hill blog industry

Academics working with industry  

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.

  1. Relevance. You know the research problem posed is one that genuinely needs solving, and the industrial partner for any solution you may develop is already engaged.
  2. Funding. Once you begin to work with an industry partner, the prospect of getting funding is much higher than in most competitive grant applications and the amount available may be defined by the extent of the problem, not the limit of a particular funding call.
  3. Intellectual capital. Most of the industry people you will be dealing with are also scientists, and they are just as clever, or far cleverer, than you (or me).  They will have defined goals but also have the same scientific curiosity which can be harnessed within the project.
  4. Flexibility. If you have embarked on the project and you find you have gone down a blind alley, it is usually possible to have a discussion with your partners and change the project design.  You don’t have to go back to the funders for permission to adjust the dreaded Gantt chart and ‘deliverables’, or have to justify to grant reviewers why you have gone off track. If a project extension is required you can often simply argue for it, no need to write a new grant and experience the inevitable downtime ‘between funding’.
  5. Urgency. Working with a student or a post-doc on a problem can be exciting, but sometimes a good or a bad result seems important only to the two of you.  It really adds urgency when an industry meeting is looming on the horizon, when you know the funders are directly invested in the outcomes of the experiments, and when the pressure really builds on the team.  In these moments some intense brainstorming and problem-solving can be required, which can create a real sense of excitement within the project and which can be a tremendous learning experience for junior members of the team.
  6. Career development. Most of the students and postdocs in the lab will not end up in academia, nor should they.  It is valuable training for young scientists to have a first-hand exposure to industry-based science so that they can make an informed choice on their next step in their career.

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”.

reid probiotics definition

You’d think we’d know probiotics by now

Prof. Gregor Reid, PhD MBA, Lawson Research Institute, University of Western Ontario, Canada

When I took my MBA, it was primarily to understand business and its relationship with science. I thought I learned quite a lot, but some things puzzle me to this day. Marketers know that messages are more effective when repeated. But, a guy called Thomas Smith (maybe related to Scotland’s famous Adam Smith who pioneered political economy, whatever that means!) wrote a guide in 1885 (yes that long ago!) called “Successful Advertising,” that noted:

The 1st time people see or read something, they don’t see it.
The 2nd time, they don’t notice it.
The 3rd time, they are aware that it is there.
The 4th time, they have a fleeting sense that they’ve seen it before.
The 5th time, they actually read the ad.
The 6th time, they thumb their nose at it.
The 7th time, they get a little irritated with it.
The 8th time, they think, “Here’s that confounded ad again.”
The 9th time, they wonder if they’re missing out on something.
The 10th time, they ask their friends or neighbors if they’ve tried it.
The 11th time, they wonder how the company is paying for all these ads.
The 12th time, they start to think that it must be a good product.
The 13th time, they start to feel the product has value.
The 14th time, they start to feel like they’ve wanted a product like this for a long time.

This goes on and on. It made me think about the definition and interpretation of probiotics. The version published in 2001 through two large respected organizations (WHO and UN FAO) has pretty much been universally accepted, and again reiterated in 2014 in a highly prestigious journal. That article is widely cited, so you’d think people would get it, right? They’d know what a probiotic is and what it’s not, right?

Yet, I speak at events around the world, and the same things keep coming back. Whether it is the 6th or 7th response (thumbing noses or being a little irritated) or a speaker confidently talking about probiotics and getting most of it completely wrong, I have scratched my head to the point my hair is falling out (a good research topic if someone would like to investigate this correlation). I even told a first year dentistry class of 55 students three times that the definition of probiotics would be an exam question. Only 8 got it correct!

I went back to the literature, as all scientists do, and asked the question “Why can’t people see what’s right in front of them?” It turns out either they believe you don’t have the answer, or you can’t have the answer, or you can’t have the answer right here and now, or they believe the answer needs to look like something else. This has a name – it’s called a schotoma – which seems appropriate, like people taking a shot at probiotics, or taking a shot at defining it, or providing their version of what it is.

With my hair now almost as thin as Glenn Gibson’s, I’m at a loss. Probiotics are not dead, not undefined/unstudied fermented foods, not in you unless you’ve taken them, not synonymous with “acidophilus”. They don’t typically colonize and they don’t have to be isolated from a human to work for humans. Products with lots of strains or a huge dose are not necessarily better products.

If you want to find the right probiotic for you, too often your doctor or health shop worker doesn’t give the best advice, because they haven’t read the articles. You should go www.usprobioticguide.com or www.probioticchart.ca and find something suitable for your needs. If you want some good general guidance, check out ISAPP infographics and ISAPP videos. If you are a company, don’t call your product a probiotic unless the contents have been tested in humans at the dose you are delivering at end of shelf-life. Call it strains of lactobacilli or something along those lines. Not being on one of these charts might be a sign that you’ve not done the needed work to call your product a probiotic.

But hey, maybe you need to read Thomas Smith’s guide. Probiotics are really quite simple. But, then again it’s only the hundredth time I’ve said that.

As for prebiotics, I’ll let someone else go bald on that one.

probiotics association of india

ISAPP Goes to India

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.

probiotic poster

Probiotics and Good Gut Health. An artistic interpretation by a student, Simranjeet Singh.

elephant india

Mary Ellen Sanders takes selfie with Sampa, a 62-year old Asian elephant.

probiotics larson photo

Probiotics: the importance of the complete product

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.

probiotics larson photo


For another perspective see Does the delivery format affect probiotic efficacy?, March 28, 2018 by Mary Ellen Sanders.

Talking Science with ISAPP’s Science Translation Committee

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!

blog foodomics image

Global FoodOmics: A Crowd-Sourced Window Into Microbes In Our Foods

January 25, 2018. By Mary Ellen Sanders, PhD , Dairy & Food Culture Technologies

Among the factors under our control, diet may be the most important determinant of our gut microbiota. Observations from the American Gut Project suggest that foods containing live microbes increase fecal bacterial diversity, which is generally associated with a healthy gut.

An initiative, Global FoodOmics, was launched earlier this year at the University of California San Diego under the auspices of the American Gut Project to learn more about bacteria in foods and the small molecules they produce. Dr. Julia Gauglitz is the project manager. Food samples (over 2000 have been collected to date) have been analyzed for their small molecule composition and will be tested by 16S rDNA sequencing to determine the bacterial species present. Although currently in its early stages, the aim for this project is to inventory the vast different foods consumed by people around the world.

Although many fermented foods (beer, bread, wine, kefir, many cheeses and others) rely on yeast or molds as fermentation or ripening agents, this project will aim to detect bacterial DNA, but these DNA approaches cannot distinguish between life and dead bacteria.  Labels and other descriptors accompanying submitted food samples may help determine if the species detected are likely to be alive. Fermented foods that retain live bacteria are more likely to influence our colonizing microbiota.

The small molecules being assayed are not limited to the ones produced by microbes. They may be due to microbial growth in the food (by food fermentation microbes or perhaps by spoilage or food poisoning microbes), may be innate to the food, or may be intentional or incidental (e.g., pesticides) additives to foods.

The intent is to turn Global FoodOmics into a crowd-sourced project. It will join the American Gut Project as an avenue for citizens to directly participate in science and enable the project to make all of the data publically available to other researchers and clinicians.

It is notable that this project is not the first attempt to understand the microbial components of food. Food microbiologists for decades have been assaying foods for microbes used to produce food, responsible for food spoilage and linked to food poisonings.  Recently, Prof. Bob Hutkins, University of Nebraska, on behalf of the International Scientific Association for Probiotics and Prebiotics (ISAPP) and with support from the National Dairy Council, embarked on a project to learn the state of knowledge about levels of live microbes in fermented foods. They dug into the published literature and emerged with “A survey of live microorganisms in fermented foods”, In Press at Food Microbiology. This paper gives us a summary of what is known about populations of live microbes in fermented foods, information that is very useful for people wanting to add live microbes to their diet.

Another effort to understand microbes in foods is the Consortium for Sequencing the Food Supply Chain, a partnership between IBM Research and Mars Inc. This project, focused on food safety, aims to develop a baseline of normal microbial communities in foods.

Both Global FoodOmics and the Consortium for Sequencing the Food Supply Chain will leverage modern DNA sequencing technologies to allow us better understand the microbes associated with foods. Global FoodOmics is the first project to understand the microbes and molecules in foods, by pairing small molecule metabolomics measurements with rDNA sequencing.

blog reid elderly

Do dietary effects on gut microbiota promote health in older individuals? Reid and colleagues gain insights into microbiota composition across the lifespan

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.

blog post resilience figure 1

Resilience as a measure of health: implications for health claims for foods

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:

blog resilience figure one

  • maintaining moderate levels of the biomarker is associated with good health;
  • high or low values are associated with ill health;
  • biomarker levels in the same person can fluctuate over time; and
  • reducing the magnitude or duration of such fluctuations in healthy people is considered desirable (Fig. 2).

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










watch with times they are a-changin quote by bob dylan

The Times They Are A-Changin’ With Probiotics

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

stethoscope and keyboard

Interpreting Risk Reduction in Probiotic & Prebiotic Clinical Trials

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.

salminen and hutkins at YINI

Fermented Foods in Nutrition & Health

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.

stool sample for lab

Microbiome Analysis – Hype or Helpful?

September 2017. By Karen Scott, PhD, Rowett Institute, University of Aberdeen, Scotland.

Since we have realized that we carry around more microbial than human cells, and that these microbial inhabitants are important to maintain our health, searching for the bacterial species that are implicated in causing disease has become the holy grail of microbiology. However, to understand which bacteria are unnaturally present or absent in a disease state, we first have to understand what constitutes normal. This is hampered by the fact that we are all different – and our microbial communities are also all different. In fact, the faecal bacterial community in samples taken months apart from one person will be identifiable as coming from that specific healthy adult, but the community will be quite distinct from samples from any other healthy adult. In the same way, the microbial community of two individuals suffering from the same disease will be different.

Despite these differences, scientists have managed to establish some facts over the past 15 years. Too many Proteobacteria, which includes Enterobacteria and E.coli, in your large intestine is not generally good news. Firstly, it means that conditions in the large intestine are probably not as anaerobic as they should be. Secondly, an expansion in these populations usually means a decline in something else – after all food and places to live are finite resources. Bacterial diversity in the adult intestine is also important. The main factor that has been found across many different diseases is that bacterial diversity is lower in diseased individuals than their healthy counterparts. This does not necessarily mean that a low diversity is causing the disease, as various features of the disease (including any antibiotic therapy, inflammation, decreased or increased transit time) may all themselves affect the diversity of the microbiota.

Although scientists have not succeeded in defining a ‘healthy microbiota,’ there is an increasing trend to get your microbiome tested. Entrepreneurial microbiome companies are bombarding us with offers to “send in a small sample and find out about your gut microbiota”. All of course, for a ‘reasonable’ price. So, should you?

This really depends why you want to know, and what level of detail of analysis is being offered. Remember the orders of taxonomy? Kingdom, phylum, class, order, family, genus, and species.  Some companies identify the bacteria in your faeces only to the phylum level. This is a taxonomic level above the level needed to differentiate mammals and fish (these are ‘classes’). If you told someone that there were more fish in the Indian Ocean than mammals would this be a surprise? It would be such an expected fact it would be meaningless. This is similar to describing the microbiota at a phylum level – Bacteroidetes numbers versus Firmicutes numbers. Such numbers are meaningless. However, continuing the fish analogy, if you said that there were more mackerel than tuna in the North Atlantic Ocean this becomes a bit more meaningful. The fisherman immediately knows what type of fish he is more likely to catch, and perhaps even which net to use. The same is true of the microbiome. Telling someone that he/she has a lot of Enterobacteria and few Roseburia is actually useful as we know from studies that this represents an abnormal balance of bacteria and something should be done to redress this. Yet the bottom line health consequence of this abnormal balance of bacteria remains to be determined. So getting your gut microbiome sequenced could be useful – depending on what level of information you will receive, and what you are prepared to do about it.

And so we come to the next problem. Having established what your gut microbiota is, how are you going to make it better? And will that make YOU better? At the moment scientists don’t really have a good answer to these questions. Specific prebiotics can certainly be useful to increase the numbers of some bacteria generally assumed to be beneficial – such as Bifidobacterium, Faecalibacterium prausnitzii and even Roseburia species. But it is not really clear what the exact health benefits of such an increase in bacterial numbers would be. Health claims on prebiotics are currently limited to ‘improve intestinal transit’ and ‘lower the glycaemic response’. If you found out that your microbiota had a low diversity, increasing the variety of foods in your diet, in particular the fibre component, could certainly improve this. Our gut microbiota basically relies on our undigested food to survive, so providing a greater amount and more types of food containing fibre and prebiotics will definitely encourage populations of diverse bacteria to expand. In addition to improving digestive health, fibre fermentation by gut bacteria also results in the production of microbial products that have been shown to have health benefits.

So by all means get your gut microbiome analyzed if you want to, but perhaps instead, save your money and just increase your prebiotic and fibre consumption, which will increase levels of the potentially beneficial bacteria that are already there in your gut.

brain-gut relationship illustration

Bugs on the Brain: the Microbiota-Gut-Brain Axis

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!


Kombucha: Trend or New Staple?

September 2017. By Prof. Bob Hutkins, Khem Shahani Professor of Food Science, University of Nebraska, Department of Food Science and Technology, Lincoln.

This blog post is adapted from a piece published by the Lincoln Journal Star. The article, first published May 4, 2016 and written by Prof. Bob Hutkins, appeared as a response to a reader’s question: “I keep hearing about kombucha… What is this stuff?”

Kombucha (pronounced kom-BOO-chuh) is made by fermenting sweetened tea using a combination of yeasts and bacteria. This mixture of live cultures that starts the fermentation is called SCOBY, short for “symbiotic colony of bacteria and yeast.” The SCOBY takes the form of a gooey mat that can be re-used for each batch or shared with friends.

Kombucha is one of many trendy fermented foods, like kimchi and kefir, that are now found everywhere. No longer just the fare of hipster cafes and posh restaurants, you can find kombucha at your local grocery store—or even at Walmart.

Kombucha’s origins go back at least 2,000 years, to China; the drink gradually spread throughout Asia and Europe. In the U.S., kits for home-brewing kombucha became available to consumers in the early 1990s, and bottled versions soon appeared on grocery store shelves.

Several factors may explain the popularity of kombucha. First, many people like the flavor: uniquely sweet and sour, with a vinegary overtone. Some ethanol (alcohol) may also be present, although commercial products must contain less than the legal limit of 0.5 percent. The fermentation reaction yields carbon dioxide, which gives kombucha a pleasant fizziness. Flavor combinations are endless, from ginger, mango, and blood orange to lavender and cinnamon.

It’s probably the suggested health properties that are most responsible for the kombucha craze. The live cultures in some blends have antimicrobial activity, which may have been valuable in past eras when antibiotics were not available. However, these properties depend on the particular mix of microbes, which varies from batch to batch or brand to brand. Other suggested health benefits range from improved gut health and digestion to treatment of cancer and other diseases. Unfortunately, there is no scientific evidence to support these health claims.

It may be that kombucha is not for everyone—the acidic nature of the drink may not sit well for some people. Microbiologists have also expressed concern that home-brewed kombucha could possibly contain toxin-producing fungi. (See related post on making safe fermented foods at home.)

Nonetheless, there’s no doubt that many consumers are drinking kombucha. Annual sales in the U.S. are over $500 million, with double-digit growth. Around half of the coveted 25-to-34 age group (i.e. millennials) are kombucha drinkers. Yes, it’s popular now, but it also seems that kombucha is likely to be around for a while.


Bob Hutkins is the Food Doc. He is a professor at the University of Nebraska-Lincoln, where he teaches and conducts research in food science and food microbiology. Questions on any topic related to food, food safety, food ingredients and food processing can be sent to the Food Doc at features@nulljournalstar.com.

bowl of yogurt with strawberries

Advice from a Nutritionist:  Eat More Fermented Foods.

September 2017. By Christopher Cifelli, PhD, VP of Nutrition Research, National Dairy Council.

Whenever I tell someone that I have a degree in nutrition science, I usually get asked, “Are carbs bad?” or “Should I avoid added sugars?” Rarely do I get asked “What should I be eating more of?” While vegetables, fruits, dairy and whole grains would all be perfectly suitable answers to that question, my go-to response is fermented foods.

Fermented foods have been around for thousands of years. Fermentation is the process of using specific microbes – for example, bacteria, yeast, and molds – to transform one food into another. For example, the fermentation process transforms milk into yogurt. Fermented foods are unique because they can contain live microbes, which can confer health benefits beyond simple nutrition. For instance, did you know that the microbes in fermented foods can help inhibit pathogen growth in the gut? Or, that eating certain fermented foods, such as yogurt, is associated with reduced chronic disease risk?

Government organizations across the globe provide dietary recommendations to help guide people choose the type of foods or diets that promote health. Commonalities include eating more fruits, vegetables, whole grains, beans, legumes and dairy. Another commonality – albeit a disconcerting one – is the lack of a recommendation for consuming fermented foods even though fermented foods, including red wine, kimchi, soya, and yogurt are key parts of healthy diet patterns.

Several recent publications have discussed the need to encourage the consumption of foods that can directly and beneficially impact our gut microbiota to improve overall health (e.g., Bell et al. or Gordon et al.). Identifying and consuming foods that can selectively impact the microbiota to benefit the host health should be a priority.

The time is now. Health professionals should review available evidence to determine how fermented foods fit into dietary recommendations to promote a healthy microbiota. They should encourage the public to increase their consumption of fermented foods to support the health of their microbiota and body. That way, the next time any of us are asked “What should I be eating” we can point to dietary recommendations and say — Fermented Foods!

Read more on fermented foods here and here.

Bacteria illustration

Suggestions for Making Safe Fermented Foods at Home

September 2017 – By Drs. Bruno Pot and Frédéric Leroy, Vrije Universiteit Brussels, Brussels, Belgium.

The impact of lifestyle on the composition and diversity of the human gut microbiota over the last five decades has been tremendous. This is thought to be mainly the result of a cumulative effect ascribed to the increased use of antibiotics and other drugs as well as dietary changes, including consuming less fermented foods that contain live microorganisms.

Fermented foods are important for a healthy diet, as they have the potential to improve the microbiota quality and diversity, are related with reduced disease risk, and can provide essential nutrients.  Consumers are constantly being informed about these benefits, leading to pleas for a return to home-made fermented foods. However, there is rarely mention of the risks that home-made natural fermentations can entail. While making fermented foods at home can be a good idea and help you consume more beneficial microbes, we should realize that the empirical knowhow, skills and equipment to make safe food fermentations may have disappeared over time. This blog is a gentle warning about the possible risks of non-controlled fermentations.

  • Use a starter culture: The use of specific starter cultures at sufficiently high concentration is recommended to properly initiate the fermentation of specific foods and to obtain sufficient control over the process. Relying on spontaneous fermentation (i.e., hoping that environmental bacteria or yeasts initiate the fermentation) increases the risk that uncontrolled fermentations by unsuitable bacteria, yeasts and molds will result in bad or variable quality. In the worst case, dangerous end-products will be obtained.
  • Twice is nice: Starters should not be used repeatedly. Because bacteria multiply several times per hour, their genetic material is changing continuously and the quality of the starter will change over time. It is therefore not a good idea to re-use your ‘old’ product to restart a ‘new’ fermentation all too often, although some fermented food ecosystems such as sourdough or water kefir may usually be ‘backslopped’ frequently. The risks are that off-flavours will be formed or that acidification, which protects your food against the growth of spoilage or pathogenic bacteria, will be too slow.
  • Choose wisely: Not all starters are necessarily safe, although commercially available ones should in principle have been checked for safety (See Helpful Information links below for guidance on findings the right starter). Some yeasts and lactic acid bacteria (LAB) can form compounds (for example, biogenic amines from amino acids) that can result in many health troubles like headache, blood pressure drops, diarrhoea, and even heart problems. You can avoid the production of biogenic amines by using selected starters that do not have the metabolic machinery to make them.
  • To breathe or not to breathe: Some fermentations, like the production of water kefir (usually using dried figs), should be performed in the absence of air and thus require a rubber sealing. For other fermentations, a complete submerging in brine or a covering with oil is necessary. Kombucha, on the contrary, needs a wide opening covered by a cloth that allows oxygen into the vessel. Uncontrolled anaerobic conditions can increase the risk for the growth of clostridia. In cheese making they can be the cause of cheese blowing up, in other conditions they may produce the deadly botulin toxin.
  • Avoid Moulds. Moulds are another problem linked to (too much) oxygen. Moulds can make mycotoxins which can make one very sick and any visible contamination should ring bells! It is not wise to scrape them off, as often they have produced toxins already, left spores or will remain present through their ‘roots’ which most of the time are not visible.
  • Hold the alcohol: During fermentation, sugars are converted to lactic and acetic acids, but also to ethanol. Therefore, the concentration of sugar added may impact the final alcohol levels of the end-product.
  • Pass the gas: In the case of water kefir, the use of a water lock can be necessary, as the CO2 gas which is formed during the fermentation may increase the pressure in the vessel, leading to potential breaking or surprises during opening. Therefore, blown fermented foods products should never be consumed.
  • Party crashers and acid balance: Not all bacteria are your friends. Some undesirables can be present on fresh vegetable products and can in themselves lead to spontaneous fermentation. Therefore, it is important to not let your fermentation be hijacked by these bacteria. The good bacteria should grow and produce acid quickly for a safe fermentation. Pathogens generally cannot grow in high acid environments (below pH 4 is a safe target). This acidity should be reached as quickly as possible during fermentation to avoid the growth of bacteria which can produce toxins or off flavours.
  • Nothing lasts forever: While high acid is essential, it does not protect the food indefinitely. Some yeasts and fungi can grow in high acid. As they grow, some can reduce acidity locally so that (mainly at the surface) other (potentially pathogenic) bacteria can develop
  • Use good quality raw materials. Use only good quality and fresh ingredients when deciding to ferment. While fermentation helps to preserve your fresh foods longer, it will not rescue (almost) spoiled products!
  • Summer and winter milk. If you use milk in your fermentation, it is also possible that the quality of the end product will be different along with the season, as summer milk, harvested from cows in the field, has a different composition from milk harvested from cows fed winterfeed.
  • Temperature. Temperature control is important. While for sauerkraut room temperature 18-22 (65-72°F) is fine, yoghurt fermentation is much better at 37°C (100°F). You, therefore, can expect differences in summer and winter if you do not control the temperature. Find the right spot in the house for both summer and winter.
  • Water activity. In addition to acidification, microbial control is often achieved by reduction of the water activity, generally by sufficient salting and/or drying. This is of major importance to produce fermented sausages. It is important to point out that raw meat is a particularly hazardous matrix, requiring even more care and attention when performed at home.
  • Salt and acetic acid (vinegar) concentration. Both ingredients help keep the pathogens at bay. Stick to recipes that have proven to be reliable.
  • Fermentation time. This is an important factor which can vary a lot and, in turn, impact the quality of your end product. Its critical nature is well known from wine making, in which the duration of the primary and secondary fermentation is well known to be crucial to the quality of the result. While in wine the primary fermentation usually takes between 3 to 7 days, the secondary fermentation can take much longer and will depend on the vial, the alcohol concentration and the yeast used. The fermentation of sauerkraut goes in three stages. ALL three are essential for a safe and tasteful product; a minimum of three to four weeks is necessary. Industrially produced yoghurt can be made in 8 hours, but at home it may take a few hours more. How much more again depends on the milk quality, the starter and the temperature.
  • Do’s and don’t’s: Do invest in a kitchen weighing scale and a thermometer that goes from 0 – 100 °C. Don’t even think about home-made sausage.  Don’t even think about raw-milk cheese.  Do start with simple foods like yogurt or kefir.  There are fool-proof kits for making beer (although they require some hardware).  Sauerkraut and kimchi are relatively easy to make.

Being aware of these simple concepts can help ensure the production of a healthy, tasty fermented food. Consumers should expect that the quality of the resulting fermented food will vary from lot to lot and they should be able to judge when a product is still safe for consumption and when it is not. Consumers should also be aware of the risk factors above and know how to select and handle equipment and execute procedures that will yield safe and nutritious end products.

For additional information:

Fermented Foods on the www.ISAPPscience.org website.

Preparing Fermented Foods and Pickled Vegetables

The University of Georgia Cooperative Extension, the National Center for Home Food Preservation

Safe Preserving: Fermented Foods From the University of Wisconsin Extension

ISAPP Annual Conference photos

ISAPP – Going beyond the science at our annual meetings.

June 2017. By Prof. Glenn Gibson, The University of Reading, UK.

Having never wrote a blog in my life (nor sent a twit nor Instamatic-gram nor facial networking book message), I had to consult my social media savvy children on what this blogging business was all about and who cares anyway. Both looked at me with exasperation, as if I had just crawled out of a cave, and gave me the highly informative answer “Write about what you want, you luddite, but try to make it less boring, than normal. If you write it, then it should perhaps be called clogging not blogging.”

What you might call a total vote of no confidence; anyway it did get me thinking. If this blog was for the ISAPP website, then surely it must have to at least mention probiotics and prebiotics – but that is what I have written about each day for as long as I can remember, and none of that ever had any impact! So, if you are reading this expecting to be educated on bugs, guts, health, faeces, etc, then please do move along to your next Google page.

When I think about what ISAPP has done differently, the science springs to mind, but then there has also been our annual meeting and the associated “fun” (for some people anyway….) activities that have been a hallmark. So, here is my reflection on these. This is all from my-  rapidly fading – memory and all mistakes are my own. I apologise if you have never attended ISAPP and hope that the below text does not discourage you from ever doing so!

It all began in London, Ontario in May 2002 with a treasure hunt in the woods and various ball games (remember, all delegates take part in these exercises). Bob Rastall eventually emerged as the winner and came out of the nearby woods clutching his hard earned treasure like it was a golden fleece. Actually it was a cuddly teddy bear – pink I think, to match his eyes. To this day, he still brags to students about the riches that can be gained with perseverance and unstinting application – as well as several pints of cold drink before tackling the task.

Next year, it was off to Henley UK for the epic Team Probiotics vs Team Prebiotics cricket match. Perhaps about 1% of participants fully understood the rules. Highlights included the Americans pitching the ball like a baseball (known as a beamer in cricketing parlance and highly illegal); Willem de Vos taking mobile phone calls while fielding at deep mid-wicket (which as you know is equidistant between deep square leg and cow corner but at the opposite side of the wicket to cover, point and extra cover i.e. 45o from mid on and fine leg); various attempts to catch the ball with one hand while clutching a full beer in the other; me being out for nothing (a duck) to the worse ever ball bowled in cricket history; the Americans (again) dropping the bat when running. As befitting a game that can last for 5 whole days, a draw was declared.

2004 saw us in the dizzy heights of Copper Mountain resort in Colorado. Here, the fun event took on added sophistication with a GPS driven game and various tasks to be completed. Have you ever seen over 100 highly trained scientists trying to master a small electronic gadget? (think Keystone Cops on amphetamines). Mary Ellen and family were the official adjudicators with Rick being introduced by her as “the nearest thing I’ll get to a secretary.” Gregor’s late night turn in the bar as a hybrid between Dave Lee Roth and one of the Supremes was not to be missed either.

On to Coleraine, Northern Ireland for a tour of the local attractions, including the spectacular Giants Causeway and Carrick-a-Rede rope bridge. Next, was London UK for an open meeting in 2007 where we were entertained by Jimmy Bright the professional comedian. He won over the notoriously tough scientific audience with his tales of British eccentricities and foibles – at least true for those who understood his accent.

The only venue to have hosted ISAPP twice is London, Ontario to where we returned in 2008. The social event here was a user friendly guide to social media by Amber MacArthur. Almost a decade later I write my first blog – well, these things do take time.

In 2009, we visited Newport Beach, California. Here, we hosted a joint meeting with NAS Sackler and therefore had to be on our best behaviour (for proof of this see the image). One highlight was seeing dolphins in the wild from Newport pier.

It was back to sporting excellence in 2010 at Castelldefel. Lots of Spanish family Sunday afternoons were completely ruined by the entire ISAPP descending on their beach for games, loudness and hilarity. This included football (Gregor acting as referee and goalscorer), volleyball, sand pictionary, quiz. Team Black Cats triumphed (had to mention that).

The next meeting was in Berkeley, I was not there so have no thoughts on the social prowess of the conference, but I did hear rumours of broken buses.

Cork in October 2012 featured a distillery trip and céad míle fáilt or póite (a hundred thousand hangovers). The next one in 2013, was joint with New York Academy of Sciences and featured one of the best views ever from a lecture hall. We also took time for a night boat trip on the Hudson.

Aberdeen was our location in 2014 for a joint meeting with the Rowett Institute of Nutrition and Health and INRA. Full scientific humiliation was evident at the Scottish Country Dancing event.

Georgetown, Washington had the ISAPP experience in 2015. This featured a once in a lifetime visit to the National Academy of Sciences for a posh dinner, and many contrived poses in the lecture auditorium.

Last year, we visited Turku, Finland and were transported back to the 1600’s for a medieval banquet hosted by Duke John and Princess Katherine, including the use of bread as a plate.

The 2017 meeting is almost upon us and we turn our mixture of science and fun towards Chicago. There is to be a bowling and beer event. Who knows what will happen, it won’t be pretty but it will definitely be competitive and, hopefully, memorable.

Goodness knows what new humiliation lies ahead for Singapore in 2018?

probiotics bottle

Ever evolving microbial friends – new microbes that could impact health

May 2017. By Prof. Seppo Salminen, Director of the Functional Foods Forum, University of Turku.

Bacteria have been part of our life and part of human nutrition since ancient times. Microbes have a variety of essential roles in fermentations and other production processes, as reviewed by Marco et al (2017). Generally, the bacteria used in fermented foods have a very long history of safe use.

Traditional probiotics, such as species of Lactobacillus and Bifidobacterium, are deemed safe for our food supply, for providing certain nutritional support and as supportive agents for medical treatments. Pediatric and gastroenterology organizations recommend specific Lactobacillus, Bifidobacterium and Saccharomyces probiotics for different benefits, including treatment and prevention of acute pediatric gastroenteritis, antibiotic-associated side effects and diarrhea (ESPGHAN, WGO). Currently, probiotics appear more effective in infants and children than in adults and elderly. Thus, there is a need to continue to develop new probiotic tools for nutrition and medicine especially for adults and the elderly.

New non-traditional species of bacteria being researched for their health benefits are now being proposed for use in foods. These have to be assessed for safety as novel foods or ingredients for food production. With the new regulation in Europe, it is sometimes challenging to find the road to market. In European Union, the novel food legislation has just been revised (EU 2015), applying also to the safety assessment of novel microbes. Two novel microbes have recently been approved in the EU:  Clostridium butyricum and Bacteroides xylanisolvens (the latter only in heat-treated form).  Both approvals concern only safety assessment; health claim applications may be expected later.

Clostridium butyricum has been used as a probiotic in Japan and many other countries, but in Europe, its classification as probiotic without a health claim is unlikely. This is not due to anything unique about C. butyricum, but due to the word ‘probiotic’ being considered a health claim requiring authorization. Bacteroides xylanisolvens in its heat-treated form does not fit the definition of probiotic (Hill et al 2014) as no viable bacteria are present in the product.

Taken together, opportunity exists today for the development of new microbial tools for foods, nutrition, supplements and pharmaceutical targets.  Several research paths are underway, likely resulting in new novel food applications and safety assessments. For example, Akkermansia muciniphila a normal, human colonizing microbe, has shown benefits for obesity-related metabolic effects, but so far only in mice (Gomez-Gallego et al 2016, Plovier et al 2017). Human studies are underway. Animal studies suggest that Faecalibacterium prausnizii treatment may improve hepatic health, and decrease adipose tissue inflammation in mice and these results warrant further studies to discover the therapeutic potential in humans (Munukka et al 2017). However, safety assessment is an essential part of future work for these novel probiotics and the human intervention studies are required to understand the role of novel microbes in health and disease. Thus, there are a lot of challenges for both researchers and the industry to uncover novel effective and safe microbes for future foods and drugs.

fermented foods

That bacteria in your food — It may not be so bad

April 2017. By Chris Cifelli, PhD, VP of Nutrition Research, National Dairy Council, Rosemont, IL.

Bacteria and food. For most people, those two words never belong in the same sentence and, when they do appear together, immediately conjure thoughts of contamination, spoilage, food poisoning, and worse. It is true that unwanted microbes can ruin good food and make us sick if proper food handling procedures are not followed. But what if there were unique situations where food and bacteria did belong together? What if certain microbes could help transform milk, cabbage, cucumbers, grapes, and more into wondrously delicious and healthy foods? This idea is not that farfetched. Quite the opposite – it’s called fermentation and it’s been around for thousands of years.

Fermentation is the process of using specific microbes – for example, bacteria, yeast, and molds – to convert one food to another. Some examples? Milk can be changed into natural cheeses and yogurt. Cucumbers are transformed into pickles. Fermenting cabbage yields kimchi and sauerkraut. Grapes are converted into wine. Some of our most recognized foods are the products of fermentation. What are the benefits of these changes? First, fermentation creates new textures and flavors that increase palatability. Second, fermentation was, and in certain parts of the world continues to be, an important tool for converting a very perishable food into something that has a longer shelf-life. Finally, fermented foods are good for your overall health. For example, fermented foods:

  • Represent a safe way to increase our consumption of live microbes
  • Provide key nutrients as the microbes used in fermentation can make certain essential vitamins
  • Can help inhibit pathogen growth in the intestine
  • Can reduce the risk of developing certain chronic diseases. The most studied has been yogurt, which is associated with less weight gain and reduced risk for cardiovascular disease and type 2 diabetes.

Healthy, balanced diets should include live microbes. Adding fermented foods to your diet is an easy and delicious way to accomplish that. So – next time you think of bacteria and food together maybe you’ll think of a winning combination that can improve health!

happy and sad microbiota

You Have the Microbiota You Deserve!

March 2017. By Colin Hill, PhD, APC Microbiome Institute, School of Microbiology, University College Cork, Ireland

Your microbiota has been selected stochastically from all of the microbes you have encountered during your life, from or perhaps even before your birth. It has also been modified by a number of variables, including your genome, your birth mode, your diet, your health status, your environment and many other factors. At this moment in time it is in a particular configuration as a result of your multiple encounters with nature and nurture. It is unique to you, and hopefully it is relatively stable and resilient. However, if you change your diet significantly, take antibiotics, become unhealthy or regain health, lose or gain weight, move to a less or more developed country, your microbiota will also change. So, at what point is your microbiota optimal and at what point is it sub-optimal and perhaps contributing to ill-health – a state often referred to as ‘dysbiosis’?

Dysbiosis is a very loaded term; ‘dys’ is defined as a combining form meaning “ill” or “bad”, implying that the microbiota being described is actually causing harm. Can we really say that any particular microbiota is ‘ill’ or ‘bad’? Maybe, to paraphrase Tolstoy’s comment on families, we can say that in healthy individuals all microbiotas are optimal, but that in unhealthy individuals all microbiotas are dysbiotic in their own way. But this is instinctively unsatisfying, and means that the term has little value as a scientific descriptor. It becomes even more confusing if we consider your microbiota and my microbiota – your beneficial microbiota could well drive disease in me and therefore be considered dysbiotic, even though we could share many characteristics, including our general health or disease status.

But suppose you have a relatively stable gut microbiota and your doctor prescribes a broad spectrum antibiotic. Your microbiota is disrupted and within a few days you succumb to antibiotic associated diarrhoea – surely we can refer to this as dysbiosis? Well, maybe not. It could be argued that disrupted microbiota may well be appropriate for someone following antibiotic treatment – and perhaps diarrhoea may well be the correct evolutionary response to a massive microbial disruption? Perhaps we have evolved to react to a substantial change in the gut microbiota with a version of colonic irrigation to ‘purge’ the system and accelerate the return to a stable diverse microbiota.

It could be reasoned that there are other instances where the term ‘dysbiosis’ might be useful. Consistent observations of reduced diversity or specific alterations in the microbiota of individuals with certain disease states could be thought of as dysbiosis. But an individual with a specific chronic health condition may be simply selecting for a microbiota with reduced diversity, or altered ratios of specific phyla, genera or species. It may even be that someone with a particular disease may benefit from having such an altered microbiota.

The aphorism attributed to Baas Becking – ‘Everything is everywhere, but, the environment selects’ – may be the key concept. Inevitably, each different environment will select a different microbiota. The microbiota then influences the environment, which influences the microbiota, until a stable outcome is achieved. Any external perturbation now has the potential to disrupt this homeostasis. These changes may be subtle or dramatic, they may slow down or reverse disease development, or they may exacerbate or sustain a chronic disease state. We need more evidence of causality before we can even begin to discuss ‘good’ and ‘bad’ members of the microbiota, and we are a long way from identifying an optimal microbiota. This is true for any given individual, never mind the problem of defining what constitutes a good microbiota at a population level. Even if we adopt the concept that the microbiota in a healthy individual is intrinsically healthy, we still cannot know if it is actually driving as yet unseen health defects (cancer, inflammation, neurological diseases?) which will only be obvious over extended time.

There is also the evidence that faecal microbiota transplants (FMT) work well in individuals with Clostridium difficile associated diarrhoea, and promising results are emerging for other health states. This suggests that ‘good’ microbiotas can supplant dysbiotic ones and confer health benefits. But FMT has not been subjected to the kind of rigorous blinded and controlled investigations that more precise interventions would be expected to undergo, and the jury has to remain out for now on whether we can characterise FMT as the replacement of a dysbiotic microbiota with an optimal one.

So, can we talk about ‘good’ and ‘bad’ microbiotas in general terms? Perhaps we can. Resilience to change is almost certainly a feature of a stable microbiome; and if you are healthy, not changing is almost certainly a good thing. Also, the concept of diversity as an asset is not limited to microbiotas, but is an established ecological principle. Of course, we also have to recognise that there will be exceptions to every rule, and that the optimal vaginal microbiota may well be one of low diversity. Nonetheless, we can still have meaningful discussions about increasing diversity and supporting resilience as desirable targets, particularly in complex microbiotas such as that in the gut. But we should be careful of assuming that increasing diversity is always beneficial, because introducing a member of one microbiota to another (and therefore increasing diversity) may have unforeseen consequences. For a ‘real-world’ example, introducing rabbits into the Australian environment increased diversity by one species in the short term, but in the absence of appropriate predators they have caused tremendous damage to a previously stable ecosystem.

We can suggest that where an individual symbiont (such as a healthy human) is in a state of homeostasis and has a stable microbiota, any disruption could present a risk to health. But we don’t need to call this ‘dysbiosis’. We can simply refer to it as ‘changed’, ‘altered’, ‘modulated, ‘disrupted’ or ‘in flux’. So, let’s be careful about speaking of dysbiotic microbiotas. At this point in our understanding we cannot know whether you have a ‘good’ or a ‘bad’ microbiota, but we can say that based on your life to date ‘you have the microbiota you deserve’!

caution sign with picture of antibiotics

Antibiotics: Use with Caution

February 2017. By Karen Scott, PhD, Rowett Institute of Nutrition and Health, University of Aberdeen, Scotland.

Since the discovery of penicillin by Sir Alexander Fleming in 1928, antibiotics have saved millions of lives, and have rightly been described as wonder drugs. Yet since the late 1990s we have become increasingly aware that bacterial resistance to antibiotics is threatening their very use. We can no longer be complacent that we will be able to treat outbreaks of infectious diseases using our existing antibiotic repertoire.

The indiscriminate use of antibiotics in their heyday has led to many bacteria developing resistance to survive. This creates an obvious problem in medicine, where previously treatable diseases become untreatable. The emergence of multi-drug resistant pathogens—methicillin resistant Staphylococcus aureus (MRSA), vancomycin resistant Enterococcus (VRE) and even multiple drug resistant tuberculosis (MDR-TB)—is the result of this problem. Globalization means that no country can solve this independently; it requires a worldwide initiative. European countries were first to recognise that the widespread use of antibiotics in intensive agriculture, primarily to shorten the time for meat production, was resulting in the spread of resistant bacteria to the human population. In response, the EU banned the use of all antibiotics in farming except to actually cure disease, and certain medically important antibiotics, known as “antibiotics of last resort,” were banned completely. As early as 1969 the SWANN report suggested that the use of medically important antibiotics be restricted in agriculture and this came into practice in 1972 in many European countries. This was followed by a complete ban on the use of antimicrobials as growth promoters, first in Sweden in 1986 and subsequently Europe-wide in 2006. However, China and India have actively used antibiotics as growth promoters since the 1990s, after the European ban. Furthermore, unless procedures are put in place that offer alternatives and monitor compliance, such a ban does not work. Prebiotics are one such alternative in animal husbandry, promoting the growth and activity of the ‘good bacteria’ that are already resident in the animal gut.

Without enforcement, many farms find a way around the rules: in the Netherlands, the amount of antibiotics used did not change between 2006 and 2011, the ‘therapeutic use’ simply increased! There are still many countries around the world where there are no restrictions on the use of antibiotics and bacterial super-pathogens continue to evolve, killing people through treatment failures. Bacteria recognise no borders – travellers frequently return with more than what they intentionally packed in their luggage.

The development and overuse of broad-spectrum antibiotics has created an additional problem. They indiscriminately kill not just the target pathogenic bacterium, but many other bacteria the antibiotic contacts. Pair this with our new awareness that humans are heavily colonised inside and out with diverse bacterial populations performing essential functions to keep us healthy, and the problem becomes apparent. In his book Missing Microbes, Martin Blaser posits that the diversity of our microbial symbionts is declining with each generation. The reduction is so severe that bacterial species that colonised our parents may not be around to colonise our kids. If one of those bacteria performed a unique function, that function would be lost as well. Consider Oxalobacter formigenes, a Gram-negative bacterium that resides in our gut and is capable of degrading oxalate and thus reducing deposition of calcium oxalate, the main component of kidney stones.  The prevalence of O. formigenes in a population ranges from 38% to 62%, with colonization lowest in people susceptible to kidney stones and in people with greater antibiotic exposure, indicating that the bacterium may be particularly sensitive to antibiotics. Are we dooming future generations to ever increasing rates of kidney stones if we eliminate our saviour bacterium from our gut microbiota?

While we are undergoing antibiotic therapy, bacterial diversity within the gastrointestinal tract decreases, although most bacterial species return to detectable numbers once the selective pressure is removed. However, during the time of decreased diversity our resilience to other infections decreases. One very important opportunistic pathogen, Clostridium difficile, has perfected the art of colonising the gut during the at-risk period. C. difficile produces toxins that affect the gut wall, and its infection can develop into a life threatening disease. It is important that we do as much as possible to alleviate the effect that antibiotics have on the commensal microbiota. One approach is using probiotics. There is evidence that consuming probiotics along with antibiotics can prevent C. difficile infection, possibly by creating a temporary bacterial barrier until the normal microbiota recovers. Despite difficulties in comparing scientific studies with different numbers of patients, different ages, and different probiotic strains, the general benefit is outlined in a recent review.

Overall, we need to reduce the use of antibiotics and recent evidence suggests that probiotics can also have a role here. Analysis of data gathered in 12 separate studies showed that routine consumption of probiotics can reduce the number of people developing upper respiratory tract infections (by 11%), reduce the duration of the infection, and importantly reduce the number of antibiotic prescriptions given out for these infections.

Bacteria are very resilient. Faced with extinction due to antibiotic killing, they will try everything to survive. They can acquire resistance genes from neighbouring bacteria lucky enough to contain them. They can even play dead by changing into spores: dormant, non-replicating bacterial forms that cannot be affected by antibiotics, and which can regenerate once the antibiotic pressure is removed. These strategies mean that bacterial antibiotic resistance is here to stay. In order to keep ahead of the game and make sure that antibiotics remain effective in treating infectious disease for our children through to our great-great-great grandchildren, we have to act now, saving antibiotics for situations where they are really needed. It may well be that probiotics and prebiotics will help us to do this.

probiotics as superman cartoon

It Needn’t End Up Toxic

December 2016. By Gregor Reid PhD FRSC, Lawson Health Research Institute and Western University, London, Canada –  November was a dramatic month with the shock Trump US Presidential victory, Earthquakes in New Zealand and Japan, and the “Prophet of Doom” in South Africa finally brought to justice for spraying pesticides in the faces of the faithful to cure their cancers and HIV infections. While global warming has believers and non-believers, the ability of humans to massively pollute the planet is indisputable. The US Environmental Protection Agency’s 2010 National Lakes Assessment found that nitrogen and phosphorus pollution affected almost 20 percent of the 50,000 lakes surveyed (1). Use of pesticides, herbicides and fertilizers in food production is high in many countries that provide food for those of us who want our favorite fruits on demand all year. I believe, it’s time to care about these issues and how our body copes with toxic chemicals.

Could it be that the microbes in our airways, skin and gastrointestinal tract are providing more of a barrier function than we ever thought? The ability of microbes to degrade oil and waste has long been known and used as part of the strategy to clean up our environment. In humans, many chemicals interact with P450 enzymes in ways that can lead to reactive products that evoke toxic and/or carcinogenic effects, or to chemically inert products that are removed from the body (2). In addition, the microbiota can affect cellular detoxification through enhanced cytochrome P450 (CYP) enzyme activity (3). So, the potential for some lactic acid bacteria (LAB) and probiotic microbes to supplement this process is now being explored.

LAB can degrade some organophosphate pesticides that are known to contaminate milk. In addition, using a Drosophila model, we recently showed that L. rhamnosus GR-1 and other strains can reduce toxic organophosphate exposure by passive binding (4) and by countering immune suppression (unpublished). Using a C. elegans model, a Lactobacillus casei gavage was found to upregulate the phase-II detoxification enzymes coding genes metallothioneins (mtl-1 and mtl-2) and glutathione-S-transferase (gst-8) and thereby eliminate organophosphorus insecticide malathion from the host (5).

While skin ointments are being developed for the military to protect against chemical warfare agents such as sulfur mustard and VX, they can also block parathion pesticide and acrolein irritants (6). The potential for probiotic strains and lysates to up-regulate the skin barrier is also being examined, although not yet against adsorption by toxic chemicals (7,8).

Some LAB can bind to heavy metals and express antioxidative properties to protect against heavy metal toxicity. Although only so far shown in mice, L. plantarum CCFM8610 was protective against acute and chronic cadmium toxicity through decreasing intestinal Cd absorption, reducing tissue accumulation, alleviating tissue oxidative stress, and even reversing hepatic and renal damage (as reviewed in 9). In other words, multiple mechanisms are at play. The human study we performed in Tanzania, showed children and pregnant women are indeed exposed to mercury and arsenic, likely from consumption of fish from Lake Victoria, and daily intake of L. rhamnosus GR-1 supplemented yogurt significantly reduced metal uptake (10). This is stimulating others to examine metals responsible for neurotoxicity and cognitive development of children.

In summary, I am heartened that people are (albeit slowly) now considering employing so-called beneficial microbes to protect us from some of the toxic effects of environmental chemicals. Lowering exposure to, and use of, these compounds will take a paradigm shift in how we view what we eat and how we treat the land. But, by empowering consumers through probiotic food and supplement options, we may be able to save some lives and improve a whole lot of others. In the end, it really needn’t end up quite so toxic thanks to our tiny microbial helpers.

Papers cited

1. https://www.epa.gov/nutrientpollution/where-occurs-lakes-and-rivers

2. Shimada et al. Binding of diverse environmental chemicals with human cytochromes P450 2A13, 2A6, and 1B1 and enzyme inhibition. Chem Res Toxicol. 2013 Apr 15;26(4):517-28

3. Collino S, et al. Metabolic signatures of extreme longevity in northern Italian centenarians reveal a complex remodeling of lipids, amino acids, and gut microbiota metabolism. PLoS One. 2013;8(3):e56564.

4. Trinder M, et al. Probiotic Lactobacillus rhamnosus reduces organophosphate pesticide absorption and toxicity to Drosophila melanogaster. Appl Environ Microbiol. 2016 Sep 30;82(20):6204-6213.

5.  Kamaladevi A. Lactobacillus casei stimulates phase-II detoxification system and rescues malathion-induced physiological impairments in Caenorhabditis elegans. Comp Biochem Physiol C Toxicol Pharmacol. 2016 Jan;179:19-28.

6. Dachir S, et al. Dermostyx (IB1) – High efficacy and safe topical skin protectant against percutaneous toxic agents. Chem Biol Interact. 2016 Jul 11. pii: S0009-2797(16)30284-8.

7. Jeong JH, et al. Probiotic lactic acid bacteria and skin health. Crit Rev Food Sci Nutr. 2016 Oct 25;56(14):2331-7.

8. Kim H, et al. Effects of oral intake of kimchi-derived Lactobacillus plantarum K8 lysates on skin moisturizing. J Microbiol Biotechnol. 2015 Jan;25(1):74-80.

9. Zhai Q, et al. Dietary strategies for the treatment of cadmium and lead toxicity. Nutrients. 2015 Jan 14;7(1):552-71.

10. Bisanz J., et al. Randomized open-label pilot study of the influence of probiotics and the gut microbiome on toxic metal levels in Tanzanian pregnant women and school children. MBio. 2014 Oct 7;5(5):e01580-14.

probiotics and fermented foods flow cytometry

Alive or active? Active and alive! Flow cytometry has arrived.

November 8, 2016. By Bruno Pot, PhD, Vrije Universiteit Brussels, Belgium –

Probiotics need to be alive and confer health benefits for the host (Hill et al. 2014; FAO/WHO 2001). There are no further specifications as to the mechanisms underpinning these health effects. A large number of papers currently describe the wide diversity of the probiotic mechanisms, varying from the production of specific metabolites (see references 1-6, below), the presence of cell wall compounds (7-10) or the production of specific proteins (11), and covering a wide variety of possible probiotic or commensal bacteria.

While many of these mechanisms require the bacteria to be active at the site of action, they rarely require the bacteria to actively multiply. This observation has triggered the notion ‘active’ in addition to ‘alive’. While it is clear that active bacteria are alive, and therefore in agreement with the consensus definition of probiotics, the problem lies in the difficulties of counting active cells that are not multiplying. The latter will, obviously, not give rise to colonies, excluding traditional colony counting methods for their enumeration. In contrast, approaches like 16S-rRNA based PCR (quantitative or qualitative) will detect dead bacteria, which we do not want to count.

While validation of microbiological methods is difficult for many reasons (see here) flow cytometry technologies offer very interesting perspectives in detecting active bacteria. The technology has been used for a long time for analyzing subpopulations of bacteria in probiotic products or dairy starters (12). Moreover, flow cytometry was known to be able to discriminate between viable and dead cells also for nearly 25 years (13). While also the validation approaches for microbiological methods were known, it was not until January 2016 that the method, through a joint effort of ISO and International Dairy Federation, was formally validated, resulting in the ISO 19344 (IDF 232) standard. This standard now provides a flow cytometry-based method to quantify lactic acid bacteria in fermented products, starter cultures and dairy probiotics. Besides being able to discriminate between- and quantify- active and total cells, flow cytometry has other advantages such as high testing speed and low variability. Therefore the method is very useful during production and shelf life follow up.

Flow cytometry is also promising for fundamental research in the field of probiotics as well as in the evaluation of microbiological parameters in clinical trials with these products. It will be useful to quickly to count active bacteria or to measure a differential count between active and colony forming bacteria. Further, probiotic producers may be especially interested in the method as the colony count method likely underestimates the number of live bacteria in their products.

Will we start to see probiotic labels where CFU is replaced by ‘numbers of active bacteria’? Probably not anytime soon. The idea of detecting and counting ‘active’ bacteria is here to stay, but the use of that information on a label seems unlikely in the near future, as the notion ‘active’ versus ‘alive’ does not really change the way probiotics exert their beneficial activity. The positive point of the new method is that it potentially allows a much more precise determination of the probiotic in the product, positively drawing industries’ attention to the number of bacteria, definitely an important aspect of the probiotic definition.


  1. Elise Heuvelin, Corinne Lebreton, Corinne Grangette, Bruno Pot, Nadine Cerf-Bensussan, Martine Heyman. Mechanisms Involved in Alleviation of Intestinal Inflammation by Bifidobacterium Breve Soluble Factors. PLOS. 2009 ; http://dx.doi.org/10.1371/journal.pone.0005184)
  2. Elise Heuvelin, Corinne Lebreton , Maurice Bichara, Nadine Cerf-Bensussan and Martine Heyman. A Bifidobacterium Probiotic Strain and Its Soluble Factors Alleviate Chloride Secretion by Human Intestinal Epithelial Cells. J. Nutr. 2010; 140 (1):7-11. (http://jn.nutrition.org/content/140/1/7)
  3. Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermúdez-Humarán LG, Gratadoux JJ, Blugeon S, Bridonneau C, Furet JP, Corthier G, Grangette C, Vasquez N, Pochart P, Trugnan G, Thomas G, Blottière HM, Doré J, Marteau P, Seksik P, Langella P. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients ;  Proc Natl Acad Sci USA. 2008 Oct 28;105(43):16731-6. doi: 10.1073/pnas.0804812105. Epub 2008 Oct 20.
  4. E Quévrain, M A Maubert, C Michon, F Chain, R Marquant, J Tailhades, S Miquel, L Carlier, L G Bermúdez-Humarán, B Pigneur, O Lequin, P Kharrat, G Thomas, D Rainteau, C Aubry, N Breyner, C Afonso, S Lavielle, J-P Grill, G Chassaing, J M Chatel, G Trugnan, R Xavier, P Langella, H Sokol, P Seksik. Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn’s disease. Gut 2014; doi:10.1136/gutjnl-2014-307649.
  5. Ghalia Kacia, Denise Goudercourt,  Véronique Denninc, Bruno Pot,  Joël Doré, S. Dusko Ehrlicha, Pierre Renault, Hervé M. Blottière, Catherine Danielc,d,e,f and Christine Delorme. Anti-Inflammatory Properties of Streptococcus salivarius, a Commensal Bacterium of the Oral Cavity and Digestive Tract. Appl. Environ. Microbiol. 2014; 80(3): 928-934.
  6. Carissa M. Thomas, Teresa Hong, Jan Peter van Pijkeren, Peera Hemarajata, Dan V. Trinh, Weidong Hu, Robert A. Britton, Markus Kalkum, James Versalovic. Histamine Derived from Probiotic Lactobacillus reuteri Suppresses TNF via Modulation of PKA and ERK Signaling. PLOSone http://dx.doi.org/10.1371/journal.pone.0031951.
  7. Corinne Grangette, Sophie Nutten, Emmanuelle Palumbo, Siegfried Morath, Corinna Hermann, Joelle Dewulf, Bruno Pot, Thomas Hartung, Pascal Hols and Annick Mercenier. Enhanced anti-inflammatory capacity of a Lactobacillus plantarum mutant synthesizing modified teichoic acids. PNAS. 2005. 102(29):10321–10326, doi: 10.1073/pnas.0504084102
  8. Macho Fernandez E1, Valenti V, Rockel C, Hermann C, Pot B, Boneca IG, Grangette C. Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide. 2011. Gut. 2011 Aug;60(8):1050-9. doi: 10.1136/gut.2010.232918. Epub 2011 Apr 6.
  9. Deutsch SM, Parayre S, Bouchoux A, Guyomarc’h F, Dewulf J, Dols-Lafargue M, Baglinière F, Cousin FJ, Falentin H, Jan G, Foligné B. Contribution of surface β-glucan polysaccharide to physicochemical and immunomodulatory properties of Propionibacterium freudenreichii. Appl Environ Microbiol. 2012 Mar;78(6):1765-75. doi: 10.1128/AEM.07027-11. Epub 2012 Jan 13.
  10. Foligné B., Deutsch S. M., Breton J., Cousin F.J., Dewulf J., Samson M., Pot B. and Jan G. (2010). Promising immunomodulatory effects of selected strains of dairy propionibacteria as evidenced in vitro and in vivo. Appl. Environ. Microbiol. 76:8259-8264.
  11. Fang Yan and D. Brent Polk. Characterization of a probiotic-derived soluble protein which reveals a mechanism of preventive and treatment effects of probiotics on intestinal inflammatory diseases. Gut Microbes. 2012 Jan 1; 3(1): 25–28. doi:  10.4161/gmic.19245.
  12. Christine J. Bunthof and Tjakko Abee. Development of a Flow Cytometric Method To Analyze Subpopulations of Bacteria in Probiotic Products and Dairy Starters. Appl Environ Microbiol. 2002 Jun; 68(6): 2934–2942 ; doi:  10.1128/AEM.68.6.2934-2942.2002
  13. J. P. Diaper, K. Tither, C. Edwards. Rapid assessment of bacterial viability by flow cytometry. 1992. Applied Microbiology and Biotechnology. Volume 38, Issue 2,  pp 268–272.
illustration of doctor on see saw with bacteria

A Tipping Point for Probiotic Use? A Clinician’s Perspective

November 2016. By Daniel Merenstein, MD, Georgetown University Medical Center –

As a clinician and clinical researcher in the probiotic field, I am beginning to think we have reached a tipping point for clinical use of probiotics.

This month, the Journal of the American Medical Association (JAMA) published three articles dealing with probiotics. I heard about these through a friend of mine who asked, “Can you send me this article? I’m curious how probiotics are disparaged this time.” (For example, see here.) This is a reasonable refrain, as too often as probiotics are lumped together with questionable supplements. Part of this blame clearly falls on the probiotic industry, as there are some products that are sold with limited or no evidence base. However, the medical community seems finally to be catching up with the research on the probiotics that have been well-studied. This changing opinion was clearly evidenced by the article; while I assumed my friend’s pessimism would be justified, we were instead both surprised that probiotics were not just mentioned in the article, but they were generally recommended and supported.

The first paper was a survey of supplement usage in the United States. They reported a 156% increase in probiotic usage over last 10 years (p value trend=0.03).  The second paper was an accompanying editorial, which primarily addressed all the problems with supplements: the lack of studies, efficacy questions and limited enforcement of regulations. This editorial stated, “Not all supplements, of course, lack evidence of efficacy. Many supplements, including vitamins, minerals, and probiotics, are important components of modern health care.” Finally, the third paper was a very thorough review published under the JAMA heading, JAMA Clinical Evidence Synopsis. This paper summarized the evidence for probiotics for prevention of antibiotic-associated diarrhea (AAD) in infants and children. The authors concluded, “BOTTOM LINE: Moderate-quality evidence suggests that probiotics are associated with lower rates of antibiotic-associated diarrhea in children (aged 1 month to 18 years) without an increase in adverse events.”

Although the likes of JAMA seem to be embracing the probiotic data, and articles about probiotics or the microbiome are now commonplace in today’s mainstream news and are regularly featured in medical journals, there is still room for improvement in how probiotics are implemented medically. The three large health care systems that operate near me in the Washington DC area carry a probiotic product in their formularies that has limited to no evidence base. Recently, I reached out to the American Society of Hospital Pharmacists to see if ISAPP could work with them to develop a more evidence-based approach to the products offered in hospitals. I am confident that a tipping point has been reached and that in a few years nearly all hospitals and physicians will adopt an evidence-based approach to probiotic administration.

Even considering the need to do better, I think that probiotics have now achieved a firm status in the medical community. Patients and consumers have accepted them for years as the survey data demonstrate, and an increasing number of physicians have as well. For some indications such as ulcerative colitis, traveler’s diarrhea and colic it is more often the norm than the exception when physicians recommend probiotics. I believe that the three articles in the JAMA issue reflect this evolving awareness of probiotics among physicians and importantly reflect a shift to higher expectations of evidence for use.

As this field expands, a risk is that even more products with limited evidence will try to partake in this market opportunity. To protect the important gains made by these important and well-studied probiotics, we need to be ever more vigilant to guard against poor products tainting the evidence-based products by association.

Dan Merenstein, M.D.
Associate Professor
Department of Family Medicine
Georgetown University Medical Center

Elizabeth D. Kantor, Colin D. Rehm,  Mengmeng Du,  et al. JAMA.  2016;316(14):1464-1474. doi:10.1001/jama.2016.14403

Pieter A. Cohen. JAMA. 2016;316(14):1453-1454. doi:10.1001/jama.2016.14252

Bradley C. Johnston, Joshua Z. Goldenberg, Patricia C. Parkin. JAMA.  2016;316(14):1484-1485. doi:10.1001/jama.2016.11838

truth about probiotics illustration

Consumer Reports: Helping or Hurting Consumers?

October 2016.

By Mary Ellen Sanders, PhD, Executive Science Officer ISAPP –

In July, a well-respected source of unbiased product ratings, Consumer Reports (CR), published a damning article on dietary supplements.

The article begins with an account of a premature infant who died from intestinal mucormycosis believed to be caused by a mold contained in a probiotic supplement given to prevent necrotizing enterocolitis (NEC). (See here and here). NEC is a life-threatening disease most common in premature infants. CR spent over 500 words discussing this tragedy as a lead-in to make the point that dietary supplements are unsafe.

As a scientist, I question CR’s decision to focus on an example that says nothing about the inherent safety of the substance (a probiotic) being used as a supplement. This is a case about a product that appears to have been contaminated by a mold that was dangerous to a vulnerable, premature infant. It is not a case about probiotic safety. A peer-reviewed article published in the Journal of Pediatric Gastroenterology and Nutrition characterized this incident correctly: “The fatal adverse event affected a premature infant; it was accidental and related to the consumption of a contaminated dietary supplement” (Agostoni et al. 2016).

CR conflated the safety of substances used as dietary supplements and the potential safety risk of a contaminated product. Risks associated with contaminated products are not limited to dietary supplements. In this example, the contaminant likely posed no risk to a generally healthy person. But to a premature infant, this mold was deadly.

CR continues to tell about this ill-fated incident in a section titled “Unproven Treatments,” completely ignoring that probiotic use to prevent NEC is far from unproven. A recent Cochrane Collaboration review of the evidence for use of probiotics to prevent morbidity and mortality associated with NEC showed a 57% decrease in incidence of NEC and 35% decrease in death in premature infants given probiotics. The review concluded that available evidence strongly supports a change in medical practice to implement probiotics to prevent NEC, although they acknowledge that additional studies are important to assess the “most effective preparations, timing and length of therapy to be utilized” (AlFaleh and Ahabrees 2014).

Premature infants who develop NEC have an uncertain path ahead. Infants with NEC risk surgical removal of their colon or death (mortality ranges from 20-40%). Those who survive are at increased risk of neurodevelopmental disability and if surgical intervention was necessary, may develop short bowel syndrome. Clearly, prevention of this dangerous condition is the goal, and probiotics are useful to achieve this.

CR’s stated objective is to empower “consumers with the knowledge they need to make better and more informed choices” and to “advocate for truth and transparency.” Yet this article obfuscated the efficacy data on a treatment that could significantly prevent morbidity and mortality among premature infants. I expect this article will have a net negative impact on consumer health. Misguided readers and physicians discouraged or afraid to use probiotics to prevent NEC will lead to higher incidence of infant death and serious morbidity. Consumers interested in other probiotic benefits, such as management of symptoms of functional bowel disorders or prevention of antibiotic-associated diarrhea, may also be dissuaded from products with potential benefits.

There is clearly a need for dietary supplements used in at-risk populations to meet quality criteria necessary to reasonably assure safety. A probiotic targeted for premature infants may need more stringent microbiological standards (Sanders et al. Probiotic Use in At-Risk Populations. In Press. J. Amer Pharmacists Assoc.). CR should have made this point instead of trying to convince consumers that probiotics – which are among the best studied supplement ingredients for both efficacy and safety – are unsafe.

Related article: The Importance of Quality in Probiotic Products