for pets
Many ingredients, including dietary fibers, prebiotics, probiotics, synbiotics, postbiotics, and other immunomodulators may provide gastrointestinal benefits to pets, but today we will focus on prebiotics. The most recent ISAPP expert consensus panel on prebiotics clarified that the prebiotic concept not only applies to humans, but also to companion and production animals (Gibson). Dogs and cats evolved as Carnivora, mainly consuming high-protein, high-fat diets that were low in fiber, and their short, simple gastrointestinal tracts have a limited capacity to ferment non-digestible substances. Nonetheless, they possess an active microbiota population, primarily in the colon, that may be manipulated by diet to impact health.
Most prebiotic research in pets has focused on the gastrointestinal tract. Prebiotic administration has been shown to reduce the incidence or severity of infections (Apanavicius; Gouveia), improve stool consistency (Kanakupt), and beneficially shift fecal microbiota and metabolite profiles (Propst). A few have reported the benefits that prebiotics may have on metabolic health, demonstrating improved glucose metabolism and insulin sensitivity in pets consuming prebiotics (Respondek; Verbrugghe). Since we’re looking at foods rather than at medicines that address disease, the majority of research has been conducted in healthy animals so evidence of health improvements in diseased pets is sparse.
Types of pet-friendly prebiotics
Although a few studies have tested galactooligosaccharides (GOS), mannanoligosaccharides, and other potential prebiotics, by far the most common prebiotics studied and present in pet foods are the non-digestible fructans. Natural sources, such as chicory, or isolates and extracts that have a high purity, including short-chain fructooligosaccharides (FOS), oligofructose, and inulin, are all present in pet foods.
Which pets benefit most?
Similar to dietary fiber, the need for prebiotic inclusion is dependent upon diet type and formulation. Animals consuming plant-based diets that are rich in natural fibers and non-digestible oligosaccharides likely do not require additional fermentable substrate in the formula. Dogs and cats fed high-protein, meat-based diets, however, typically have greater fecal odor, a higher colonic pH, and higher density of potential pathogens due to a high rate of protein fermentation. In those diets, prebiotic inclusion may help animals normalize their gut microbiota abundance and metabolism.
Prebiotics may be fed to all pets, but will likely provide the greatest benefits to geriatrics, animals who are or have received antibiotics, those under high stress conditions, or those with certain gastrointestinal disorders. The low caloric density of prebiotics and the metabolic benefits that come from their fermentation will be most beneficial to pets with obesity and diabetes. As for all functional ingredients, dosage is important. When comparing dogs and cats, dogs usually can tolerate a higher dosage than cats. In regard to dog size, small dogs can typically tolerate a higher dosage (per unit body weight) than large dogs, which are more susceptible to loose stools. In most commercial pet foods, prebiotic inclusion levels are <0.5% of the formula to limit side effects.
Further research on prebiotic substances
Using the powerful tools that are now available to study gut microbiota and host physiology, future research can hopefully determine what microbes are most important to the health of dogs and cats and identify mechanisms by which prebiotics provide health benefits to pets. Further testing, which may include plant-based ingredients, yeast-based products, and milk oligosaccharide mimics, will hopefully identify other prebiotic substances and continue to expand our knowledge in the field.
Kelly Swanson joined the ISAPP board of directors in June, 2020, providing valuable expertise in animal gut health and overall health. Swanson also chaired the 2019 ISAPP-led international consensus panel on the definition of synbiotics.
ISAPP’s popular educational videos now feature subtitles in multiple languages
/in News /by KCISAPP’s series of six English-language videos are a useful resource for helping consumers answer important questions about probiotics, prebiotics, and fermented foods. In order to make these popular educational videos accessible to a wider global audience, ISAPP has now updated them with subtitles in multiple languages: Dutch, French, German, Indonesian, Italian, Japanese, Russian, and Spanish.
Dr. Roberta Grimaldi, a principal clinical research scientist who served as ISAPP’s Industry Advisory Committee representative from 2017-2019, led the video subtitling efforts.
“The videos are a good way to communicate information about these products, which are still not fully understood by consumers,” says Grimaldi. She says that while consumers see “a lot of miscommunication and misleading information” online, the easy-to-understand ISAPP videos help bring the scientific perspective to a broad audience.
Multi-lingual members of the ISAPP community stepped up to help with the translations, with Grimaldi managing the task and co-ordinating with the video production agency. She says, “It was definitely an amazing team effort, which I think gave us really great results.”
Science Translation Committee head Dr. Chris Cifelli underlines how worthwhile the video subtitles project has been for ISAPP. “Since ISAPP is an international organization, we have been working hard to make our educational materials accessible to as many people as possible. The subtitles allow the information in these videos to be shared much more widely, ultimately helping consumers make more informed decisions about probiotics, prebiotics, and fermented foods.”
Many of ISAPP’s infographics are also available in multiple languages.