“Navigating the world of probiotics: Helping patients make good choices”
This 30-min CME activity, which took place on April 17th, by Medscape is now available online https://www.medscape.org/
“Navigating the world of probiotics: Helping patients make good choices”
This 30-min CME activity, which took place on April 17th, by Medscape is now available online https://www.medscape.org/
By Prof. Glenn Gibson
In just a few days ISAPP will host its first meeting outside of Europe or North America, when we have an open conference in Singapore1,2. There are about 200 registrants and we cannot wait. The meetings are always scientifically informative but fun also. These are main drivers behind our annual jamboree, but this year there is another task…… I am hoping that first timers to ISAPP, and particularly our Asian friends, break with tradition and pronounce the name of the organisation correctly.
I have written one blog in the 56 years of my existence. This first was last year on the various social events we have at the meetings. But this was prior to Chicago in 2017, where we had a bowling alley experience. My PhD student Xueden Wang (Holly) has never let us forget her winning efforts at this:
The above picture and Holly’s endless bragging came to an abrupt end however, when we had our lab Christmas party in December3 – also at a bowling alley this time in Wokingham UK:
Let’s call that revenge of the supervisor shall we? The open top bus parade is now cancelled Holly I am afraid. By the way, if you don’t know what Chicago or Wokingham look like, then both are pictured below. I will leave you to guess which is which:
Anyway, I disgress (justifiably). This is therefore my second blog, and there is a reason for dusting off the quill pen and rehearsing the hieroglyphics once more.
In the last few years ISAPP has published 2 consensus papers, one on probiotics and one on prebiotics4. What we cannot agree on, however, is how to say the name of our esteemed society. Some say ISAPP with the I as “eye”, while others say ISAPP (with the I as in sIt). Admittedly, there is a slight bias in numbers as it is possible to count on the fingers of one finger the number of people who use the latter. It is me. So, that makes about 852 attendees at previous ISAPP meetings incorrect.
Think of the full name of the ISAPP organisation and say it to yourself now…………………
Did anyone say Eye-Nternational? Or did you say International?
At this stage, I should just say that the case for the prosecution is concluded and no further witnesses your honour!
However, let’s look at things a little more closely. If the anarchists, heretics and Eye-Sappers get their way then we may need to change the logo of the organisation to:
We see the letter “I” in front of many things these days such as i pad, i mac , i max, i alex cross, i pod, i robot. A quick search of the internet (or as some say eyeNternet) suggests that the “I” can stand for individual, imagination or internet, but usually refers to intelligent. We might have to live with ISAPP standing for intelligent sapps. Here is a picture of 2 saps:
Still, 852 people can’t be wrong. I’ll put that another way – 852 people are wrong. So the spotlight turns to Singapore to show us the light, the truth and the way forward.
But……. It gets worse. The terms probiotic and prebiotic are not used on products in Europe now as they are an implied health benefit. Let’s put aside that the very body who devised this “rule” have turned down all but about one health claim. If we go along with this puffed up lunacy5 then we might have to call ISAPP:
International Scientific Association for @%?!&.. and @%?!&..
Maybe we can get away with just using the first letters of these disgustingly offensive, abhorrent and abusive terms. So, ISAPP becomes:
International Scientific Association for P@%?!&.. and P@%?!&..
It still does not seem right, so ISAPP becomes:
International Scientific Association for PAP
Now we are getting somewhere, as PAP means “Noun. 1. Nonsense, rubbish. 2. Faeces. Verb. To defaecate. e.g. ‘He was so scared he papped his pants.’.” This embodies exactly what ISAPP is all about and where pro/prebiotics work!!! So, I propose another new logo:
1I’ll be flying there with British Airways. One highlight is always the safety demo where they say “in the unlikely event that the plane should land on water.” I always feel that “unlikely” is not quite definitive enough. If you were to ask at check in about the chances of the 777 landing on water and the reply was “er… well…on balance it is unlikely”, you would probably not board the old crate.
2Travel tip: Always aim for row 13 and upon reaching it say “oh no, me and my luck, I’m in death row again”, it often leads to vacating of the seat next to you.
3Also attended by a group of leading food science researchers, who face such crucial issues as:
4By the way, in the olden days (1995) I wanted to call prebiotics parabiotics. Only because MASH was on TV at the time and featured paramedics. So these could be known as biotics that help medics.
5Please note that these opinions are those of the author and do not represent the views of EYESAPP, aside from Gregor.
The 2017 Annual Report on ISAPP’s activities to advance scientific excellence in probiotics and prebiotics is now available. The Report covers the 2017 Annual Meeting in Chicago IL, as well as the publications, webinars, meetings and other activities accomplished during the past year. Finally, ISAPP is grateful to the 43 Industry Advisory Committee Members who support ISAPP’s endeavors. See more here.
ISAPP Board member and Professor of Medicine, Dan Merenstein MD, served as faculty for a new continuing education activity on probiotics and prebiotics. “The Expanding Health Benefits of Prebiotics and Probiotics” was developed by Pharmacy Times and is available free of charge here (registration is required to log in to access the materials). This concise, practice-oriented review summarizes evidence for probiotic interventions for clinical conditions and is an excellent summary for all healthcare practitioners.
Prof. Dan Merenstein MD and Mary Ellen Sanders, PhD will present a 30 min webinar titled, “Navigating the World of Probiotics: Helping Patients Make Good Choices” April 17 at 12:30 ET*. Developed by Medscape, the target audience is medical professionals. Dr. Sanders will provide basic information about choosing probiotics and Prof. Merenstein will discuss the strength of evidence for different clinical applications for probiotics. The webinar is free, but you must register with Medscape to sign up. Register here.
*An earlier announcement by Medscape listed the wrong time zone.
Want some guidance on knowing which probiotic products have been tested for which clinical benefits, and understand the level of evidence supporting those benefits? Check out the 2018 versions of Clinical Guide to Probiotic Products Available in USA and Clinical Guide to Probiotic Products Available in Canada. Currently, these are the only 2 geographical regions covered by this initiative, although they are considering expanding to other regions. This guide is updated annually. Some changes for 2018 include addition of new indications ‘Mood and affect’, ‘Liver health’, ‘Weight management’ (Canada) and ‘Seasonal allergies’ and ‘Eczema/Dermatitis-Adult’ (United States). Evidence is reviewed independently by six academic experts and graded as Level I (highest), II or III. A grade of Level I requires evidence from at least one properly designed randomized human trial. This guide is produced by the Alliance for Education on Probiotics, and is an industry funded effort (see industry sponsors for US and Canadian versions).
Update April 16, 2018: Recording and slides from the webinar available here.
The International Scientific Association for Probiotics and Prebiotics (ISAPP), in partnership with the International Life Sciences Institute (ILSI) Europe’s Prebiotics and Functional Foods Task Forces, has jointly organized a free webinar, titled “Microbial Metabolism Associated with Health”. The webinar runs April 12th, 2018 at 15:00 CET, and will highlight recent activities of both ISAPP and ILSI on the beneficial aspects of gut microbial fermentation. The specific focus will be on gut microbiota functions, the effects of the intestinal microbiota on selected nutrients and non-nutrients, and the health benefits of fermented foods. Scientists from both academia and industry may find the webinar of interest. Sign up here.
Webinar participants will learn the status of the science making the links between live microorganisms in the diet and host health. The host gut microbiota is a key factor in determining gut function, nutritional status, biochemical transformations of food and the overall impact on health. This diverse microbial community inhabiting the human gut assists in food metabolism and contributes to the bio-availability of nutrients and non-nutrients; it also has an extensive metabolic repertoire that complements mammalian enzymes in the liver and gut mucosa. Microbial metabolism is an important factor to consider when discussing the management of host health and conditions such as obesity and metabolic syndrome.
The enhanced nutritional and functional properties of fermented foods are being increasingly recognized; not only do microbes transform the substrates and form bioactive or bioavailable end-products, but also, fermented foods contain live microorganisms genetically similar to the strains found in probiotics. The webinar will cover the possible interactions of fermented foods and beverages with the gut microbiota, and potential links to health.
The 90-minute live webinar will be hosted on StreamGo, and will include a question and answer period at the end. There is no cost; however, participants are required to register online beforehand.
Publications from ISAPP and ILSI-Europe related to the webinar topics:
by Dr. Colin Hill, APC Microbiome Ireland & School of Microbiology, University College Cork, Ireland
Many scientists have reservations about working with industry. While characterising it as going over to the dark side might be an overstatement, there is a certain wariness that principles may have to be compromised (in terms of the ambition of the work and the freedom to follow your nose that is the supposed hallmark of ‘pure’ research), dull routine work may have to be performed, and publication in the best journals will be unlikely. There may also be concerns that students or post-docs working on ‘industry’ projects may suffer from these constraints, which will restrict their career development. There can also be a perception that the ‘best’ scientists work on fundamental problems, unfettered by the demands of industrial partners or short-term commercial goals. Some of you reading this opening paragraph may be amused at the simplicity of this stereotyping – “no one really thinks like that” – but I can assure you that some do, including a younger version of myself.
I have only really worked closely with industry in the last decade. Before that, I wrote grants which assured potential funding agencies that what I wanted to investigate was incredibly relevant and important, would represent good value for the taxpayers’ investment, but was just a ‘little bit too early’ for industry to take on. I genuinely believed this for the most part, although part of getting older is learning that fooling myself has always been a much easier task than fooling anyone else. Nonetheless, I managed to forge a career in science. I had a reasonable success rate of about one in four or five applications, which still seemed a poor return for the effort involved. I would take my hard-earned funding and do my best to deliver on the promises I had made. On occasion, the grants were successful, and we ended up filing a patent or developing a prototype or a process and essentially delivering on the promises made in the grant application. But all too often I discovered that what we had achieved, or the problem we had solved, was not really the burning issue I had thought it to be, or at least could not be translated for the benefit of society without suitable industry partners. In essence, we had self-tasked ourselves to solve a problem that no one really needed to be solved (or, at least not yet, or not in the precise manner we had solved it).
Of course, on occasion I was successful in getting truly ‘fundamental’ or ‘basic’ grants which were simply aimed at generating knowledge, and these were absolutely vital in developing new skills and opening up new research areas and possibilities. However, over the past decade or more, I have begun to work closely with industry partners. At first, this was driven by changes in funding policy in Ireland which linked scientific excellence to industry relevance – grants had to pass rigorous peer-reviewed scientific assessment, but also had to be validated by an industry partner willing to put skin in the game in the form of co-funding. This necessitated finding industry partners and identifying a research problem together, before developing a solution. I hope that now I have a perspective on both aspects of scientific research – often simplistically referred to as basic versus applied research – and I have good news. Working with industry can be just as scientifically rewarding as not working with industry.
As I have experienced it, working with industry has several obvious advantages.
Are there negatives? Well, honestly, not all industry sponsored research involves cutting edge science. But if you are completely uninterested in the outcomes then don’t take it on. What about bias? Does industry funding create a bias towards positive outcomes? I genuinely have not found this to be the case. Reputable industry partners have no interest in biased results, since the company’s reputation is at stake and of course, no one is more invested in the scientific validity of their product than the industry partner. And given that science is ultimately self-correcting no reputable scientist wants to be associated with misleading outcomes. Individuals on either side can make mistakes or display bias, but that is no less true in the basic sciences.
The ideal academic-industry relationship recognises that there have to be rewards for both partners. For both it is really important that the experiments be conducted to the highest possible standards with appropriate controls. For the academic the right to publish the results in a timely fashion is particularly important when junior scientists are involved and a clear understanding of how results will be disseminated must be reached before the collaboration gets underway. For the industry partner, it is important that the work stay focused on the agreed goals of the project and not veer off into the ‘nice to know’ rather than ‘need to know’ areas of the research problem. As in most things, problems can be avoided by having a clear agreement on the goals, methods and publication strategy and having transparent reporting structures. Further, both sides must put effort into maintaining a good working relationship.
Finally, it is not a binary choice – working with industry obviously does not close off any other type of research you may want to perform. You can still write grants and get funding from other sources. In fact, I would propose that the ideal research mix requires an element of exploratory science to keep the laboratory fresh and industry-funded science to ensure relevance. And when in doubt always defer to the great Louis Pasteur, who said “There are no such things as applied sciences, only applications of science”.
Both webinars – eligible for continuing education credit – on probiotics involving ISAPP board members are scheduled. The first is scheduled for Thursday, March 15th 11am-noon CST. It features Mary Ellen Sanders, PhD on the topic of “Be a Pre and Probiotic Pro” and is sponsored by General Mills Bell Institute of Health and Nutrition. Register here.
The second, “Navigating the World of Probiotics: Helping Patients Make Good Choices,” is under development by Medscape. Both Prof. Dan Merenstein MD and Mary Ellen Sanders, PhD will speak during this 30 min webinar. It will take place April 17. Register here.
By Mary Ellen Sanders PhD and Dan Merenstein MD
ISAPP sent two key-note speakers to the Probiotics Association of India meeting, held Feb 16-17 in New Delhi. Prof. Dan Merenstein MD spoke on “Evidence for clinical indications: how do probiotics measure up?” and Dr. Mary Ellen Sanders addressed “Is it time for live cultures to be included in official dietary recommendations?” Dr. Merenstein also gave a second talk on an ISAPP-supported project: the evidence that probiotic consumption can reduce antibiotic utilization. This is the 3rd PAi meeting that ISAPP has supported through speaker sponsorship.
The meeting featured talks on synbiotics to prevent late-term sepsis (Pinaki Panigrahi), the impact of diet on the Indian gut microbiome (Yogesh Shouche), autism (Sheffali Gulati) and 10 selected student/young investigator presentations on diverse microbiota/probiotic studies. Because of the high quality student presentations, judges were unable to choose the best to award prizes. The solution: all 10 presentations were awarded 5000 INR, supported by Prof. Pinaki Panigrahi’s Center for Global Health and Development. A poster session and original probiotic-themed drawings (see below for one submission) were also presented.
Dr. Sanders also spoke on “The contribution of probiotics to health” in an event held February 15 sponsored by the Gut Microbiota and Probiotic Science Foundation (India). This event was attended by ~150 professionals in nutrition, medicine and microbiota/probiotic research.
Of course, the trip was not all work. Below, Mary Ellen takes a selfie with her new elephant friend, Sampa.
Probiotics and Good Gut Health. An artistic interpretation by a student, Simranjeet Singh.
Mary Ellen Sanders takes selfie with Sampa, a 62-year old Asian elephant.
February 11, 2018. By Dr. Olaf F.A. Larsen, Assistant Professor (0.2 FTE) at Athena Institute, VU University Amsterdam, The Netherlands, and Science Manager at Yakult Netherlands.
Probiotics are, according to the WHO and later updated by a consensus panel convened by ISAPP, defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”. Most scientific literature ties probiotic properties to individual strains, although evidence suggests that some health benefits may generalize to the species or genus level. Another important factor in how a probiotic performs is the type of matrix (e.g., a milk drink) that carries the probiotic. Indeed, many successful commercial probiotic products are largely defined by both the probiotic contained and the final product format. A plethora of probiotic products are available, ranging from fermented milks/yogurts, cereal products, juices and freeze-dried products (powders and pills). Some products claim to be probiotic but lack substantiation, such as “probiotic” pizzas and mattresses. It is likely that the probiotic properties are not solely determined by the probiotic strain itself, but also by the harbouring matrix. Hence, in order to fully understand the parameters that drive functionality of a specific probiotic, the total product should be evaluated.
Recently, the influence of the matrix on measures of probiotic functionality was reviewed. The data suggest that the matrix impacts several parameters, including number of viable probiotic microorganisms present in the product through shelf life and survival of the probiotic through the gastrointestinal tract. As an example, the number of viable microorganisms in the product as a function storage time can be profoundly different depending on the combination of probiotic strains and matrices used. Some products in which lyophilized probiotics are incorporated into a peanut butter matrix can have storage times up to 50 weeks. Whey proteins present in milk may improve gastrointestinal tract survival. Therefore, one should be aware that it is likely that viability of the probiotic will be impacted by the carrier matrix.
Another way that matrix can be important is through delivery of additional beneficial substances. For example, milk products contain various vitamins, calcium and high quality protein. In the case of a fermented probiotic product, the fermentation process may yield functional substances such as antihypertensive peptides. These effects can be considered as “additional benefits” of the matrix, beyond the impact of matrix on probiotic survival both in the product and in your body.
The body of scientific evidence falls short, however, of proving the importance of matrix on health endpoints. For a given amount of probiotics delivered, we lack comparative studies that prove that the end-benefit of one carrier matrix is better than another. Many supportive studies suggest that this will be the case, but until head-to-head human studies are conducted, we don’t know for sure.
Given the impact the matrix exerts on probiotic survival, and the possible effect on probiotic effectiveness, keep in mind the importance of efficacy studies conducted on the complete probiotic product. We need more research to fully understand the role of matrix on probiotic effectiveness, but the strongest evidence comes from studies conducted on the complete probiotic product.
Figure: Determinants of probiotic product parameters (adapted from Flach et al. 2017). Mark B. van der Waal is gratefully acknowledged for producing the artwork.
For another perspective see Does the delivery format affect probiotic efficacy?, March 28, 2018 by Mary Ellen Sanders.
ISAPP Board Members, Professors Michael Cabana MD MPH and Seppo Salminen PhD, will be participating in the 4th Annual Prebiotics and Probiotics in Pediatrics conference in Bari, Italy April 12-14, 2018. Prof. Cabana will be chairing a panel on colic and will discuss findings from a meta-analysis of L. reuteri as an intervention for colic. This meta-analysis, published December 2017, was the outcome of discussion groups convened at the 2014 and 2016 ISAPP meetings, both led by Prof. Cabana of University of California, San Francisco.
Prof. Salminen will share his decades of knowledge of probiotics, colonizing microbiota and pediatric applications in his presentation titled “Bacteriome and Friends.”
Don’t miss the 4th Annual Prebiotics and Probiotics in Pediatrics conference, which is a unique opportunity to meet major experts in the field while learning the most updated basic and clinical research on prebiotics and probiotics for the developing human. The three-day meeting will cover the major novelties in pediatric gastroenterology, obesity, allergy, nephrology, neonatology and the new scenario on gut-brain communication.
By Christopher Cifelli, PhD, VP of Nutrition Research, National Dairy Council.
Communicating with others is an essential part of everyday life. We are constantly sharing information about a variety of topics with friends, family, and even strangers. Most of the time the interaction is easy and natural – and sometimes even fun. But, have you ever talked to a scientist or asked a scientist a question?
Scientists love to talk about their research. And, other scientists want other to know about their research. They enjoy expounding on the minute details of their work and can spend hours on the littlest detail. That is one trait that makes a scientist effective – the attention to detail needed to posit hypotheses and then experimentally test them in controlled, thought-out manners. Scientists can talk to other scientists easily – but, ask some of them to explain their work to the average person and it doesn’t always go so well.
ISAPP is composed of scientists that are world-renowned experts on probiotics, prebiotics, and fermented foods. And, like other scientists, ISAPP wants others to know and understand these complex topics so that they can make informed decisions that may benefit their health. The question was – how does ISAPP do that? The answer: focusing on effectively translating the science. I offered ISAPP my leadership of a new committee to take on this task. ISAPP formed the Science Translation Committee nearly 3 years ago with a goal of taking complex scientific topics and making them easy to understand for consumers and health professionals. The result of this effort has been the development of numerous infographics, blog posts, and informational videos that translate years of research into easily digestible nuggets of information that people can use. The most recent infographic focused on dispelling some common myths about probiotics – because, who doesn’t like some myth busting!
Effective science communication is essential – essential because it can help people understand the complex and enable them to make choices that can benefit their overall health. ISAPP – which is grounded in science – will continue to be the voice of probiotic and prebiotic science and work to help people understand these fun and interesting topics. So, check out our website and our resources and start learning!
January 22, 2018. By Dr. Gregor Reid
ISAPP Board of Directors member Dr. Gregor Reid recently co-authored a cross-sectional study in a cohort of over 1000 very healthy Chinese participants from 3 to over 100 years of age in order to gain insights on ‘healthy’ microbiota composition and whether this changes with age. Using next-generation sequencing (Illumina MiSeq platform) and large-scale compositional data analysis techniques, the study demonstrated that there was very little difference in the fecal microbiota composition of individuals between the around 30 years of age and around 100—as long as the individuals were extremely healthy.
The concept of consuming live microorganisms that offer a benefit to the host (probiotics), or a substrate that is selectively utilized by host microorganisms conferring a health benefit (prebiotics), to promote health in aging populations is becoming more popular. However, it is not currently known what constitutes a ‘healthy’ gut microbiota composition, or what specific prebiotic/probiotic might help establish it.
Discussing the study results in a Reddit Ask Me Anything session, Reid explains, “It is hard to pin down outcomes to one factor such as food, and which components of those foods are critical, but seeing the super-healthy elderly having the same microbiota profile as the super-healthy young adult might make us see if some food practices from 75 years ago have returned.”
Although the study design (cross-sectional) does not allow for a cause and effect relationship to be established, the results may signify that the similarity of gut microbes across ages is a consequence of an active lifestyle and good diet—in contrast with previous hypotheses that aging per se affected gut microbiota composition. Based on these findings, it is reasonable to hypothesize that reestablishing a dysbiotic microbiota composition in older adults, to mirror that of a 30-year-old, may promote health. Moreover, the results offer an established baseline microbiota composition by which other cohorts with chronic or acute disease may be compared.
How often do you hear information about probiotics that is just plain wrong? Too often write-ups on probiotics in blogs, websites, articles written by the lay press, and even sometimes in scientific journals is not true to the science. The latest ISAPP infographic corrects several common misconceptions about probiotic dose, sweetened probiotic yogurts, fermented foods, and more. In doing so, this infographic furthers ISAPP’s core values of stewardship, advancing the science and education.
This resource was developed by ISAPP’s Science Translation Committee and approved by the ISAPP board of directors.
January 16, 2018. By Mary Ellen Sanders PhD, Sylvie Binda PhD, Seppo Salminen PhD, Karen Scott PhD
Demonstrating health benefits for healthy people is a challenge faced by those attempting to communicate claims on a health promoting food. Foods, in many global regulatory frameworks, are intended for the general population. Therefore, any benefits ascribed to them, the logic goes, must be demonstrated in the generally healthy population.
An old concept has new-found notoriety in the context of offering an approach for establishing health benefits for healthy people. It is the concept of resilience. In an ecological sense, resilience refers to the ability of an ecosystem to withstand perturbation and continue normal function, i.e. maintain homeostasis. In the context of human physiology, resilience enables a host to remain healthy even when exposed to a stress, or to recover from a stress faster. A variety of external challenges such as drugs, pathogens, emotional stress, poor diet among others, may perturb normal physiological function or disrupt the gut ecosystem. Individuals more able to maintain stability of physiological functions when exposed to such challenges would be healthier than those who cannot maintain stability. Thus, a food would be considered to have a beneficial effect if it could increase the resilience of the consumer to a challenge.
This concept was described in an EFSA guidance document on biological relevance of data in scientific assessments:
“When subject to a disturbance, a biological system enters in a transient state: a process variable has been changed and the system has not yet reached steady state. Some systems, including humans, have the capacity to regulate their internal environment and to maintain a stable, relatively constant condition of properties; it is called ‘homeostatic capacity’. Resilience represents the amount of disturbance that can be absorbed by a system before the system changes or loses its normal function, or the time taken to return to a stable state, within the normal operation range following the disturbance…” [Reducing] “homeostatic capacity … might be detrimental, whereas increasing the capacity could be beneficial.”
This concept aligns with the definition of ‘health’, which includes the ability to adapt to the environment.
Resilience of gut microbiota
This concept of resilience can be applied to the human microbiota as an ecosystem. Once established in early childhood, our colonizing microbiota reaches a relatively stable state. Although brief fluctuations occur, especially in relation to daily diet and medicines used, the microbial ecosystem of a healthy adult provides relatively stable functionality. Disruption of the microbiota by repeated stressors can be associated with poorer health. There seems to be a solid rationale that the ability of the colonizing microbiota to resist, or recover quickly from, perturbations reflects a person’s ability to remain healthy. The microbiota stability may be indicated in either populations of bacteria or their metabolic output.
Homeostasis and health: a statistical approach
“A statistical approach to measuring improved health was proposed by Dr. Dan Tancredi at the 2010 ISAPP meeting. It is reprinted here from: Sanders, et al. 2011. Health claims substantiation for probiotic and prebiotic products. Gut Microbes 2:3, 1-7.
An approach to measuring improved health may be to measure homeostasis, as suggested by D. Tancredi. From a statistical point of view, if an intervention were able to minimize the variation around the mean for a specific measure (even in the absence of changing the mean; Fig. 1), it could be a reflection of improved health, assuming a biological rationale exists that tighter control of the parameter is physiologically advantageous. In other words, lessening the fluctuation around an individual’s biomarker could be interpreted as contributing to improving health. This novel idea emphasizes the importance of homeostasis as a focus of studies on health, and provides a rationale based in solid statistical theory as a way to measure this.
One challenge to demonstrating the value of this approach is to identify appropriate biomarkers that could be studied. The following properties would be important to a relevant biomarker for homeostasis:
Such a biomarker could be an individual endpoint or be formed as a ratio of two other biomarkers, when maintaining the same relative amounts of the two component biomarkers would be desirable.
Assuming a biomarker with the above properties is available, it could be used as the outcome measure in a randomized controlled trial to provide evidence that the experimental food is able to improve the maintenance of health in humans. Statistically, the trial would be set up to address the hypothesis that the experimental substance is associated with lower variation in biomarker levels, compared to the control arm, in subjects who were healthy at baseline. Such a trial would be able to use information on within-person variations in biomarker levels, even those who did not become ill. Partly as a result of the more efficient use of study data, such a trial would require far fewer subjects than an intervention that instead addressed the hypothesis that treatment is associated with fewer healthy persons becoming ill.
A mounting understanding of the value of stability of the colonizing microbial communities makes this endpoint an attractive one to consider. Perturbation of gut microbiota is associated with intestinal dysfunction, as illustrated during antibiotic treatment. Specific probiotics have been shown to promote a quicker rebound from antibiotic-induced microbiota disruption, including a study on Lactobacillus rhamnosus GG (LGG) (Cox et al. 2000). This paper concludes ‘…that a key mechanism for the protective effect of LGG supplementation on the subsequent development of allergic disease is through the promotion of a stable, even and functionally redundant infant gastrointestinal community.’
However, it would be useful to define additional biomarkers that would be appropriate targets for this type of investigation.
In pediatric nutrition, the measurement of metabolic homeostasis has become a standard approach when developing infant formulas (Heird, 2005). The concept of homeostasis as a model to distinguish between foods (including food supplements) and medicinal products was explored by the Council of Europe (2011), and is an interesting correlate to the above hypothesis.”
The recent recognition by EFSA that maintenance of homeostasis is a valid measure of health provides an opportunity to apply this concept to validate health benefits of specific foods and food ingredients. Stability of microbial populations, microbial metabolism or host physiological readouts could be measured to reflect the concept of resilience. Since there is no definitive composition of a ‘healthy human microbiota’, a more reasonable target for measuring positive impacts of a probiotic on the microbiota would be reflected not in absolute levels of specific microbes but in the ability of a specific probiotic or prebiotic to bolster the resilience of the microbiota.
Council of Europe. Homeostasis, a model to distinguish between foods (including nutritional supplements) and medicinal products 2008; (Accessed February 24, 2011, at http://www.coe.int/t/e/social_cohesion/soc-sp/homeostasis%20%282%29.pdf ).
Cox MJ, Huang YJ, Fujimura KE, Liu JT, McKean M, Boushey HA, et al. Lactobacillus casei abundance is associated with profound shifts in theGunderson LH, 2000. Ecological resilience: in theory and application. Annual Review of Ecology and Systematics, 31, 425–439.
EFSA guidance document: Guidance on the assessment of the biological relevance of data in scientific assessments; July 12, 2017; EFSA Journal 2017;15(8):4970
Heird WC. Biochemical homeostasis and body growth are reliable end points in clinical nutrition trials. Proceedings of the Nutrition Society 2005; 64:297-303.
Huber M, Knottnerus JA, Green L, van der Horst H, Jadad AR, Kromhout D, Leonard B, Lorig K, Loureiro MI, van der Meer JW, Schnabel P, Smith R, van Weel C, Smid H (2011). “How should we define health?” BMJ. 343:d4163.
Sanders, et al. 2011. Health claims substantiation for probiotic and prebiotic products. Gut Microbes 2:3, 1-7; May/June 2011
January 12, 2018. Antibiotics are amongst the most commonly prescribed drugs in UK hospitals. However, as well as treating infection they can cause disruption to the gastrointestinal microbiota. This can lead to the relatively common side-effect of antibiotic-associated diarrhoea (AAD) which often delays discharge. More concerning is that a disruption to the normal gut microbiota can lead to reduced resistance to opportunistic pathogens such as Clostridium difficile, leading to C. difficile infection, a potentially severe or fatal infection. Based on the available evidence, probiotics are a safe and effective adjunct to antibiotics to reduce the risk of developing AAD and for the primary prevention of CDAD. The International Scientific Association of Prebiotics and Probiotics has reviewed available data and supports several published assessments, which recommend probiotics as adjunctive therapy for prevention of AAD and CDAD.
This effort was led by Dr. Claire Merrifield BSc MBBS PhD, Speciality Registrar in General Practice, St. Mary’s Hospital, Imperial College Healthcare Trust, Imperial College London and Prof. Daniel Merenstein, MD, Department of Family Medicine, Georgetown University Medical Center and ISAPP Board Member and Treasurer.
January 3, 2018.
Evidence exists for gut microbiota differences between infants with and without colic, with one probiotic strain of particular interest therapeutically for colicky infants: Lactobacillus reuteri DSM17938. Discussion groups convened at the 2014 and 2016 ISAPP meetings, both led by Prof. Michael Cabana MD MPH of University of California, San Francisco, and member of ISAPP’s board of directors, focused on the existing randomized, controlled trials and how they might inform medical recommendations.
The discussion group at the 2014 ISAPP meeting in Aberdeen Scotland resulted in a paper describing the individual patient data meta-analysis (IPDMA) protocol, which was published in BMJ Open. The 2016 ISAPP meeting in Turku Finland culminated in the publication of this IPDMA in the journal Pediatrics: Lactobacillus reuteri to treat infant colic: a meta-analysis. Dr. Valerie Sung, Royal Children’s Hospital, The University of Melbourne and Murdoch Children’s Research Institute, was lead author of this paper, whose coauthors included a team of 11 other experts spanning three continents.
This high quality meta-analysis used individual patient data rather than group means to get a more accurate picture of the efficacy of the probiotic. The paper concluded that L. reuteri DSM17938 is effective and can be recommended for breastfed infants with colic. However, data are lacking for efficacy in formula-fed infants.
“Any single randomized clinical trial involves a great deal of time and resources from investigators, institutions and most importantly, patients. By working together, our team was able to combine data to learn more about the effects of L. reuteri DSM 17983 on the treatment of infant colic. This analysis is a great example of the power of close international collaboration by clinical investigators.”
Probiotics for Colic—Is the Gut Responsible for Infant Crying After All? (Open access through Jan 10, 2018)
December 15, 2017. By Prof. Daniel Merenstein, MD, Department of Family Medicine, Georgetown University Medical Center, Washington DC.
I had a surprising encounter a few weeks ago in the clinic. I was caught off guard, had to take a step back and think about what happened. I recommended to my patient that she take a probiotic with the antibiotic I was prescribing. She said to me, “What is a probiotic?” My response was, “A probiotic,” as if it didn’t require any further explanation. It was nearly incomprehensible to me that she didn’t know what a probiotic was and maybe she just didn’t hear me or just didn’t understand me (I tend to speak too fast). But no, she just didn’t know what one was. I then realized how unusual this encounter was.
Something has been a-changing. It hasn’t been a quick process and I am not sure when it changed, but it did. Even just a few years ago when I recommended supplementing a course of antibiotics with a probiotic, people were generally receptive and had a vague idea about probiotics. However we generally had to talk about what probiotics were and how to use them. Fast forward to today and it appears to me that 95% of people respond, “I already take one.” Much more common than hearing “What’s a probiotic?” is to hear, “Of course, you always have to take a probiotic when taking an antibiotic.”
I am currently recruiting for my 8th probiotic clinical trial (PLAY ON). My team has recruited over 1,400 participants for previous studies. We have a system and a great team, but we are having the most difficult time recruiting for this study. I have thought a lot about why and I think it comes down to the times they are a-changin’. When we started on this research path 12 years ago, our research team and the subjects we recruited were excited about probiotics and their potential. But today the public doesn’t see the potential of probiotics; they know probiotics impact the gastrointestinal tract and should be used when taking antibiotics. Therein lies our challenge: to be in our study a subject has to be willing to take the chance of being in the placebo group. That makes little sense to a public that already knows to take a probiotic when on antibiotics.
My first two NIH studies were funded by the National Center for Complementary and Integrative Health, while my current study is funded by the National Institute of Child Health and Human Development. The shift has occurred from complementary, to mainstream. One need no longer attend a microbiome or probiotic conference to hear talks on probiotics; nearly all clinical conferences will now have probiotic talks. I am confident my team will adjust to these changing times but I think more important is how researchers and clinicians adjust. Probiotics are not alternative options anymore, the evidence base is robust and some indications well-studied. The discussions need to shift from, “You should have probiotics on formulary” to specific recommendations of which probiotics should be used for what indications. Similarly when discussing other disease states in the gut (e.g. necrotizing enterocolitis, infantile colic, and irritable bowel syndrome), it is time to take the next step and discuss specific recommendations. I am sure I will see another patient who has never heard of probiotics, but I’m willing to bet that doesn’t happen for many months. More likely, I expect I will be discussing the efficacy of the products my patients are already taking. That is an important change that docs need to think about.
Come gather ’round people
Wherever you roam
And admit that the waters
Around you have grown
And accept it that soon
You’ll be drenched to the bone.
If your time to you
Is worth savin’
Then you better start swimmin’
Or you’ll sink like a stone
For the times they are a-changin’.
Bob Dylan, Nobel Laureate
The Times They Are A-Changin’
Columbia Records, 1964
November 20, 2017. Probiotics are most commonly studied with for populations with a specific condition—frequent examples include diarrhea, irritable bowel syndrome, and pouchitis. But what kind of evidence exists on probiotics for healthy people?
A new ISAPP infographic gives an overview of what we know about the use of probiotics in healthy individuals. The resource was developed by ISAPP’s Science Translation Committee and approved by the ISAPP board of directors.
“Studying health benefits in healthy people is a challenge. But there is evidence that probiotics can provide dietary management of some digestive conditions that don’t reach the level of diagnosed disease as well as prevent of some common infectious diseases and. These, and other benefits, are of value to healthy people,” says ISAPP’s Executive Science Officer, Dr. Mary Ellen Sanders. The new infographic emphasizes it is not necessary to take probiotics to be in good health, but they may serve as a useful addition to a healthy lifestyle.
Research investigating how probiotics can affect healthy individuals through their microbiomes is ongoing in laboratories around the world, and ISAPP continues to track the latest findings.
November 2017. By Prof. Michael Cabana MPH MD, Professor of Pediatrics, Epidemiology & Biostatistics and Chief, Division of General Pediatrics, University of California San Francisco.
Over the last few decades there has been a rapid acceleration in the number of published studies and clinical trials focused on probiotic and prebiotic interventions. One common result that is reported is the change in risk of a condition or outcome after taking a probiotic or prebiotic supplement. News articles and broadcasts commonly highlight claims in clinical trials (e.g., “this trial suggests a 33% reduction in X…). However, in a world where news is sometimes transmitted in 140 characters or less, much nuance from a proper clinical trial can be lost. When assessing claims of risk reduction, it is important to evaluate and interpret these results in their proper context. Here are a few tips.
What type of risk reduction is being reported?
When assessing the claims from a clinical trial, determine whether the claim is being presented as a relative risk reduction or an absolute risk reduction. Sometimes the report may describe the risk of the outcome or disease directly compared to the normal incidence of the disease (i.e., incidence seen in the control group). This is a report of an absolute risk reduction. For example, if the control group had a 15% frequency of disease X and the probiotic group had a 10% frequency of disease X, then the absolute risk reduction is 5% (15%-10%=5%). Sometimes the report may describe a relative risk reduction, which is the % change between the risk in the probiotic group compared to risk in the control group. If the control group had a 15% frequency of disease X and the probiotic group had a 10% frequency of disease X, then the probiotic reduced your relative risk by 33% ([15%-10%]/15% = 5%/15% = 33%).
Is the risk reduction clinically significant?
If you notice that a relative risk reduction is being reported as statistically significant, you then need to ask yourself if the outcome is clinically significant. It is possible that a very large change in the relative risk reduction may not be clinically important. For example, if a probiotic intervention decreases the relative risk of disease X by 33%., this percentage sounds very impressive. However, if the baseline risk of contracting disease X is only 0.06% (e.g., it is a very rare condition), then the risk after the probiotic intervention is only 0.04% (still very rare, as reflected in the absolute risk reduction of 0.02%). Although the decrease of 33% that is reported as relative risk seems large, if you take into account the baseline risk, you realize that this is not clinically significant. The risk of 0.06% and 0.04% are essentially the same.
When evaluating an intervention, the context of the disease makes a difference. How often is this disease or condition occurring in the population being studied? The problem with reporting a relative risk reduction is that it is easy to overlook how common or uncommon the disease is to begin with.
Look for the “Number Needed to Treat”
One way to better assess the impact of an intervention is to calculate a “Number-Needed-to Treat” (NNT). The NNT is the inverse of the absolute risk reduction.
From our example above, a 33% relative risk reduction of a condition with a prevalence of 0.06% (e.g., a very rare condition), means that the probiotic intervention had an absolute risk reduction of 0.02%. The NNT would be equal to 1/[0.0002]= 5000. This NNT of 5000 means that you’d need to treat 5000 patients with the probiotic intervention to change the outcome of only one patient.
Take a different scenario. If the disease was much more common (e.g, 9% prevalence) and the relative risk reduction was still 33%, then absolute risk reduction would be 3%. The NNT in this case would be equal to 1/(0.03)=33.3. This NNT of 33.3 means that you’d need to treat only 33 patients with the probiotic intervention to change the outcome of one patient. This treatment is much more likely to be meaningful in the population.
The NNT is a quick way for clinicians to evaluate an intervention to take into account the risk reduction in the context of the baseline risk.
When examining the results from clinical trials, just looking at percentage changes can be deceiving. Unfortunately, relative risk reduction often results in more sensational headlines, so beware of how the press, and even top quality journals, report study results. When assessing the clinical trial results in the context of clinical care, keep in mind how common or rare the disease is. Even a large percentage change may not make a big difference overall in patient outcomes if the initial risk was very low to begin with. Evaluate and interpret clinical trial results in their proper context.
November 2017. Discussed at International Union of Nutritional Sciences (IUNS) Congress session. By Prof. Seppo Salminen, Director of the Functional Foods Forum, University of Turku.
Recently, the Yogurt in Nutrition Initiative (YINI) convened a scientific session as part of the International Union of Nutritional Sciences (IUNS) Congress, held in Buenos Aires from October 22-27, 2017. The session focused on how yogurt and other fermented foods affect the composition and activity of the gut microbiota and health. Lectures covered microbiota development in humans, metabolic effects of yogurt and fermented foods, the role of fermented dairy foods on health, and the role of yogurt and fermented foods in nutritional guidelines
Professor Robert Hutkins and I presented at the YINI session. Dr. Hutkins spoke about “Health benefits of fermented dairy foods: microbiota and beyond” and started by defining the role of microorganisms during food fermentations. He then reviewed current research findings on the impact of fermented foods on the human intestinal microbiota. He also distinguished between the microbes that perform the fermentation and those added specifically as probiotics. Although they are often closely related, they are not the same. Both culture-based and molecular methods have shown that although microbes consumed in fermented foods often survive transit, they rarely persist after consumption has ended. Still, they may be able to modulate functional activity in the gut and, in the case of yogurt bacteria, improve tolerance to lactose.
My presentation was titled “Improving your diet with fermented foods: harmonizing dietary guidelines including fermented milks” and I reviewed the role of yogurt in dietary guidelines and recommendations in different countries along with the regulatory status of yogurt and health claims. The talk focused on existing guidelines in Europe; specifically, the live bacteria in yogurt and lactose intolerance claim approved by the European Food Safety Authority. This claim states that yogurt cultures improve lactose digestion (and tolerance) in individuals with lactose maldigestion. Additionally, I suggested that fermented dairy products should be included in dietary guidelines in a more consistent manner, as recommendations currently vary from country to country. A special focus was also given to an Argentinian social program which provides at present over 200,000 school children with locally produced yogurt with a probiotic to improve their health and well-being.
The role of fermented foods and especially yogurt has gained substantial attention among researchers, clinicians, public health workers, and consumers. In addition to the live organisms present in fermented foods, peptides and other metabolites produced by these organisms may also mediate important health benefits. Thus, cultured dairy foods and other fermented products may have important effects on public health and their consumption should be encouraged.
October 10, 2017. Probiotics are a hot topic—an online search for information yields millions of hits. But how much of this easily-accessible information is scientifically accurate?
The clinicians and scientists serving on the ISAPP Board of Directors constantly receive questions about what’s true when it comes to probiotics and prebiotics. That’s why ISAPP decided to commission a series of four informational videos on probiotics. These videos were overseen by members of our board of directors without input from industry, but industry provided educational grants for their production.
The four new videos focus on these topics:
Watch for the videos to roll out during the month of October 2017! They’ll appear here on the ISAPP website video page.
With our mission to advance scientific excellence in probiotics and prebiotics, ISAPP is committed to helping consumers access science-based information on probiotics and prebiotics. To stay up to date on ISAPP news, please sign up for our monthly newsletter!
September 2017. By Eamonn M. M. Quigley, Chief Division of Gastroenterology and Hepatology, Houston Methodist Hospital and Professor of Medicine, Weill Cornell Medical College, Houston, Texas, USA.
We can all remember those instances of diarrhea (or at least frequent bowel movements) and “butterflies” that we suffered before a critical test, interview or presentation. These are examples of stress originating from the brain influencing gut function. Extensive research over the past several decades has revealed that this is a two-way street – the gut constantly signals to the brain, too. This bidirectional channel of communication between the “big brain” in the cranium and the “little brain” (i.e. the enteric nervous system) in the gut came to be referred to as the gut-brain axis. This link relies on neurons of the sympathetic and parasympathetic nervous systems, as well as circulating hormones and other neuromodulatory molecules.
We now understand that mental symptoms of stress, anxiety or depression have a clinical impact on the gut. These include situations where the brain, the gut and their channel of communication, the autonomic nervous system, are affected by the same pathologic process. Parkinson’s disease is a prime example. Indeed, a hypothesis has evolved to suggest that Parkinson’s disease actually originates in the gut and ascends to the brain. Other scenarios include those instances where neurologic symptoms are a consequence of a primarily gastrointestinal pathology. This occurs in malabsorption syndromes when nutrients such as folic acid and B12, which are critical to brain function, become deficient. Finally, and most commonly, are those situations such as irritable bowel syndrome (IBS) where it is widely believed that symptoms result from dysfunction or disturbance somewhere along the gut-brain axis. In some individuals the problem may lie primarily in the gut; in others the main issues may be a distorted representation of gut stimuli in the brain.
Recently the concept of the gut-brain axis has been extended to include the microbiota (the microbiota-gut-brain axis) and tantalizing evidence suggests that bacteria resident in the gut could have an impact on the “big brain”. Indeed, some researchers have raced ahead to suggest that assessing alterations in the microbiome could assist in the diagnosis of a host of neurological disorders and that therapies targeted at the microbiome could play a central role in disorders as diverse as Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, autism, stroke, depression and drug addiction.
We should remember that the microbiota-gut-brain axis is far from a novel concept as it was clearly described over 60 years ago with research on hepatic coma. Metabolic products of gut bacteria lead to this much feared complication of advanced liver disease and an intervention targeted at the microbiome, namely, the administration of antibiotics, was shown to be dramatically effective. In these pioneering studies the role of bacterial overgrowth in the small bowel by coliforms and other bacteria, which are normally confined to the colon, was found to be important. Subsequently, these same bacteria and the inflammatory response that they evoke have been incriminated in the pathophysiology of another common consequence of chronic liver disease, portal hypertension, as well as in other complications such as spontaneous bacterial peritonitis, systemic sepsis and hemostatic failure. Indeed, there are several manifestations of this tripartite resonance between microbiota, the liver and the central nervous system. Gut health factors such as small bowel bacterial overgrowth, an abnormal microbiota, impaired gut barrier function, a pro-inflammatory state and the appearance in the systemic circulation of neuro-active molecules generated by bacterial metabolism are all postulated to play important roles in the actual pathogenesis of a number of common liver diseases. So what is new?
From the basic science laboratories and a variety of animal models a pretty coherent message has emerged. Firstly, the microbiome can influence brain development, structure and function and lead to changes in cognition and behavior. Secondly, the manipulation of the microbiome – for example, with probiotics – can ameliorate certain brain disorders and reverse impaired function. Thirdly, the inoculation of microbiota samples from individuals with a number of neuropsychiatric disorders into animal models can recapitulate features of the human disease. So far so good.
As always, extrapolation from animal studies to humans is fraught with difficulties: differences between animal and human brains and microbiota, the limitations of animal models of psychiatric and functional bowel disorders, and, above all, the challenges of studying brain function in humans. The good news is that these challenges are being addressed. Researchers are utilizing various technologies that provide dynamic images of brain function in various parts of the brain in response to a variety of situations, stimuli and exposures. These are now beginning to provide evidence that our microbiota can influence brain function and that the gut microbiota might, indeed, be a therapeutic target for patients with disorders such as depression, Parkinson’s disease and autism. Data are preliminary and certainly not at a stage where we can offer diagnostic testing based on a fecal sample or recommend antibiotics, prebiotics, probiotics or fecal microbiota transplantation for a given neuropsychiatric disease or disorder. But watch this space!