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.

References:

  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

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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

gut bacteria illustration

Got gas? Blame it on your bacteria

September 2016.

By Prof. Robert Hutkins, PhD –

When I tell friends and family that I study gut bacteria and gut health, the most frequent question I am asked is why some foods cause intestinal gas.   The next question is almost always whether or not gas is such a bad thing.

Bloating, constipation, indigestion, and yes, intestinal gas, are among the most common health complaints among the general population.  Indeed, one of the main reasons for a person to see a gastroenterologist is due to excessive “passing of gas”.

According to the actual research, most healthy people have about 10 to 20 discharges per day.  In terms of volume, this represents about a liter of gas (about a quart’s worth).  And yes, some poor graduate student probably had to somehow measure this.

In general, intestinal gas or flatulence is only a problem in social circumstances, like business meetings, religious events, classrooms, or elevators.  Apart from the sound effects and associated aroma, gas is usually not a serious condition. At minimum it is usually only annoying or embarrassing.  When it’s more severe, however, excessive gas can have considerable impact on quality of life.  It may also be a symptom of a chronic condition, like Irritable Bowel Syndrome (IBS) or celiac disease, for which a physician should be seen.

Although there are many causes for intestinal gas, diet is certainly near the top of the list.  The notion that there are gas-generating foods has become part of our popular culture. On the American Gastroenterological Association list of such foods are milk (for lactose maldigestors only) and high-fiber grains, like whole wheat, oatmeal and oat bran.  Sweeteners like fructose and sorbitol can also be gas-producing.

Unfortunately, many of the healthy foods we are encouraged to eat, including broccoli, cauliflower, cabbage, Brussel sprouts, and other cruciferous vegetables are known to cause gas.  Likewise for onions, leeks, garlic, figs, and prunes.  However, it’s the beans, lentils, and other legumes that are perhaps the most infamous gas-causing foods (thanks, in part, to the campfire scene in Blazing Saddles).

Ultimately, there are two main reasons for intestinal gas.  One is simply swallowed air. Some, but not all, of this air is expelled via burps.

The other source of gas, and the main reason why foods are implicated, is (micro)biological.  Specifically, the foods mentioned above (beans, bran, and broccoli) all contain carbohydrates that resist digestion in the stomach and small intestine and make their way to the colon.  Upon arrival, they become food for the trillions of bacteria that reside there.  These bacteria ferment these carbohydrates and produce gases, mainly hydrogen, carbon dioxide, and methane.  Some gases are adsorbed, some are expelled via breathing, and some are recycled by other bacteria.  But the gas that remains – well, it’s got to go somewhere, and that somewhere is you know where.

It’s important to note that many of these gas-producing bacteria that feed on dietary fibers are often the same species that contribute to intestinal health.  That’s one reason why a little gas can be good, even smelly gases like hydrogen sulfide. It tells you the bacteria in your gut are doing their job.  Indeed, there is a new category of food ingredients called prebiotics that are now being added to yogurt, kefir, crackers, and other foods for the purpose of nourishing gut bacteria.

For people already struggling to get more whole grains, beans, vegetables, and fiber into their diet, intestinal gas can be quite unwelcome.  However, researchers have shown that patience is a virtue.  Consumers who increase their fiber consumption may experience gassiness, but they will often return to normal after a week or two. Gradual increases are often easier to manage. Finally, there is emerging evidence that some probiotic bacteria can reduce the frequency and volume of gas.

Prof. Robert Hutkins, PhD
Khem Shahani Professor of Food Science
University of Nebraska, Lincoln
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