The Microbiome — Can it aid in the diagnosis and therapy of irritable bowel syndrome (IBS)?

By Eamonn M M Quigley, MD FRCP FACP MACG FRCPI MWGO

Lynda K and David M Underwood Center for Digestive Disorders, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders and seems to be prevalent across the globe1. Although non-fatal, IBS impacts on quality of life, personal relationships and productivity and can impose a significant socioeconomic burden on the individual as well as on society at large. Despite considerable effort there is still no test to diagnose IBS and, in clinical practice, the diagnosis commonly rests on the presence of characteristic symptoms, such as those defined by the Rome criteria2, in an individual in which alternate diagnoses have been excluded or deemed unlikely. The concern of the IBS sufferer and his/her physician is that because IBS symptoms are relatively non-specific (abdominal pain, altered bowel habit and bloating) a diagnosis based on symptoms alone may miss “something serious”.

Several challenges confront those who attempt to design a diagnostic test or new therapy for IBS. First, IBS is not a homogeneous disorder; symptoms, their severity and impact vary considerably. Second, symptoms tend to fluctuate over time with periods of calm interposed between episodes of much distress. Third, it is almost certain that IBS is multifactorial with various factors contributing to a variable extent in each sufferer. Over the years, genetic predisposition, gut motility and sensation, how the brain senses activity in the gut, and how the body responds to stress have all been invoked to explain the development of symptoms in IBS. While all of these factors undoubtedly contribute, none has yielded a diagnostic test.

One concept, that of the gut-brain axis, has served as a useful paradigm to explain IBS symptoms with dysfunction at various points along the axis, which extends all the way from the cerebral cortex to gut muscle, nerve and mucosa and back again, variably contributing to the presentation of IBS in different individuals3,4. Now, connections between the gut and the brain have been extended to include a new participant, the microbiome. This leads to the concept of the microbiome-gut-brain axis, whereby bacteria resident in the gut could impact on the “big brain” and even contribute to neurological and neuropsychiatric disease5. There is substantial experimental data to indicate that gut microbes influence components of the gut barrier, the intestinal immune system and the neuromuscular apparatus of the gastrointestinal tract, as well as central nervous system structure and function6.

Could the gut microbiome produce a diagnostic test for IBS?

That microbiota might be a factor in IBS was first suggested by the observation that IBS could develop de novo in the aftermath of acute enteric bacterial, viral or parasitic infections7. More recently, modern sequencing technology has been applied to fecal and colonic microbiota in IBS with the aim of determining relationships between a variety of clinical and demographic parameters and microbiota. Although data remain limited, and not always consistent, it is evident that IBS patients have an altered fecal microbiota relative to healthy individuals8. Currently available data are fraught with challenges in interpretation – small study populations, variations in patient selection and methodology, not to mention a failure to account for such confounders as diet, stool form and consistency, therapy, co-morbid psychopathology and symptom severity. Nonetheless, some overall patterns have emerged: the fecal and colonic mucosal microbiota are different in IBS and the fecal microbiota may not only predict severity9, but also responsiveness to one common intervention – the low fermentable oligo-, di- and monosaccharides and polyols (FODMAP) diet10. It is now abundantly clear that the expectation that a single microbial signature might typify IBS was naïve.

Recent progress

While we are not yet able to diagnose IBS using the microbiome, some very interesting observations have resulted from applying the highest quality microbiome science to what was once regarded as fringe and unimportant.

  1. Lessons from multi-omics

In the first of these studies, Kashyap’s lab, and its collaborators, employed a multi-omics approach in a longitudinal study of a reasonably large cohort of IBS sufferers and were able to identify IBS subtype-specific and symptom-related variations in microbial composition and function and to relate certain bacterial metabolites with physiological mechanisms relevant to IBS in the host11. A disturbed microbiome or an aberrant host response to the microbiome might well involve the generation of intraluminal molecules with biological effects on motility, sensation, gut barrier function, immune activation and, of course, communication with the central nervous system. A very high level of methodological complexity was needed to identify these relationships since IBS symptoms vary not only between individuals but over time within individuals.

  1. Food-related symptoms – linking bacteria, food antigens and the immune response

IBS sufferers have been telling us for decades that having a meal often makes their symptoms worse. Various explanations have been advanced to explain this phenomenon ranging from an exaggerated gastro-colonic reflex to food allergy and intolerance. A recent paper from Aguilera-Lizarraga and colleagues reveals just how complicated this story might well be – involving an interaction between bacterial infection, dietary antigens and immunoglobulin (Ig)E and mast cell responses in the host. In a mouse model, infection with Citrobacter rodentium led to a breakdown in oral tolerance to the food antigen ovalbumin which resulted in the development of an IgE antibody-mediated response locally in the colon and ultimately to diarrhea and visceral hypersensitivity, a common feature of IBS12. They went on to show that the injection of some common food antigens (soy, wheat, gluten and milk) into the rectosigmoid mucosa of IBS sufferers resulted in edema and mast cell activation. It was notable that the development of visceral hypersensitivity in the mouse model did not appear to be related to any change in the resident microbiome or to ongoing chronic inflammation but seemed to be a very specific interaction between the original infectious insult, loss of oral tolerance and the subsequent development of IgE antibodies to a dietary antigen. The net result was the activation of neural pathways responsible for visceral hypersensitivity.  These findings certainly extend our understanding of post-infection IBS, but to what extent they relate to IBS, in general, remains to be determined.

  1. Beyond bacteria

To date the focus on studies of the microbiome in IBS (or, for that matter, in most disease entities) has been on bacteria. Das and colleagues expanded their microbiota inquiry to consider the contributions of fungi (the mycobiome) to IBS13. They found significant differences in mycobiome diversity between IBS sufferers and control subjects but the mycobiome could not differentiate between IBS subtypes. Interestingly, mycobiome alterations co-varied with those in the bacteriome but not with dietary habits. Unfortunately, as has been the case with studies of bacterial populations, these changes in the mycobiome proved “insufficient for clinical diagnosis”.

  1. Fecal microbiota transplantation and IBS

Based on the assumption that gut microbial communities are disturbed in IBS and considering the success and overall excellent safety record of fecal microbiota transplantation/transfer (FMT) in the management of severe or recurrent Clostridioides difficile infection, it should come as no surprise that FMT has been employed in IBS14-24. Results to date have been mixed and, for now, preclude a recommendation that FMT be adopted to treat IBS. Two observations are of note. Both are derived from a randomized double-blind, placebo-controlled, clinical trials where the instillation of the patient’s own feces served as the control. First, the positive clinical results in the studies by El-Salhy and his colleagues seem to relate to the use of a “super-donor”20. Second, the report from Holvoet and colleagues suggests that the baseline microbiome of the recipient predicted response to FMT albeit in a very unique group of IBS sufferers21.  Indeed, it appears that a successful FMT, in IBS, is associated with the normalization of a number of components of the colonic luminal milieu22-24. Herein may lie clues to guide the future use of “bacteriotherapy” in IBS.

Conclusions 

It should come as no surprise, given advances in techniques to study the microbiota coupled with exciting data from animal models, that the paradigm of the microbiota-gut-brain axis has been proposed as relevant to IBS. The possibility that a disturbed microbiome, or an aberrant host-response to that same microbiome, might be relevant to IBS and could impact on the CNS is now being contemplated seriously as an avenue to understand disease progression and treatment as well as to open new diagnostic and therapeutic possibilities on this challenging disorder. As much of the extant data comes from animal models one must remain cautious in their interpretation – no single animal model can recapitulate the IBS phenotype. The bi-directionality of microbiota-gut-brain interactions must also be remembered – the complex interactions between inflammation and the gut microbiota exemplify how a disease state can impact on the microbiota.  With regard to interventions, there are many intriguing approaches, but still a long way to go to achieve personalized pharmabiotic therapy for that very special individual – the IBS sufferer.

References

  1. Sperber AD, Bangdiwala SI, Drossman DA, et al. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study. Gastroenterology 2020 [epub ahead of print].
  2. Lacy BE, Mearin F, Change L, et al. Bowel Disorders. Gastroenterology 2016;150:1393-1407.
  3. Camilleri M, Di Lorenzo C. Brain-gut axis: from basic understanding to treatment of IBS and related disorders. J Pediatr Gastroenterol Nutr. 2012;54:446-53.
  4. Camilleri M. Physiological underpinnings of irritable bowel syndrome: neurohormonal mechanisms. J Physiol. 2014;592:2967-80.
  5. Quigley EMM. Microbiota-Brain-Gut Axis and Neurodegenerative Diseases. Curr Neurol Neurosci Rep 2017;17:94.
  6. Mayer EA, Tillisch K, Gupta A. Gut-brain axis and the microbiota. J Clin Invest. 2015;125:926-38.
  7. Klem F, Wadhwa A, Prokop LJ, et al. Prevalence, Risk Factors, and Outcomes of Irritable Bowel Syndrome After Infectious Enteritis: A Systematic Review and Meta-analysis. Gastroenterology. 2017;152:1042-1054.
  8. Pittayanon R, Lau JT, Yuan Y, et al. Gut Microbiota in Patients WithIrritable Bowel Syndrome-A Systematic Review. 2019;157:97-108.
  9. Tap J, Derrien M, Törnblom H, et al. Identification of an Intestinal Microbiota Signature Associated With Severity of Irritable Bowel Syndrome. Gastroenterology. 2017;152:111-123.
  10. Bennet SMP, Böhn L, Störsrud S, et al. Multivariate modelling of faecal bacterial profiles of patients with IBS predicts responsiveness to a diet low in FODMAPs. Gut 2018;67:872-81.
  11. Mars RAT, Yang Y, Ward T, et al. Longitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome. 2020;183:1137-1140.
  12. Aguilera-Lizarraga J, FlorensMV, Viola MF, et al. Local immune response to food antigens drives meal-induced abdominal pain. Nature 2021;590:151-156.
  13. Das A, O’Herlihy E, Shanahan F, et al. The fecal mycobiome in patients with Irritable Bowel Syndrome. Sci Rep 2021;11:124.
  14. Myneedu K, Deoker A, Schmulson MJ, Bashashati M. Fecal microbiota transplantation in irritable bowel syndrome: A systematic review and meta-analysis. United European Gastroenterol J. 2019;7:1033-1041.
  15. Halkjær SI, Christensen AH, Lo BZS, et al. Faecal microbiota transplantation alters gut microbiota in patients with irritable bowel syndrome: results from a randomised, double-blind placebo-controlled study. 2018;67:2107-2115.
  16. Johnsen PH, Hilpüsch F, Cavanagh JP, et al.Faecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome: a double-blind, randomised, placebo-controlled, parallel-group, single-centre trial. Lancet Gastroenterol Hepatol. 2018;3:17-24.
  17. Aroniadis OC, Brandt LJ, Oneto C, et al. Faecalmicrobiota transplantation for diarrhoea-predominant irritable bowel syndrome: a double-blind, randomised, placebo-controlled trial. Lancet Gastroenterol Hepatol. 2019;4:675-685.
  18. Johnsen PH, Hilpüsch F, Valle PC, Goll R. The effect of fecal microbiota transplantation on IBS related quality of life and fatigue in moderate to severe non-constipated irritable bowel: Secondary endpoints of a double blind, randomized, placebo-controlled trial. 2020;51:102562.
  19. Lahtinen P, Jalanka J, Hartikainen A, et al. Randomised clinical trial: faecalmicrobiota transplantation versus autologous placebo administered via colonoscopy in irritable bowel  Aliment Pharmacol Ther. 2020;51:1321-1331.
  20. El-Salhy M, Hatlebakk JG, Gilja OH, et al. Efficacy of faecal microbiota transplantation for patients with irritable bowel syndrome in a randomised, double-blind, placebo-controlled study. Gut. 2020;69:859-867.
  21. Holvoet T, Joossens M, Vázquez-Castellanos JF, et al. FecalMicrobiota Transplantation Reduces Symptoms in Some Patients With Irritable Bowel Syndrome With Predominant Abdominal Bloating: Short- and Long-term Results From a Placebo-Controlled Randomized Trial. 2021;160:145-157.
  22. Mazzawi T, Hausken T, Hov JR, et al. Clinical response tofecal microbiota transplantation in patients with diarrhea-predominant irritable bowel syndrome is associated with normalization of fecal microbiota composition and short-chain fatty acid levels. Scand J Gastroenterol. 2019;54:690-699.
  23. Goll R, Johnsen PH, Hjerde E, et al. Effects offecal microbiota transplantation in subjects with irritable bowel syndrome are mirrored by changes in gut microbiome. Gut Microbes. 2020;12:1794263.
  24. El-Salhy M, Valeur J, Hausken T, Gunnar Hatlebakk J. Changes infecal short-chain fatty acids following fecal microbiota transplantation in patients with irritable bowel  Neurogastroenterol Motil. 2020:e13983.

 

ISAPP board members look back in time to respond to Benjamin Franklin’s suggestion on how to improve “natural discharges of wind from our bodies”

Benjamin Franklin, born in 1706, was a multi-talented politician and scientist best known for his discoveries related to electricity. Historians say he was scientifically pragmatic—aiming not just to advance theories, but to solve the most vexing problems of the day.

In 1780, when Franklin read about the intellectual contests being held by The Royal Academy of Brussels (today known as the Royal Flemish Academy of Belgium for Science and the Arts – KVAB), he took it upon himself to write an amusing letter that contained a suggestion for an important scientific challenge: “To discover some Drug wholesome & not disagreable, to be mix’d with our common Food, or Sauces, that shall render the natural Discharges of Wind from our Bodies, not only inoffensive, but agreable as Perfumes.”

Over two centuries later, the organization was prompted for a reply. Writer Brian Van Hooker wrote to the KVAB: ‘I am a writer at MEL Magazine and I am working on a piece about a letter that Benjamin Franklin sent to your organization’s predecessor, the Royal Academy of Brussels, 240 years ago. The letter was entitled “Fart Proudly,” and I’m reaching out to see if anyone at your organization might like to issue a reply to Mr. Franklin’s letter’.

Since ISAPP board member Prof. Sarah Lebeer (University of Antwerp, Belgium) is a KVAB Belgian Young Academy alumna with microbiome knowledge, Bert Seghers from the Academy asked her to help draft a reply. However, since the gut microbiome is not her main area of expertise, she consulted her fellow ISAPP board members. For example, Bob Hutkins, author of a popular ISAPP blog post on intestinal gas, immediately sent her a paper entitled Identification of gases responsible for the odour of human flatus and evaluation of a device purported to reduce this odour with the comment: “The next time a graduate student complains about their project, refer them to this paper and the 5th paragraph of the methods”—a paragraph that describes how scientists in the experiment were tasked with rating the odor of flatus and differentiating between the different smells of sulphur-containing gases.

But it was the answer of Prof. Glenn Gibson (University of Reading, UK) that was incorporated into the ‘formal’ reply to Franklin’s suggestion. “Your suggested topic on improving flatulence odour is amusing, but indeed also very relevant. An outstanding answer to the contest as you formulate it would be ground-breaking,” wrote Profs. Lebeer and Gibson. They noted that gases in the intestine are mainly released by the bacteria living there—but especially the sulphate reducing bacteria contribute to the “traditional” smell due to their production of noxious H2S —and that advances in probiotic and prebiotic science could one day lead to reduced (and “nicer smelling”) gas production by switching hydrogen gas production to methane or even acetate and away from H2S.

Brian Van Hooker summarized: “In other words, Mr. Franklin, they’re working on it and, perhaps sometime within the next 240 years, your dream of non-smelly farts might just come true.”

The KVAB response to Benjamin Franklin concluded: “Your letter is a ripple through time. It may not surprise you that scientific questions can have effects across decades and even centuries. This idea remains the tacit hope of many scientists working together for the progress of humanity. We have not yet invented a reverse time machine, but we send our answer along with your question forward in time, hoping that it may inspire future scientists as your question inspired us.”

Read the MEL Magazine article here.

Read more about gut microbiota & intestinal gas here.

ISAPP ha estado trabajando en colaboración con la Sociedad de Enterocolitis Necrotizante

La Asociación Científica Internacional para Probióticos y Prebióticos (ISAPP, por sus siglas en inglés), ha estado trabajando en colaboración con la Sociedad de Enterocolitis Necrotizante (NEC Society) en el desarrollo de una infografía sobre el rol de los probióticos en la prevención de la Enterocolitis Necrotizante (ECN).

La ECN es una enfermedad intestinal que puede poner en peligro la vida principalmente en bebés prematuros. Esta enfermedad produce un proceso inflamatorio que puede provocar daños en el tejido intestinal e incluso la muerte.

La leche materna de la madre del bebé es la forma más importante de ayudar a disminuir el riesgo de ECN. La leche pasteurizada de madres donantes es la segunda mejor opción. Adicionalmente, suministrar probióticos a bebés prematuros, junto con la leche materna, puede reducir el riesgo de ECN.

Los probióticos son microorganismos vivos que, cuando se administran en cantidades adecuadas, confieren un beneficio para la salud del huésped.

Los padres con hijos con riesgo de desarrollar ECN pueden consultar a los responsables de la Unidad de Cuidados Intensivos, sobre la posibilidad de utilizar probióticos para contribuir a prevenir el desarrollo de ECN.

ISAPP ha preparado una infografía en español con mayor información sobre este tema, la cual se puede encontrar aquí.

Can fermented or probiotic foods with added sugars be part of a healthy diet?

By Dr. Chris Cifelli, Vice President of Nutrition Research, National Dairy Council, Rosemont IL, USA

What about added sugar in fermented or probiotic foods? I am almost always asked this question whenever I give a nutrition presentation, no matter the audience. It’s not a surprising question as people care about what they eat and, often, are looking for ways to reduce their intake of sugar. Yet, if someone wants to add fermented or probiotic foods such as yogurt, kefir or kombucha to their diet, they often find the products available to them contain sugar as an added ingredient.

Should these products be part of you and your family’s healthy eating plan even if they have added sugar? The simple answer – yes, they likely can still fit into a healthy eating plan.

According to the U.S. Food and Drug Administration, ‘added sugars’ are defined as sugars that are either added during the processing of foods or are packaged separately as sugars (e.g. the bag of sugar you buy to make your treats). Added sugars in the diet have received attention because of their link to obesity and chronic disease risk. The World Health Organization, American Heart Association, Dietary Guidelines for America, and American Diabetes Association all recommend reducing added sugar intake to improve overall health. While data from the US National Health and Nutrition Examination Survey (NHANES) has shown that consumption of added sugar decreased from the 2007-2010 to the 2013-2017 surveys, the most recent Dietary Guidelines Advisory Committee report noted that the mean usual consumption of added sugars was still 13% of daily energy in 2015-16, which exceeds recommendations of 10%.

Including fermented foods in one’s diet may be important for overall health. The recent ISAPP consensus paper on fermented foods indicated that fermented foods, especially the live microbes contained in them, could benefit health in numerous ways, such as by beneficially modulating the gut microbiota or the immune system. Similarly, foods with added probiotics may confer health benefits ranging from impacting digestive health to metabolic parameters, depending on the probiotic contained in the product. Our understanding of the gut microbiota continues to evolve, but one thing is for certain: it is important for health. This provides a compelling reason to find ways to include these foods in healthy eating patterns.

So, back to the question at hand. Should you reduce or eliminate fermented foods and foods with probiotics from your diet if they have added sugars? Just like a “spoonful of sugar helps the medicine go down,” a little added sugar to improve the palatability of nutrient-dense foods is okay. Indeed, government and health organizations all agree that people can eat some sugar within the daily recommendations (which is 10% of total daily calories), especially in foods like yogurt or whole-grain cereals, or other healthy foods. And, there is no scientific evidence to show that the sugar in these products reduces the health benefits associated with eating foods like yogurt or probiotics. Human studies assessing health benefits of probiotic foods typically use products with added sugar, yet health effects are still observed.

The next time you are out shopping you can choose your favorite fermented or probiotic-containing food guilt free, as long as you’re watching your overall daily intake of sugar. But, if are you are still concerned, then choose plain varieties to control your own level of sweetness or you could opt for a probiotic supplement to avoid the sugar. Whether you go with the sweetened or unsweetened version of your favorite fermented food, you’ll not only get the benefit of the live microbes in these products but also the nutritional benefit that comes with foods like yogurt.

 

The future is microbial: A post-pandemic focus on identifying microbes and metabolites that support health

By Prof. Maria Marco, Department of Food Science and Technology, University of California Davis, USA

The COVID-19 pandemic has been a sobering reminder of the significance that microorganisms have on human life. Despite the tremendous scientific and medical advances of the twentieth century, our best precautions against the virus have been to practice the oldest and most simplistic of all public health measures such as washing hands and maintaining physical distance from others. At the same time, the effectiveness of the new SARS-CoV-2 vaccines and the speed in which they were developed show how sophisticated and advanced our understanding of viruses has become. Taken together, the limitations and successes of responses to the pandemic underscore the power of investment in microbiology research. This research, which was first catalyzed by the pioneering work of Louis Pasteur, Robert Koch, and contemporaries in the late 1800s, was the basis for the overall reduction in infectious diseases during the twentieth century. Continued investment in these efforts will prepare us for the next pandemic threat.

Beyond pathogens to health-promoting microbes

As our attention turns to the promise of the New Year, we may also take this moment to appreciate the fact that microorganisms can also do good. Our “microbial friends” were first promoted by the lauded biologists Élie Metchnikoff, Henry Tissier, and Issac Kendall at the turn of the twentieth century. Since then, nearly another century passed before the power of microorganisms to benefit human health reached wider acceptance.

Marked by the emergence of laboratory culture-independent, nucleic-acid based methods to study microbial communities, there is now excitement in the identification of microorganisms that are important for health promotion. This interest is catalyzed by the urgency to find ways to prevent and treat cardiovascular diseases, cancers, and other non-communicable, chronic conditions that are now the leading causes of death worldwide. Much like the pressure to address infectious diseases as the primary cause of mortality prior to the twentieth century, so too is the need today for sustained research investments in studying how certain microorganisms contribute to, or may be essential for, preventing and treating the greatest threats to public health in the modern era.

Exemplified by the growing number of human microbiome studies, it is now broadly understood that the human microbiome contributes positively to digestive, immune, and endocrine systems function. Systematic reviews and meta-analyses of clinical trials support the use of probiotics for a variety of conditions and there are positive associations between the consumption of fermented dairy foods and good metabolic health. To understand how microbes can be beneficial, numerous mechanisms have been proposed (for example, modulation of the immune system and production of neurochemicals that can impact the gut-brain axis), and these mechanisms apply to both autochthonous microbiota and probiotics alike. However, our understanding of exactly how this occurs lags far behind what is currently known about microorganisms that cause harm.

Identifying microbes & metabolites that maintain health

The future of beneficial microbes is in identifying the specific, health-promoting metabolites, proteins, and other compounds that they make. Presently only a handful of such examples are known. Perhaps most recognized are the short chain fatty acids, butyrate, propionate, and acetate, which are known to bind specific human cell receptors to modulate numerous cell pathways including those that affect metabolism. Other microbial compounds generated as intermediate or end products of microbial metabolism (such as metabolites of amino acids), secondary metabolites (such as bacteriocins), and bacterial cell surface constituents (such as certain membrane proteins) were shown to benefit health, although a more complete description of mechanistic details for their effects remains to be discovered. Precise mechanistic descriptions of “beneficial factors”, or the microbial enzymatic pathways and molecules that induce desired cellular and systemic responses in the human body, will be pivotal for elucidation of the precise ways microorganisms sustain health and well-being (for more detail on this topic see here).

Based on what we know about the complexity of the human microbiome and the now many decades of probiotics research, this effort will require innovation and multi-disciplinary coordination. Just as early microbiologists raced to address the high rates of mortality due to microbial pathogens, we are in a new age where again microorganisms are regarded as emerging public health threats. However, we now have to our advantage the knowledge that not all microorganisms cause harm but instead the majority may offer solutions to the greatest health challenges of the twenty-first century.

 

 

Creating a scientific definition of ‘fermented foods’

By Prof. Maria Marco, Department of Food Science and Technology, University of California Davis, USA

A panel of scientific experts was recently convened by ISAPP to discuss the state of knowledge on fermented foods. While there was much agreement on the underlying microbiological processes and health-related properties of those foods and beverages, our conversation on definitions led to sustained debate. So what exactly is a fermented food?

The word “ferment” originates from fervere, which in Latin means to boil. According to the Merriam-Webster dictionary, the verb ferment is defined as “to undergo fermentation or to be in a state of agitation or intense activity”. Fermentation is defined as both a chemical change with effervescence and as an enzymatically controlled anaerobic breakdown of energy-rich compounds (such as a carbohydrate to carbon dioxide and alcohol or to an organic acid). In biochemistry, fermentation is understood as an ATP-generating process in which organic compounds act as both electron donors and acceptors. In industry, fermentation means the intentional use of bacteria and eukaryotic cells to make useful products such as drugs or antibiotics. As you can see, there are clearly many meanings implied in “ferment” and “fermentation”. We add onto this by defining how those words apply to foods.

As our ISAPP panel began to deliberate the definition of fermented foods, it quickly became clear how difficult reaching consensus can be! Even though many panel members shared similar academic backgrounds and scientific expertise, finding agreement on the definition required several rounds of debate and some consuming of fermented foods and beverages along the way. Finally, we defined fermented foods and beverages as being “foods made through desired microbial growth and enzymatic conversions of food components” (see the published consensus paper here).

Find ISAPP’s infographic on fermented foods here.

This definition is very specific by requiring microbial growth and enzymatic processes for the making of those foods. Activity of the endogenous enzymes from the food components or enzymes added to the food is not enough for a food to be regarded as fermented. Similarly, foods made by only adding vinegar or “pickling” should not be called fermented. The definition acknowledges the essential roles of microorganisms for making fermented foods but does not require their presence or viability at the time of consumption.

On the other hand, our definition does not restrict fermented foods to only those foods and beverages made using microorganisms using metabolic pathways implicit in the strict biochemical definition. Yogurt and kimchi made using lactic acid bacteria relying on fermentative energy metabolism are included as much as koji and vinegar, foods made using fermentation processes that employ fungi and bacteria that perform aerobic respiratory metabolism.

Each word in a definition needs to be carefully calibrated. The best example of this in our definition of fermented foods is the word “desired”. Unlike a food that is spoiled as a result of microbial growth and enzymatic activity, food fermentations generate wanted attributes. Other words such as “intentional”, “desirable”, or “controlled” may also be used to describe this meaning. However, those words also have caveats that not all fermented foods are made “intentionally”, at least in the way that they were first prepared thousands of years ago. Qualities of fermented foods may be “desirable’ in some cultures but not others. While some fermentations are “controlled”, others are spontaneous, requiring little human input.

The process of discussing the definition with a group of scientific experts was enlightening because it required us to deconstruct our individual assumptions of the term in order to reach agreement on descriptions and meaning. With a definition in hand, we can use a shared language to study fermented foods and to communicate on the significance of these foods and beverages in our diets. There will also certainly be more “fermenting” of these concepts to improve our knowledge on the production and health impacting properties of fermented foods for years to come.

Find the ISAPP press release on this paper here.

Read about another ISAPP-led publication on fermented foods here.

Learn more in a webinar on the science of fermented foods here.

Ambient yogurts make a global impact

By Prof. Bob Hutkins, PhD, University of Nebraska Lincoln, USA

Quick, which country consumes the most yogurt? Must be France? Or the Netherlands? Maybe Turkey? The United States, perhaps? Try none of the above: the answer is China.

While many other countries consume way more yogurt than China on a per capita basis, China’s population gives it an advantage, with 1.4 billion potential consumers. And yogurt has become one of the most popular snack foods in China. It’s especially trendy among young and affluent urbanites. Indeed, total consumption of yogurt in China now exceeds that of France, the Netherlands, Turkey, and the United States, combined!

Whereas per capita consumption of yogurt in China in 2000 was around 1 kg per person per year, it’s now approaching 5 kg. Yogurt consumption even exceeds that of fluid milk.

Considering that dairy consumption was virtually non-existent in China for thousands of years, this trend is nothing short of a cultural phenomenon. While some of the yogurt consumed in the country is produced by domestic manufacturers, yogurt and yogurt ingredients are also being imported from other countries in the region, including New Zealand and Australia.

There is, however, one major difference between yogurt typically consumed in China and the products consumed in other regions. Indeed, ambient yogurt, short for “yogurt-based product for ambient distribution”, is all the rage in China.

Ambient yogurt and yogurt drink products, as the name implies, are stable at room temperature. This is achieved by heat-treating the yogurt after fermentation.  Many ambient yogurts are aseptically processed similar to ultra-high-temperature processed (UHT) products, leaving the product commercially sterile (i.e. without live microbes) and stable for up to a year. In China, these products can still be labeled as yogurt.

Not only are these ambient yogurt products convenient for retailers, but also, a cold-chain infrastructure, often absent in rural areas of China, is not necessary during transport and distribution. Perhaps for this reason, ambient yogurts are also being introduced in other regions, including Africa, South America, and the Middle East.

The popularity of yogurt in China, in the absence of a live microbe label declaration, is evidently due to the ‘healthy’ virtues or halo effect ascribed to yogurt, because of its high protein, calcium, and vitamin content. Perhaps there are also postbiotic benefits in the yogurt – this would be an interesting topic for research. But the novel flavors, textures and grab-and-go convenience, especially for drinkable yogurt products, also appeals to teens and young adults.

Traditionalists balk at the very idea of heat-treating yogurt and inactivating the live microorganisms. In some countries, such products cannot even be labeled as yogurt. In the U.S., these products can be labeled as yogurt but must be further labeled as “heat-treated”.

In reality, consumers’ expectation of live microbes in yogurt is so ingrained that heat-treated yogurts are nearly impossible to find in the United States. Indeed, yogurt, kefir, and other cultured milk and non-dairy products are promoted, in part, on the high number of viable microbes they contain. Probiotics are added to more than 90% of the yogurts sold in the United States.

According to international CODEX standards, yogurt must be made with Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus, AND must contain at least 107 CFU/g “through to the date of minimum durability after the product has been stored under the storage conditions specified in the labeling”. Any other labeled bacteria must be present at a minimum of 106 CFU/g. The CODEX standards have been widely adopted, although some countries have lower minimum levels.

Interestingly, and despite appeals by yogurt manufacturers, the U.S. Food and Drug Administration does not require minimum numbers of CFUs for yogurt. They have been considering changes that would be consistent with CODEX for more than a decade. In regions that do not require the CODEX standards, the International Dairy Foods Association offers the Live & Active Cultures (LAC) seal, which requires 107 CFU/g of yogurt cultures at time of manufacture.

The China National Food Safety Standard for Fermented Foods does specify a minimum Lactobacillus count of 106 CFU/g, but importantly, also includes the following footnote:

“products that have gone through heat treatment after the fermentation process will not be subjected to any requirements on the minimum Lactobacillus Count”

Such products, however, must be labeled as heat-treated. It should be noted that there is still a substantial market for more traditional (chilled) yogurt containing live microorganisms.  Still, ambient yogurts account for most of the yogurt consumed in China.

Given the relatively flat yogurt market in Europe and the United States, it should not be surprising that this rapidly growing market in China has attracted so much attention.  The China Nutrition Society and government policymakers have recommended that consumers increase dairy consumption to 3 times higher than current levels. That means a lot more yogurt will be consumed in China.

Translated, that means, from culture companies to processing and packaging industries, there will continue to be plenty of interest, innovation, and investment in yogurt for the Chinese population. For example, new generation yogurt products have recently been introduced with the claim of having 90 days’ shelf-life and containing live probiotic bacteria.

Still, whether by new or traditional technologies, the availability and consumption of live microbes in yogurt and other cultured products may be expected to increase as Chinese consumers become more informed about their health benefits. Perhaps, as cold-chain infrastructure also improves, these live yogurts may become a bigger part of the yogurt culture in China.

 

ISAPP collaborates with NEC Society to help parents understand the role of probiotics in reducing the risk of necrotizing enterocolitis

By Dr. Mary Ellen Sanders, PhD, ISAPP Executive Science Officer

To date, over 50 clinical trials on probiotics and necrotizing enterocolitis have been published. Medical organizations have considered the trials completed to date and have provided guidance (ESPHGAN) and recommendations (American Gastroenterological Association) for implementing probiotics in clinical practice.

As important as the science on this issue are the perspectives from parents of babies who have suffered from NEC or are at risk of developing the disease. Such parents consistently point to the need for credible and balanced educational materials about this condition. Recently, ISAPP has been fortunate to work with the NEC Society to develop materials that will help inform parents.

See the new ISAPP infographic Probiotics and Necrotizing Enterocolitis: What Parents Should Know.

Disponible también en español. Информация также доступна на русском языке.

Also, a recent ISAPP blog Probiotics to Prevent Necrotizing Enterocolitis: Moving to Evidence-Based Use by Dr. Ravi Patel MD, a neonatologist on the NEC Society’s Scientific Advisory Council, summarizes the state of the science supporting this use, including both controlled efficacy trials and post-implementation surveys.

The NEC Society is a nonprofit organization – the only US group dedicated to NEC – with the stated mission of “building a world without necrotizing enterocolitis (NEC) through research, advocacy, and education.” They advocate for families affected by NEC by bringing together critical stakeholders to improve understanding, prevention, and treatment for NEC. Jennifer Canvasser founded the NEC Society in 2014 after her son, Micah, died from complications of NEC just before his first birthday. Micah was born at 27-week’s gestation, placing him at increased risk of NEC. Despite Micah’s risk factors and his parents asking the care team to consider offering Micah probiotics, he was not treated with probiotics. Although it is impossible to know if probiotics could have changed Micah’s course, his parents feel that more could have been done to better protect Micah from the devastation of NEC. Micah’s photo is featured in the new infographic co-created by ISAPP and the NEC Society.

“It is vital for healthcare providers to support NICU parents in understanding the protective and risk factors associated with NEC,” Canvasser shared. “Parents are the most important members of their baby’s care team. For parents to effectively engage and contribute, they need to be supported in accessing and understanding important information related to their child’s health. This new resource on probiotics and NEC will help to ensure that NICU parents are informed and feel encouraged to ask questions so they can best advocate for their child.”

The NEC Society intends to use the new infographic as a resource available to NICU parents and providers. It will be downloadable from the websites of both the NEC Society and ISAPP, and it will be shared via both social media platforms. Once in-person events are possible again, print versions will be made available. ISAPP will also work with the NEC Society’s Scientific Advisory Council to explore how we can further disseminate this resource to NICUs.

Read more about the efforts of the NEC Society here:

Head of the Herd: Jennifer Canvasser, Founder and Director, Necrotizing Enterocolitis (NEC) Society

Family Reflections: harnessing the power of families to improve NEC outcomes

10 Things All Parents of NICU Babies Need to Know

9 Things You Need to Know About Necrotizing Enterocolitis

New ISAPP-led paper calls for investigation of evidence for links between live dietary microbes and health

The past two decades have brought a massive increase in knowledge about the human gut microbiota and its links to human health through diet. And although many people perceive that regular consumption of safe, live microbes will benefit their health, the scientific evidence to date has not been sufficiently developed to justify adding a daily recommended intake of live microbes to food guides for different populations.

Recently, a group of seven scientists, including six ISAPP board members, published their perspective about the value of establishing the link between live dietary microbes and health. They conclude that although the scientific community has a long way to go to build the evidence base, efforts to do this are worthwhile.

The collaboration on this review was rooted in an ISAPP expert discussion group held at the 2019 annual meeting in Antwerp, Belgium. During the discussion, various experts presented evidence from their fields—addressing the potential health benefits of live microbes in general, rather than the narrow group of microbial strains that qualify as probiotics.

Below, the authors of this new review answer questions about their efforts to quantify the relationship between greater consumption of live microbes and human health.

Why is it interesting to look at the potential importance of live microbes in nutrition?

Prof. Joanne Slavin, PhD, RD, University of Minnesota

Current recommendations for fiber intake are based on protection against cardiovascular disease—so can we do something similar for live microbes? We know that intake of live microbes is thought to be health promoting, but actual recommended intakes for live microbes are missing.  Bringing together a talented group of microbiologists, epidemiologists, nutritionists, and food policy experts moves this agenda forward.

Humans need proper nutrition to survive, and a lack of certain nutrients creates a ‘deficiency state’. Is this the case for live microbes?

Dr. Mary Ellen Sanders, PhD, ISAPP Executive Science Officer

I don’t think we’ll find that live microbes are essential in the same way that vitamins and minerals lead to deficiency diseases. After all, gnotobiotic animal colonies are viable. But I believe there is enough evidence to suggest that consumption of live microbes will promote health. Exactly how and to what extent remains to be established.

Why think about intake of ‘live microbes’ in general, rather than intake of probiotic & fermented foods specifically?

Prof. Maria Marco, PhD, University of California Davis

We are constantly exposed to microorganisms in our foods and beverages, in the air, and on the things we touch. While much of our attention has been on the microbes that can cause harm, most of our microbial exposures may not affect us at all or, quite the opposite, be beneficial for maintaining and improving health. Research on probiotic intake as a whole supports this possibility. However, probiotic-containing foods and dietary supplements are only a part of our dietary connection with live microbes. Non-pasteurized fermented foods (such as kimchi and yogurts) can contain large numbers of non-harmful bacteria (>10^7 cells/g). Fruits and vegetables are also sources of living microbes when eaten raw.  Although those raw foods they may contain lower numbers of microbes, they may be more frequently eaten and consumed in larger quantities. Therefore, our proposal is that we take a holistic view of our diets when weighing the potential significance of live microbe intake on health and well-being.

What are dietary sources of live microbes? And do we get microbes in foods besides fermented & probiotic foods?

Prof. Bob Hutkins, PhD, University of Nebraska Lincoln

For tens of thousands of years, humans consumed large amounts of microbes nearly every time they ate food or drank liquids. Milk, for example, would have been unheated and held at ambient temperature with minimal sanitation and exposed to all sorts of microbial environments.  Thus, a cup of this milk could easily have contained millions of bacteria. Other foods like fruits and vegetables that were also exposed to natural conditions could have also contained similar levels of microbes. Even water would have contributed high numbers of live microbes.

Thanks to advances in food processing, hygiene, and sanitation, the contemporary western diet generally contains low levels of microbes. Consider how many foods we eat that are canned, pasteurized, or cooked – those foods will contain few, in any live microbes. Fresh produce can serve as a source of live microbes, but washing, and certainly cooking, will reduce those levels.

For sure, the most reliable sources of dietary microbes are fermented foods and beverages. Even if a fresh lettuce salad were to contribute a million bacteria, a single teaspoon of yogurt could contain 100 times more live bacteria. Other popular fermented foods like kefir, kimchi, kombucha, and miso, can contain a large and relatively diverse assortment of live microbes. Other fermented foods, such as cheese and sausage, are also potential sources, but the levels will depend on manufacturing and aging conditions. Many fermented, as well as non-fermented foods are also supplemented with probiotics, often at very high levels.

What’s the evidence that a greater intake of live microbes may lead to health benefits?

Prof. Dan Merenstein, MD, Georgetown University

Studies have shown that fermented foods are linked to a reduced risk of cardiovascular disease, reduced risk of weight gain, reduced risk of type 2 diabetes, healthier metabolic profiles (blood lipids, blood glucose, blood pressure and insulin resistance), and altered immune responses. This link is generally from associative studies on certain fermented foods. Many randomized controlled trials on specific live microbes (probiotics and probiotic fermented foods) showing health benefits have been conducted, but randomized controlled trials on traditional fermented foods (such as kimchi, sauerkraut, kombucha) are rare. Further, no studies have aimed to assess the specific contribution of safe, live microbes in diets as a whole on health outcomes.

Why is it difficult to interpret past data on people’s intake of live microbes and their health?

Prof. Colin Hill, PhD, University College Cork

It would be wonderful if there were a simple equation linking the past intake of microbes in the diet and the health status of an individual (# MICROBES x FOOD TYPE = HEALTH). In reality, this is a very complex challenge. Microbes are the most diverse biological entities on earth, our consumption of microbes has not been deliberately recorded and can only be estimated, and even the concept of health has defied precise definitions for centuries. To further confuse the situation microbes meet the host in the gastrointestinal tract, the site of our enormously complex mucosal immune system and equally complex microbiome.  But the complexity of the problem should not prevent us from looking for prima facie evidence as to whether or not such a relationship is likely to exist.

Databases of dietary information have data on people’s intake of live microbes, but what are the limitations of our available datasets?

Prof. Dan Tancredi, PhD, University of California Davis

Surveys often rely on food frequency questionnaires or diaries to determine consumption of specific foods. These are notoriously prone to recall error and/or other types of measurement error. So, even just measuring consumption of foods is difficult. For researchers seeking to quantify survey respondents’ consumption of live microbes, these challenges become further aggravated because the respondents would not typically know the microbial content in the foods they consumed. Instead, we would have to have them tell us the types and amounts of the foods they ate, and then we would need to translate that into approximate microbial counts—but even within a particular food, the microbial content can vary, depending on how it was processed, stored, and/or prepared prior to consumption.

See ISAPP’s press release on this paper here.

Locally produced probiotic yogurt for better nutrition and health in Uganda

By Prof. Seppo Salminen, Director of Functional Foods Forum, University of Turku, Turku, Finland

Can locally produced probiotic yogurt be a way to increase the health and wealth of people in resource-poor areas of Uganda? Recently Dr. Nieke Westerik, a researcher from the Netherlands, partnered with a local Ugandan team to explore a yogurt production and distribution program similar to one that had previously proved successful in low-income areas of Argentina.

Since 2008, “Yogurito Social Program” has been operating in Argentina and now some 350,000 schoolchildren in less developed provinces enjoy the benefits of daily probiotic yogurt developed locally. Dr. Westerik (Free University of Amsterdam and Yoba 4 Life Foundation), with support from former ISAPP board member Prof. Gregor Reid, has now helped adapt the program to local needs in Uganda, making use of a well-known probiotic (Lacticaseibacillus rhamnosus GG) plus a yogurt starter (produced by the Yoba 4 Life Foundation) for production of the yogurt. The probiotic’s health effects have been demonstrated in human intervention studies.

The team worked on technical training and quality control of the locally produced yogurt, developing a production protocol suitable for Ugandan small-scale manufacture of probiotic fermented foods. Dr. Westerik’s team then conducted two clinical studies that demonstrated that the consumption of this probiotic product improved natural defenses and prevented respiratory infections (e.g. the common cold) and intestinal infections, which are the infectious conditions of greatest relevance in childhood in Uganda.

Yogurt is a new tool for individuals in developing areas of Uganda to achieve better health through diet, with potentially significant social and economic implications. Both the Ugandan and Argentinian experiences illustrate the power of microbes to positively impact the lives of women, men, and children. Given the positive results from these two different contexts, such activities could be replicated in other geographical areas—with either dairy, vegetable, or grain fermentations used locally with defined, well-studied starter cultures.

Further reading:

Julio Villena, Susana Salva, Martha Núñez, Josefina Corzo, René Tolaba, Julio Faedda, Graciela Font and Susana Alvarez. Probiotics for Everyone! The Novel Immunobiotic Lactobacillus rhamnosus CRL1505 and the Beginning of Social Probiotic Programs in Argentina. International Journal of Biotechnology for Wellness Industries, 2012, 1, 189-198.

Westerik N. 2020. Locally produce probiotic yoghurt for better nutrition and increased incomes in Uganda. PhD thesis, Free University of Amsterdam, The Netherlands.

Reid G, Kort R, Alvarez S, Bourdet- Sicard R, Benoit V, Cunningham M,  Saulnier DM, van Hylckama  Vlieg JET, Verstraelen H, Sybesma W.  Expanding the reach of probiotics through social enterprises. Beneficial Microbes, 9 (5): 707-715.

YOGURITO –the Argentinian social program with a special yogurt

 

 

 

New Spanish-language e-book about fermented foods now available for download

By Dr. Gabriel Vinderola, PhD,  Associate Professor of Microbiology at the Faculty of Chemical Engineering from the National University of Litoral and Principal Researcher from CONICET at Dairy Products Institute (CONICET-UNL), Santa Fe, Argentina

Fermented foods and beverages such as yogurt, wine, beer, kefir, kombucha, kimchi, and miso are created with the help of microbes. After more than 10,000 years of practice around the globe, fermentation has finally caught massive attention from a general public interested in knowing more about the fascinating, invisible world of microbes. In essence, the act of fermentation places food in a unique place between raw and cooked. The flavours, tastes, textures and potential health benefits of fermented foods, made possible through the presence of viable or non-viable microbes and their metabolites, are achieved through this set of ancestral food processing techniques. Today’s science allows us to see the functions of fermentation microbes that can make certain nutrients more bioavailable in foods. Fermentation can also reduce certain anti-nutrients and generate a large number of potentially beneficial microorganisms.

To help people learn about fermented foods, I was pleased to collaborate on an e-book with Ricardo Weill, an Argentinian dairy industry expert who first introduced Lactobacillus rhamnosus GG in Argentinian fermented milks in the 1990s, and Alejandro Ferrari, a biologist and scientific communications expert. The book is titled ‘Fermented Foods: microbiology, nutrition, health and culture’, and is currently available only in Spanish.

The book aimed to reach the general public, with scientific concepts but in easy-to-follow language for people with little or no previous knowledge of microbiology, nutrition or food technology. It tells the stories of many types of fermented foods around the world and adds a scientific perspective on their health benefits. The book brings together information from 38 authors from Argentina, Colombia, Japan, Spain and Finland, including ISAPP President Prof. Seppo Salminen, and Martin Russo, a professional chef in Argentina who specializes in fermentation. The book includes the following sections:

Fermentation: An anthropological view

Variety of fermented foods in Japan and other East Asian countries, and the microorganisms involved in their fermentation

Introduction to the intestinal microbiota: its role in health and the disease

Consumption of probiotic fermented milk and its impact on the immune system

Fermented milks, yogurts and probiotics

Kefir and artisanal fermented foods

Fermented meat sausages: Contribution of lactic bacteria in global quality

Lactic fermentation of cereals and Andean ancestral grains

Fermented vegetables and legumes

Fermentation of fruit drinks and drinks

Yeasts in beer and baked goods

Role of fermented foods in diet

Role of lactic acid in the beneficial effects of fermented foods

Microbiological safety of fermented foods

Fermented foods and chronic non-communicable diseases: A narrative review of the literature

Fermentation and gastronomy: A cook among scientists, a scientist among cooks

This e-book initiative started in October 2019, when a symposium about fermented food was organized by the Danone Institute of the Southern Cone (DISC).

The Danone Institute of the Southern Cone (DISC) was founded in 2008, and it is the local chapter for Argentina, Chile and Uruguay of the Danone Institute International network, which gathers 14 Danone Institutes (13 local Institutes and 1 International) in 15 countries. All Danone Institutes are non-profit organizations, dedicated to non-commercial activities and promotion of science.

Since its foundation, the DISC has collaborated with more than 200 experts taking part in different projects, and has served as a collaborative meeting place to reflect with their peers—all of them remarkable scientists coming from different and complementary specialties, focusing on key aspects of public health linked to food.

See the link to our book here:

Fermented Food: Microbiology, Nutrition, Health & Culture. (2020)

See the ISAPP press release about this book in English and en español.

Some previously-produced nutrition books that are freely available in Spanish on the DISC website are:

  • Impact of Growth and Early Development on the Population’s Health and Wellbeing. Perspectives and Reflections from the Southern Cone. (2009)
  • Healthy Growth. Between Malnutrition and Obesity in the Southern Cone. (2011)
  • The Role of Calcium and Vitamin D in Bone Health and Beyond. Perspective from the Southern Cone. (2013)
  • Methodologies Employed in Food Evaluation. An Ibero-American Vision. (2015)
  • Their Impact in Nutrition and Health. A Vision from the Southern Cone. (2018)

Hear from ISAPP board members in webinar covering probiotic and prebiotic mechanisms of action

This webinar is now complete — see the recorded version here.

New probiotic and prebiotic trials are published all the time – but when they show a health benefit, what do we know about the basic science behind it?

To provide insight into this topic, ISAPP has partnered with the International Life Sciences Institute (ILSI) Europe on a free webinar titled Understanding Prebiotic and Probiotic Mechanisms that Drive Health Benefits. This webinar helps scientists, members of the public, and media take a deep dive into what we know about the mechanisms of action of probiotics and prebiotics.

The live webinar is scheduled for Thursday, September 17, 2020 from 3 – 4:15pm Central European Time.

Short, 10-minute perspectives will be provided by the following top experts:

  • Prof. Sarah Lebeer, University of Antwerp, Belgium
  • Prof. Colin Hill, University College Cork, Ireland
  • Prof. Karen Scott, University of Aberdeen, UK
  • Prof. Koen Venema NUTRIM School of Nutrition and Translational Research in Metabolism, Venlo, The Netherlands

The presentations will be followed by a 35-minute live Q&A session, enabling participants to probe deeper into the science behind mechanisms of probiotics and prebiotics.

ILSI Europe is a non-profit organization that aims to improve public health and well-being from a science-based approach.

To learn more about probiotic mechanisms of action in advance of the webinar, see ISAPP’s blog post here.

¿Cómo permanecen vivos los probióticos hasta el momento de ser consumidos?

Por Gabriel Vinderola, Dr. en Química, Investigador Principal del Consejo Nacional de Investigaciones Científicos y Técnicas (CONICET) en el Instituto de Lactología Industrial (INLAIN, CONICET-UNL) y Profesor Asociado de la Facultad de Ingeniería Química de la Universidad Nacional del Litoral.

Como docente-investigador, la mayor parte del tiempo se comparte con personas del ambito académico y científico. Pero a través de las actividades de divulgación, tengo también la posibilidad de interactuar con personas que no tienen formación en ciencias, pero que tienen curiosidad por el mundo científico. Una pregunta que me hacen a menudo es: “¿Es posible que los probióticos sigan vivos cuando están deshidratados y en una cápsula?” La respuesta es sí. Permítanme proporcionar algo de información básica sobre los probióticos y explicar mi respuesta.

La idea de consumir microbios vivos para promover la salud no es nueva. En 1907, Élie Metchnikoff, discípulo de Louis Pasteur, el padre de la microbiología, asoció el consumo de leches fermentadas que contenían lactobacilos vivos, con una vida prolongada y saludable en campesinos búlgaros (see here). Esta idea fue retomada más tarde por el concepto de probióticos: microorganismos vivos que, cuando se administran en cantidades adecuadas, confieren un beneficio para la salud del huésped (Hill et al. 2014). Son cuatro criterios sencillos y pragmáticos los permiten concluir si determinadas cepas de microorganismos reúnen las condiciones para ser consideradas probióticos. Los probióticos deben: i) estar correctamente identificados (género, especie, cepa); ii) ser seguros para el uso previsto; iii) estar respaldados por al menos un ensayo clínico en humanos que demuestre su eficacia; y iv) estar vivos en el producto, y en cantidades suficientes para ser eficaces, durante todo el período de conservación (Binda et al. 2020). Estar viables en el momento del consumo es una de las características clave de los probióticos.

La vida es la condición que distingue a los animales y las plantas de la materia inorgánica. La vida implica actividad metabólica y la capacidad de crecer y reproducirse. Para que la vida sea posible, deben darse ciertas condiciones ambientales, las cuales difieren para los distintos organismos. Para los microorganismos en general, la disponibilidad de agua y nutrientes, la temperatura adecuado y la ausencia de inhibidores de crecimiento (como la acidez o los antibióticos) son condiciones esenciales para su desarrollo. Sin embargo, es posible manipular ciertas condiciones para lograr un estado en el que el crecimiento puede ponerse en “stand-by”, pero el microorganismo seguirá vivo. Nosotros los humanos no podemos imaginarnos en una condición “en modo de espera”, en la que estemos vivos aún sin ninguna actividad metabólica, pero para los microbios esto sí es posible. Los probióticos pueden estar en alimentos (ciertos yogures, jugos de fruta, barras de cereales) o en suplementos alimenticios (cápsulas, píldoras, sachets) en un estado de “hibernación”, caracterizado por la ausencia de crecimiento, de reproducción, en espera a que se den las condiciones adecuadas para retomar la actividad metabólica. Esto último ocurre cuando los probióticos llegan al intestino, donde encuentran la temperatura adecuada, los nutrientes necesarios, la ausencia de inhibidores y el agua necesaria para retomar su actividad metabólica. Por lo tanto, en el caso de los microorganismos, hay una disociación de la vida y la actividad metabólica. Incluso sin tener ninguna actividad metabólica, pueden seguir vivos, pero en un estado de latencia.

Al abrir un suplemento alimenticio que contenga probióticos, probablemente encontraremos un polvo seco blanco. Así es como los microorganismos pueden estar en un estado de latencia, debido a un proceso tecnológico llamado liofilización. La liofilización es un proceso de dos etapas en el que las células primero se congelan rápidamente a temperaturas muy bajas (de -40 a -70°C, o menos, utilizando nitrógeno líquido, por ejemplo). Luego, el agua congelada se elimina mediante un proceso de evaporación a baja presión y baja temperatura, llamado sublimación. Este proceso elimina la mayor parte del agua de las células, dejando a los microorganismos en un estado de inactividad o latencia. La actividad de agua es la forma en que los científicos miden la disponibilidad de agua para los probióticos. Esta medida tecnológica oscila entre 0 (sin disponibilidad de agua) y 1 (con total disponibilidad agua). Una actividad de agua cercana a 0 impide el crecimiento. En los suplementos dietarios, la liofilización deja la actividad de agua en un valor menor a 0,2, lo que asegura que no se produzca actividad metabólica durante la vida útil del producto.

Células de un probiótico constituido por bifidobacterias liofilizadas (indicadas por un círculo rojo). Esta es una imagen de microscopía electrónica de barrido amplificada 10.000 veces. Las células están incrustadas en una matriz de polidextrosa deshidratada, sin agua.

Así es que sí, los probióticos en los suplementos alimenticios están vivos, a su manera. Este es el caso también de los probióticos incluidos en ciertos alimentos como barras de cereales. En el caso de alimentos con actividades de agua más cercanas a 1, como los yogures, las leches fermentadas, los quesos o los jugos de fruta que contienen probióticos, el factor que limita la actividad metabólica es la baja temperatura a la que se conservan estos productos, combinada en ciertos casos (como los yogures y jugos de fruta) con el bajo pH (o alta acidez) de estos productos. La combinación de baja temperatura y acidez es eficaz para mantener a las células probióticas en un estado de latencia, lo que impide la actividad metabólica que pueda provocar estrés celular y muerte a lo largo de la vida útil del producto. Sin embargo, aunque se controlen estrictamente los factores que impiden la actividad metabólica durante la conservación, puede producirse cierta pérdida de viabilidad celular durante la vida útil de los probióticos en los productos que los contienen. En este caso, se agregan cantidades adicionales de probióticos para que la concentración de células viables necesaria para proporcionar un efecto benéfico sea la adecuada hasta el final de la vida útil del producto.

En los alimentos y suplementos probióticos, el número de células viables se expresa comúnmente como un número de unidades formadoras de colonias, abreviado “UFC”. Como los probióticos están presentes en altas concentraciones, el número de células viables suele alcanzar los miles de millones dentro de una cápsula o en una porción de yogur. Para poder contar un número tan grande de células, los microbiólogos deben hacer diluciones sucesivas del producto probiótico. Luego, pondrán una pequeña gota de las mayores diluciones en la superficie de una placa de Petri que contiene un medio de cultivo en el que crecerán los probióticos. Cada célula probiótica (o grupo de células) es una unidad formadora de colonias, que crecerá en su lugar y formará una colonia visible que puede ser observada a simple vista, y contada.

Placa de medio de cultivo que contiene colonias de una bacteria probiótica. Las células depositadas en la superficie del medio de cultivo se duplicaron varias veces hasta formar una cantidad visible de células: una colonia.

En síntesis, los probióticos están presentes en los alimentos y suplementos como cultivos vivos, pero en un estado de vida diferente al de los organismos superiores. Durante la vida útil de los probióticos, la actividad metabólica se detiene mediante la liofilización (en el caso de suplementos alimenticios) o mediante una combinación de baja temperatura y acidez (en el caso de yogures y jugos de fruta con probióticos, por ejemplo). El crecimiento activo de los probióticos suceso otra vez cuando estos microorganismos entran en el intestino y encuentran las condiciones adecuadas de nutrientes, temperatura, acidez y agua para estar activos y producir sus efectos benéficos sobre la salud.

How do probiotics stay alive until they are consumed?

By Prof. Gabriel Vinderola PhD,  Associate Professor of Microbiology at the Faculty of Chemical Engineering from the National University of Litoral and Principal Researcher from CONICET at Dairy Products Institute (CONICET-UNL), Santa Fe, Argentina

See the Spanish version of this blog post here.

As a professor, most of my days are spent with people from the academic and scientific world. But through some outreach activities, I am also fortunate to interact with many people who are not scientists by training, but have curious, scientific minds. One question I am often asked is, “Is it really possible for probiotics to still be alive when they are dried and in a capsule?” The answer is yes. Let me provide some basic background on probiotics and explain my response.

The idea of consuming live microbes to promote health is not new. Back in 1907, Élie Metchnikoff, a disciple of Louis Pasteur, the father of microbiology, associated the intake of fermented milks containing live lactobacilli, with a prolonged and healthy life in Bulgarian peasants (see here). This idea was later captured by the concept of probiotics: live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (Hill et al. 2014). Four simple and pragmatic criteria allow one to conclude if specific strains of microorganisms qualify as a probiotic for use in foods and dietary supplements. Probiotic strains must be (i) sufficiently characterized; (ii) safe for the intended use; (iii) supported by at least one human clinical trial showing they are effective; and (iv) alive in the product at an efficacious dose throughout shelf life (Binda et al. 2020). Being alive at the moment of consumption is one of the key characteristics of probiotics.

Life is the condition that distinguishes animals and plants from inorganic matter. Life includes the capacity for growth, for reproduction and for metabolic activity. In order to sustain life, certain environmental conditions must be met, but these differ for different organisms. For microbes, the availability of water and nutrients, adequate temperature and pH (acidity), and the absence of growth inhibitors are essential conditions. However, it is possible to manipulate certain conditions to bring about a state where growth may be put in “stand-by mode”, yet the microbe remains alive. We cannot imagine ourselves in a condition where life is preserved even without any metabolic activity, but for microbes it is possible. Probiotics can be in foods (yoghurts, fermented milks, fruit juices, cereal bars) or in food supplements (capsules, compressed pills) in a “hibernation” state, characterized by no growth, no reproduction and no metabolic activity, waiting for the proper conditions to come back to full metabolic life. This occurs when the microbes reach the gut, which has proper temperature, nutrient availability, lack of inhibitors, adequate acidity and water. Thus, in case of microbes, there is an uncoupling of life and metabolic activity. Even without having any metabolic activity, they can still be alive, but in a dormant state.

Open a food supplement containing probiotics and you will probably find a white dry powder. This is what the microbes may look like in their dormant state, due to a technological process called freeze-drying or lyophilization. Freeze-drying is a two-stage process where cells are first quickly frozen at very low temperatures (-40 to -70°C, or less, using liquid nitrogen for example). Then, frozen water is removed by a gentle process of evaporation at low pressure and temperature, called sublimation. This process removes most of the water from around and inside the cells, leaving the microbes in a dormant state. Water activity is scientists’ way of measuring water availability for the microbes. This technological measure ranges from 0 (no water) to 1 (pure water). A water activity close to 0 impairs growth. In food supplements, freeze-drying leaves water activities less to 0.2, ensuring that no metabolic activity will take place during the shelf life of the product.

Bifidobacteria cells (circled in red) freeze-dried in a probiotic powder. This is a scanning electron microscopy image amplified 10,000 times. Cells are embedded in dry polydextrose.

So yes, probiotics in food supplements are alive in their own way. This is the case also for probiotics included in certain foods such as cereal bars. In case of food products with water activities closer to 1, such as yogurts, fermented milks, cheeses or fruit juices containing probiotics, the factor that limits metabolic activity is the low temperature at which these products are stored, combined in certain cases (yogurts, fermented milks, fruit juices) with the low pH (or high acidity) of these products. The combination of low temperature and acidity is effective in maintaining probiotic cells in a dormant state, impairing any metabolic activity that may lead to cell stress and cell death along the shelf life of the product. Yet, even while tightly controlling factors that impair metabolic activity, some cell death may occur during the shelf life of probiotics in the products that deliver them. In this case, responsible manufacturers are sure to add extra probiotic cells so that the necessary amount of viable cells needed to deliver a health effect are present through the end of the shelf life of the product.

In both probiotic foods and food supplements, the number of viable cells is commonly expressed as a certain number of colony forming units, or by the abbreviation “CFU”. As probiotics are present in high concentrations, the number of viable cells often reaches into the billions within a capsule or in a serving of yogurt. To be able to count such enormous numbers of cells, microbiologists must make serial dilutions of the probiotic product. Then, they will put a small drop of a dilution on the surface of a Petri dish containing a culture medium on which probiotics will grow. Each probiotic cell (or clump of cells) will grow in place and form a visible colony that can be observed to the naked eye, and counted.

Agar plate containing colonies of a probiotic bacteria. Cells deposited on the surface of the agar plate duplicated several times until forming a visible amount of cells: a colony.

In brief, live probiotics are present in food and supplements, but in a state of life different to that of higher organisms where metabolic activity is taking place at all times. During shelf life, the metabolic activity of probiotics is stopped by freeze-drying them (food supplements) or by a combination of low temperature and acidity (yogurts and fruit juices, for example). Active growth returns when these microbes enter out gut and find the proper conditions of nutrients, temperature, acidity and water to be active and deliver their health effects.

GG + BB-12 don’t reduce antibiotic use in an elderly, institutionalized population

By Mary Ellen Sanders, PhD, ISAPP Executive Science Officer

Close to two years ago, a team convened by ISAPP conducted a meta-analysis showing that probiotics may reduce number of antibiotic prescriptions, with evidence primarily in children (ISAPP-initiated systematic review and meta-analysis shows the association of probiotic consumption with reduced antibiotic prescriptions). A recent study suggests that this outcome likely does not extend to elderly care home residents.

A newly published randomized, placebo-controlled trial tested a combination product comprising two well-studied probiotic strains, Lacticaseibacillus (formerly known as Lactobacillus) rhamnosus GG and Bifidobacterium animalis subsp lactis BB-12, administered at ~1.5 × 1010 per day to institutionalized residents 65 years of age or older to test if this treatment reduced antibiotic administration. The study showed no reduction in antibiotic use compared to the control. Further, the probiotic was not associated with improvement in secondary endpoints, which included many that probiotics are hypothesized to mitigate, including incidence of common infections, duration of infections, C. difficile infection, antibiotic associated diarrhea, hospitalizations, or presence of antibiotic resistant microbes in fecal samples.

Other endpoints suggested that the probiotic group fared worse than the placebo group. Statistically significant differences were found between the probiotic and placebo groups for antibiotics administered for lower respiratory tract infections and well-being scores at 3 months.

This was a well-controlled, comprehensively reported study.  Some factors to consider in interpreting these results:  The population was elderly (mean age = 85.3 years) and infirmed (66% lacked capacity to consent and 63 of 310 randomized subjects died prior to conclusion of the study). Stool culture at 3 months showed L. rhamnosus present in 84% of intervention group compared to 37% of placebo group, although the groups were matched for this factor at baseline. This suggests some cross-contamination between the placebo and intervention groups may have occurred. As the authors state, exposure of the placebo group to the probiotic “would dilute any between-group differences in outcomes.” A higher number of C. diff positive subjects were assigned to the probiotic group than the placebo group (7.2% vs 0%, respectively).

Overall, this study provides evidence that L. rhamnosus GG + B. lactis BB-12 are not effective prophylactically in a population of elderly care home residents.

 

Bulgarian yogurt: An old tradition, alive and well

By Mariya Petrova, PhD, Microbiome insights and Probiotics Consultancy, Karlovo, Bulgaria

Family and family traditions are very important to me. Some of you may have seen my previous blog post on fermented food and my father’s tradition of making fermented cabbage and vegetables every autumn. Of course, this is not limited to my family – in Bulgaria, it is our culture and our country’s tradition. But despite the fact that I wrote about fermented vegetables first, Bulgarians are much more proud of another fermented product – yogurt.

I still remember waking up every morning when I was a kid and having a healthy homemade yogurt to start the day. I still do when I am back at home, because my father continues to make yogurt at home. Here, I’ll take you on a new adventure and tell you all about Bulgarian yogurt, an old tradition still alive in every home.

Élie Metchnikoff and his work are well familiar to anyone involved in probiotic research. In short, Metchnikoff observed in 1907 that Bulgarian peasants lived longer lives and he attributed this to their daily consumption of yogurt.

Thanks to Metchnikoff, research on Bulgaria and Bulgarian yogurt was put on the map because of our healthy way of living and eating fermented foods. You may know this part of the story. Still, few actually know that Metchnikoff was intrigued by the work of the Bulgarian researcher Stamen Grigorov a few years earlier. In fact, it was because of Stamen Grigorov’s work that we now know ‘who’ (i.e. which microbes) live in our yogurt and how essential those tiny bacteria are. In 1905 Stamen Grigorov actually discovered and isolated for the first time Lactobacillus bulgaricus (now known as Lactobacillus delbrueckii subsp. bulgaricus) from homemade yogurt. That’s why we are so proud of Bulgarian yogurt. Not only do we love to eat it, but the probiotic research was partially initiated in our country, and an entire Lactobacillus species is named after our country. There is even a small museum dedicated to Bulgarian yogurt and to the work of Stamen Grigorov, located in the house where he was born. In the museum, if you are visiting Bulgaria, you can learn how to make yogurt at home and a bit more about the history of Grigorov’s discoveries.

We are so proud of our yogurt that many Bulgarians will tell you that ancient Bulgarian tribes were the ones who discovered yogurt by accident. Since Bulgarian tribes were nomadic, they carried the milk in animal skins, which created an environment for bacteria to grow and produce yogurt. This is indeed the way people learned to make yogurt, but it most likely happened in many places independently. Of course, I know many countries make yogurt but I remain proud of all the discoveries that happened in my country (I am saying this because at times I have been judged when I tried to say how important we find the yogurt in Bulgaria and how proud we are).

Yogurt is a tradition in Bulgaria. I don’t know a Bulgarian who does not eat yogurt on a daily basis, up to a few pots per day. And I am not talking about those sweet yogurt products that are made by adding jam or vanilla. I am talking about real, natural yogurt, slightly sourer than most of the products that can be found in the Western world. We add yogurt to almost everything, it is just the perfect addition. It is even the basis of a traditional Bulgarian cold summer soup called “tarator,” made of yogurt, water, cucumber, garlic, and dill. We also make a salad with it called “snezhanka”, and it contains yogurt, cucumbers, garlic, and walnuts. (Recipes can be found below if you want to try something new during the lockdown.) In fact, I am so “addicted” to our yogurt that in every country I go to, the first thing I have do is to find a good yogurt. It took me years to find a good one in Belgium when I lived there (even though one product was labelled ‘Bulgarian yogurt’, it was not the same for sure). In Canada, it was somehow easier. After trying a few different products, it was even faster to find something that I like in the Netherlands, but they have many kinds of milk products. Yet none of them are truly comparable with what you can find in Bulgarian shops. Even the smallest shops have at least 3 to 4 different types because we have a lot of yogurt factories. Every product is different, it has a unique taste and can be made of different kinds of milk.

But honestly, nothing is the same as the homemade yogurt. Many people still make yogurt at home, including my father. I don’t quite remember a time when there was no homemade yogurt on the table at home. It was initially my grandmother making the yogurt and the white Bulgarian cheese (it is nothing to do with Feta but that’s the closest way to explain what it is). So it was somehow logical that my father started making yogurt as well. He knows the technique from his grandmother and grew up with fresh homemade yogurt. My grandparents had a lot of cows, sheep, and goats, so we always had plenty of milk to ferment. Making yogurt at home is so very simple that more and more young people dare to do it. In fact, making yogurt is so easy, I wonder why I am not doing it myself during the lockdown.

How to make it, you may ask?

So you need fresh milk, which my family in Bulgaria currently gets from a local farm. The milk is carefully boiled, and while it is still warm, transferred to a preferable container where you want to make the yogurt. We use old yogurt jars that were very popular before. For some time, my father also used Tupperware, so you can choose anything that you find handy. Before transferring the milk, my father also separates the cream from the milk in a separate jar and uses it to make homemade butter by constantly shaking the jar for around 10 minutes (it is an intensive workout, I tried it a few times!). The biggest problem these days is having a good starter culture so you can begin the milk fermentation. As a starter culture, most of the people, including my father, use a spoon or two of the previous batch of yogurt. So my father never finishes all the yogurt; he always makes sure that there are some leftovers so he can start a new fermentation. He usually adds one tablespoon of the old yogurt to 500 ml warm milk (around 45 C). Of course if the milk is too hot, the bacteria present in the starter culture will die, and nothing will happen. There is also the case that the milk is too cold, and then it will most likely still ferment, but it will have a strange consistency, something between milk and yogurt. If my father is out of old yogurt to start a new fermentation, he usually buys his favorite yogurt from the shop and uses this as starter. Once the jars are filled, he packs blankets all around them to keep the environment warm so the fermentation will begin. From here, you need around 4h to 5h to have a nice homemade yogurt. Simple and straightforward. The next morning you can have a great family breakfast, remembering the old traditions, talking about old memories, passing on the torch to the new generation, and enjoying a healthy start to the day.

The next time you have yogurt, I hope you enjoy it and remember the Bulgarian traditions!

 

Tarator soup recipe:

What you need: 1 cucumber, 250 -300 g yogurt, 1-2 cloves crushed garlic, salt, oil, water, fresh chopped dill. (Most of the ingredients depend on your taste so feel free to add more or less of certain ingredients. Some people also add parsley and walnuts, but it is up to your taste.)

How to make it: Peel and cut the cucumbers into cubes and put them in a preferred bowl; add the crushed garlic, and the minced dill. Beat the yogurt until it turns to liquid and mix it with the rest of the ingredients. Add salt and oil to taste. Add water to make the soup as liquid as you like. Put into the refrigerator to cool it. You can also make it with cold yogurt and cold water. It is perfect for the hot summer days.

Snezhanka (which means “Snow White” in Bulgarian) salad recipe:

What you need: 1 cucumber, 500 g yogurt, 1-2 cloves crushed garlic, 2-3 spoons ground walnuts, salt, oil, fresh chopped dill. (Again, it depends on your taste, if you like more cucumber or yogurt just add more.)

How to make it: First strain the yogurt for a couple of hours, so that all unnecessary water is drained away. Peel and cut the cucumbers into cubes and put them in the bowl. Add the strained yogurt. Add the fresh dill, salt and oil to taste. Sprinkle the walnuts on top of the salad. Perfect for all seasons. If you don’t have a fresh cucumber, you can also use pickles — the final result is also very delicious.

Are prebiotics good for dogs and cats? An animal gut health expert explains

By Kelly S. Swanson, PhD, The Kraft Heinz Company Endowed Professor in Human Nutrition, University of Illinois at Urbana-Champaign, USA

Pet dogs and cats are cherished companions. In developed countries, many households with pets treat them like family members. Similarly to humans, a high level of nutrition and veterinary care promotes health and longevity. As people become more aware of what they feed themselves and their human family, they make the same considerations for their canine and feline companions. Pet food trends have closely followed those of the human food industry over the last couple decades, with high-quality natural and organic foods gaining popularity.

One way pet food companies have enhanced their products is by incorporating functional ingredients into their formulas. Functional ingredients provide benefits beyond that of their nutrient content. One of the most popular target areas for functional ingredients is pet gastrointestinal health, with structure/function claims of “supporting digestive health”, or something similar, being quite common. Loose stools, constipation, and various gastrointestinal disorders and diseases such as inflammatory bowel diseases and irritable bowel syndrome are common in pets. The task of “poop scooping” after the dog in the park or cleaning out the cat’s litterbox provides owners with an opportunity for daily assessment of stool quality and serves as a reminder of how important diet is to gut health.

Benefits of prebiotics for pets

Many ingredients, including dietary fibers, prebiotics, probiotics, synbiotics, postbiotics, and other immunomodulators may provide gastrointestinal benefits to pets, but today we will focus on prebiotics. The most recent ISAPP expert consensus panel on prebiotics clarified that the prebiotic concept not only applies to humans, but also to companion and production animals (Gibson). Dogs and cats evolved as Carnivora, mainly consuming high-protein, high-fat diets that were low in fiber, and their short, simple gastrointestinal tracts have a limited capacity to ferment non-digestible substances. Nonetheless, they possess an active microbiota population, primarily in the colon, that may be manipulated by diet to impact health.

Most prebiotic research in pets has focused on the gastrointestinal tract. Prebiotic administration has been shown to reduce the incidence or severity of infections (Apanavicius; Gouveia), improve stool consistency (Kanakupt), and beneficially shift fecal microbiota and metabolite profiles (Propst). A few have reported the benefits that prebiotics may have on metabolic health, demonstrating improved glucose metabolism and insulin sensitivity in pets consuming prebiotics (Respondek; Verbrugghe). Since we’re looking at foods rather than at medicines that address disease, the majority of research has been conducted in healthy animals so evidence of health improvements in diseased pets is sparse.

Types of pet-friendly prebiotics

Although a few studies have tested galactooligosaccharides (GOS), mannanoligosaccharides, and other potential prebiotics, by far the most common prebiotics studied and present in pet foods are the non-digestible fructans. Natural sources, such as chicory, or isolates and extracts that have a high purity, including short-chain fructooligosaccharides (FOS), oligofructose, and inulin, are all present in pet foods.

Which pets benefit most?

Similar to dietary fiber, the need for prebiotic inclusion is dependent upon diet type and formulation. Animals consuming plant-based diets that are rich in natural fibers and non-digestible oligosaccharides likely do not require additional fermentable substrate in the formula. Dogs and cats fed high-protein, meat-based diets, however, typically have greater fecal odor, a higher colonic pH, and higher density of potential pathogens due to a high rate of protein fermentation. In those diets, prebiotic inclusion may help animals normalize their gut microbiota abundance and metabolism.

Prebiotics may be fed to all pets, but will likely provide the greatest benefits to geriatrics, animals who are or have received antibiotics, those under high stress conditions, or those with certain gastrointestinal disorders. The low caloric density of prebiotics and the metabolic benefits that come from their fermentation will be most beneficial to pets with obesity and diabetes. As for all functional ingredients, dosage is important. When comparing dogs and cats, dogs usually can tolerate a higher dosage than cats. In regard to dog size, small dogs can typically tolerate a higher dosage (per unit body weight) than large dogs, which are more susceptible to loose stools. In most commercial pet foods, prebiotic inclusion levels are <0.5% of the formula to limit side effects.

Further research on prebiotic substances

Using the powerful tools that are now available to study gut microbiota and host physiology, future research can hopefully determine what microbes are most important to the health of dogs and cats and identify mechanisms by which prebiotics provide health benefits to pets. Further testing, which may include plant-based ingredients, yeast-based products, and milk oligosaccharide mimics, will hopefully identify other prebiotic substances and continue to expand our knowledge in the field.

 

Kelly Swanson joined the ISAPP board of directors in June, 2020, providing valuable expertise in animal gut health and overall health. Swanson also chaired the 2019 ISAPP-led international consensus panel on the definition of synbiotics.

 

 

 

What makes a synbiotic? ISAPP provides a sneak peek at the forthcoming international scientific consensus definition

By Kristina Campbell, science and medical writer

The word ‘synbiotic’ is found on the labels of many different products, from supplements to chocolate bars, and it has generally been understood to be a combination of a probiotic and a prebiotic. But what happens when scientists want to test whether these combination products really deliver any health benefits? Can these products be tailored to have specific effects on the body or on the human gut microbiota? Agreeing on a clear definition of synbiotics is needed to provide focus for scientific research in this area, to facilitate the design of studies, and to allow for progress wherein their health effects are uncovered.

The scientific definition of synbiotic was the central topic of the international scientific panel brought together by ISAPP in May 2019 in Antwerp, Belgium. Members of the panel, eleven of the top academic experts in the field of probiotics and prebiotics, gathered to clarify a scientifically valid approach for use of the word ‘synbiotic’, and to communicate this by position paper. The outcome of this consensus panel is currently in press at Nature Reviews Gastroenterology & Hepatology.

Kelly Swanson, Professor in the Department of Animal Sciences and Division of Nutritional Sciences at University of Illinois at Urbana-Champaign, chaired the panel and led the paper’s publication. Swanson has been studying gastrointestinal health in both humans, companion animals (dogs and cats) and rodent models for the past 20 years—and having followed the rapid advances in the field of probiotics and prebiotics during those two decades, he knew the task of creating a synbiotic definition would not be easy.

He says, “The field is highly complicated, so an interdisciplinary panel was essential. The main areas of expertise included microbiology and microbial ecology; gastrointestinal physiology; immunology; food science; nutritional biochemistry and host metabolism.”

A timely discussion

According to Swanson, an increase in research interest, built on a foundation of recent scientific and technical gains, made this the right time to come to consensus on a synbiotic definition. He says, “Over the past decade, technological advances have allowed scientists to study the gut microbiome at a molecular level. In addition to characterizing the composition of the gut microbes, researchers are learning more about their biological activity and how they may impact host health.”

Furthermore, clarity about the definition was urgently needed because of the rapidly growing synbiotics market. Consumers seem to be more aware of synbiotics than ever, but they face a bewildering array of product offerings labeled as ‘synbiotic’ without a clear understanding of what that term entails and with no framework for establishing scientific efficacy. Swanson says, “As the field has moved forward and the sales of probiotics and prebiotics have increased, there has been more interest in combining substances to enhance efficacy. Some of these combinations may function as synbiotics, but it is not guaranteed. Rather than randomly combining substances together, there should be scientific rationale supporting their use.”

Clarifying the concept

One of the first questions the panel members had to tackle was whether to stick to the idea of a synbiotic as ‘probiotic plus prebiotic’, thus leaning heavily on the ISAPP-led international consensus definitions of probiotics and prebiotics published in 2014 and 2017, respectively. But the panel members decided this narrow scope would ultimately limit innovation in the synbiotic category.

Swanson explains, “While many synbiotics may be composed of an established prebiotic and established probiotic, the panel did not want to restrict scientific advances in the synbiotic category by requiring use of components already established on their own.”

As a result, he says, previously untested live microbes and potential prebiotic substances could be considered a synbiotic if the combination showed efficacy, and if the health benefit came from administering both the live microbe and the substrate it utilized—that is, the microbe together with its ‘food’.

Another conclusion from the panel is that probiotics (with known health benefits) and prebiotics (with known health benefits) cannot be called synbiotics unless they have been tested together. “There should be a rationale supporting the combination used, and then testing of the combination to confirm its efficacy,” says Swanson.

The panel suggests a synbiotic may be composed of either of the following, as long as efficacy is demonstrated for the combination:

  • Established probiotic + established prebiotic (each component meeting the efficacy and mechanistic criteria for each)
  • Previously untested live microbe + a substrate that is selectively utilized by the co-administered live microbe

Further details, including two different ‘categories’ of synbiotics, will be provided in the published paper.

In addition to the definition, the publication will cover the history of synbiotic-type products, how these products can be characterized, levels of evidence that currently exist versus levels of evidence desired, points about safety documentation and reporting, and relevant characteristics of the target hosts.

A remaining challenge—not just for the expert group, but also across the field—is the difficulty of establishing causal links between substances’ effects on the gut microbiota (e.g. ‘selective utilization’ of a substrate) and health outcomes.

While the publication of the synbiotic definition will be an important milestone, Swanson anticipates further discussion in the years ahead. “As more is learned, I expect the criteria for assessing synbiotic efficacy will continue to change,” he says.

An update on the scientific consensus definition of synbiotic was presented to ISAPP members at the 2020 virtual meeting in June.

 

ISAPP partners with British Nutrition Foundation for fermented foods webinar

Did you miss the live webinar? Access the archived version here. Read the speaker Q&A here.

From sourdough starter tips to kombucha flavor combinations – if you’ve checked a social media feed lately, you’ll know how many people are sharing an interest in fermented foods as they self-isolate during the pandemic. And with this rise in popularity comes a host of questions about the practice and the science of fermented foods.

To meet the need for science-based information about fermented foods, ISAPP has partnered with the British Nutrition Foundation (BNF) on a free webinar titled ‘Fermented Food – Separating Hype from Facts.’ The BNF is a UK-based registered charity that brings evidence-based information on food and nutrition to all sectors, from academia to medicine.

The webinar, designed for practicing dietitians and nutrition-savvy members of the public, featured three leading scientific experts who explained the microbiology of fermented foods, the evidence for their health effects, and who might benefit from making these foods a regular part of the diet. Viewers will come away with a clear understanding of what fermented foods are and what evidence exists for their health benefits.

The webinar was held live on Wednesday, July 1, 2020 from 1pm-2pm (BST).

Webinar speakers & topics

 Understanding fermented foods: Dr. Robert Hutkins, University of Nebraska, USA

Exploring the evidence for effects of fermented foods on gastrointestinal health – how strong is it? Dr. Eirini Dimidi, Kings College London

What role can fermented foods have in our diet? A public health perspective, Anne de la Hunty, British Nutrition Foundation

For a quick primer on fermented foods, see the short ISAPP video here or the ISAPP infographic here.

[IN SPANISH] Creciente interés en Argentina en microorganismos benéficos y alimentos fermentados

Dr. Prof. Gabriel Vinderola, Investigador Principal CONICET, Instituto de Lactología Industrial (INLAIN, CONICET-UNL), Profesor Asociado, Cátedra de Microbiología, Facultad de Ingeniería Química, Universidad Nacional del Litoral, Santa Fe, Argentina.

El interés sobre las bacterias intestinales, los alimentos fermentados y los probióticos está en aumento en Argentina y la región. Nutricionistas e influencers, que en los últimos años han comenzado a promover un estilo de vida más saludable, están aprovechando sus redes sociales para publicar recetas sobre cómo hacer alimentos fermentados, consejos para promover una microbiota más saludable e información sobre el posible papel de los probióticos y prebióticos en la salud humana. Pero, ¿están estas recomendaciones basadas en la ciencia? No siempre! En particular, he tenido la oportunidad de contribuir a que la comunicación sobre la microbiota, los alimentos fermentados, los probióticos y los prebióticos se haga desde la ciencia, para una audiencia amplia y con un leguaje simple.

En Argentina, y desde hace 50 años, hay un programa de televisión con un formato particular: la anfitriona, la Sra. Mirtha Legrand, cada domingo invita a almorzar a 4-6 personas para hablar, durante 3 horas, de política, economía, cultura popular, arte e incluso ciencia. Según ella, se trata del programa de televisión que se ha transmitido, ininterrumpidamente, por más tiempo en el mundo. Cada domingo, miles de personas de Argentina, Uruguay y Paraguay lo sintonizan. En octubre de 2019, me invitaron a unirme a la mesa y hablar sobre el mundo invisible que existe dentro y alrededor de nosotros. Discutimos cómo podemos beneficiarnos de las bacterias a través de alimentos fermentados y los probióticos, y cómo alimentar nuestros microbios intestinales con prebióticos. De hecho, en 2019, di más de 40 charlas sobre este tema a audiencias muy variadas a través de conferencias para profesionales, cursos para estudiantes de doctorado, seminarios y talleres para gente sin formación científica. Estas acciones están dirigidas no sólo a científicos y estudiantes, sino también a niños en escuelas, adolescentes en clubes deportivos y gimnasios o personal que trabaja en hospitales. El interés por los “bichos amistosos” es amplio y variado, y se alimenta de la información que circula por programas de radio y televisión.

“Almorzando con Mirtha Legrand”, un talk show que ha estado al aire en televisión por más de 50 años en Argentina, donde la discusión sobre microorganismos benéficos fue llevada a la mesa por Gabriel Vinderola (último a la derecha). Mirtha Legrand, de 93 años, está en el centro de los invitados (03/10/2019).

El entusiasmo de la audiencia fue inmediato. Se recibieron numerosos mensajes por correo electrónico, WhatsApp, Facebook o Instagram. La gente demostró estar interesada en saber más, preguntando por fuentes confiables para leer material con base científica, pero “fácil de entender”, planteando preguntas específicas sobre cuestiones intestinales, de dónde obtener probióticos y prebióticos o cómo hacer alimentos fermentados de manera segura. Afortunadamente, las infografías de la ISAPP sobre probióticos y prebióticos ya estaban disponibles en español, traducidas por Miguel Gueimonde (España) y por mí, y fueron un recurso muy utilizado. Sin embargo, la gente solicitaba más información, y hacía más y más preguntas específicas.

Estimulado por el creciente interés, me puse en contacto con una chef local, Ana Milena Giacomini, quien dejó atrás su carrera profesional de abogada para abrir un pequeño restaurante con un menú basado principalmente en alimentos fermentados. Ella ofrece sabrosos platos que incluyen yogur casero, chucrut, kimchi, kéfir de agua, humus fermentado, pan de masa madre, panqueques hechos de harina de arroz fermentada, kombucha, kvass y bebidas gasificadas a base de jengibre fermentado. Con ella organizamos talleres de 4 horas de duración, que actualmente están suspendidos debido a la pandemia por COVID-19. En estos talleres Ana prepara en vivo algunos de estos alimentos fermentados, para a continuación degustarlos, mientras yo explico la ciencia y la microbiología que hay detrás de ellos. Se discuten aspectos relacionados con la identidad, seguridad, estabilidad y los posibles efectos sobre la salud de estos productos. Siempre enfatizo las diferencias entre los alimentos fermentados y los probióticos, a la vez que discuto el potencial valor de incorporar alimentos fermentados, probióticos y prebióticos a la alimentación diaria como una forma de promover la salud intestinal. En estos talleres proporciono además información más específica sobre los efectos en la salud de probióticos para los que se dispone de sólidos meta-análisis que apoyan el uso de ciertos microorganismos en la prevención de la diarrea asociada a antibióticos en niños, el tratamiento de cólicos infantiles, la prevención de alergias y la reducción de la inflamación intestinal. Otros talleres con diferentes chefs de diferentes lugares de Argentina están en lista de espera para cuando esta pandemia de coronavirus termine.

Cena de cuatro pasos que incluye alimentos fermentados en cada plato, preparada por el chef argentino Martin Russo. La entrada consistía en zanahorias fermentadas y hummus, servidas en pan de masa madre.

En estos talleres se espera la asistencia de 30-35 personas cada vez. Entre ellas, nutricionistas interesados en dar respuestas adecuadas a sus pacientes, que se enteran de estos temas en los medios de comunicación o en las redes sociales. Pero también asisten personas que quieren aprender cómo hacer alimentos fermentados, dónde encontrar probióticos y prebióticos, u obtener una orientación clara sobre cómo incorporar bacterias vivas a su dieta. También asisten otros profesionales de la salud (gastroenterólogos, pediatras), docentes e incluso gente de la industria.

El postre eran bochas de helado cubiertas por la madre del vinagre (círculo transparente en la parte superior), enjuagadas y endulzadas.

La mayoría de los interesados en asistir a estos talleres tienen poca experiencia en alimentos fermentados, sólo están familiarizados con productos como el yogur, el queso, el vino o la cerveza. Es más, muchos de ellos desconocen que estos alimentos son fermentados, o no poseen una idea clara de lo que es la fermentación. La mayoría de ellos también tienen un conocimiento muy limitado, o incluso información errónea, sobre los probióticos y prebióticos. Estos talleres ofrecen la posibilidad de que personas interesadas en estos temas aprendan y prueben nuevos alimentos, de que conozcan la ciencia que hay detrás de los alimentos fermentados, los probióticos y los prebióticos, y de que aprendan las diferencias entre ellos de forma científica y en un “lenguaje fácil de seguir”. Estos encuentros son una forma de expandir el interés del público en general sobre el mundo invisible que habita dentro y alrededor nuestro.

Growing interest in beneficial microbes and fermented foods in Argentina

By Prof. Gabriel Vinderola PhD, Associate Professor of Microbiology at the Faculty of Chemical Engineering from the National University of Litoral and Principal Researcher from CONICET at Dairy Products Institute (CONICET-UNL), Santa Fe, Argentina

Awareness of gut microbes, fermented foods and probiotics has been on the rise in Argentina. Nutritionists and influencers, who in recent years have begun promoting a healthier lifestyle, are leveraging their social networks to post how-to instructions for making fermented foods, advice to promote a ‘healthier’ microbiota, and information on the potential role of probiotics and prebiotics in human health. But are these news items and recommendations based on science? Not always! I’ve been fortunate to have had the opportunity to make sure the science is correctly communicated to a broad audience on the microbiome, fermented foods, probiotics and prebiotics.

In Argentina, for the last 50 years, there has been on the air a TV show with a particular format: the hostess, Miss Mirtha Legrand, invites 4-6 people to have lunch every Sunday, talking about politics, economy, popular culture, arts and even science for 3 hours. According to her, this is the longest continuously running TV program in the world. Every Sunday several thousands of people from Argentina, Uruguay and Paraguay tune in. In October 2019, I was invited to join the table and to comment about the invisible world inside and around us. We discussed how we can profit from bacteria through fermented foods and probiotics, and how to feed our gut microbes with prebiotics. In fact, in 2019, I gave more than 40 talks on this topic to scientific audiences at conferences, as courses for Ph.D. students, as seminars and as workshops. These efforts are targeted not only to local scientists and students, but also to children in schools, local sport clubs in small towns, gyms and hospitals. The interest in friendly bugs is wide-ranging and varied, and fueled by information from radio and TV programs.

“Having lunch with Mirtha Legrand”, a talk show on television for more than 50 years in Argentina, where the discussion on beneficial microbes was brought to the table by Prof. Gabriel Vinderola (far right). Mirtha Legrand, now 93 years old, is in the center (October 3rd, 2019).

The enthusiasm of the audience was immediately evident. Lots of messages came by email, WhatsApp, Facebook or Instagram. People were anxious to know more, inquiring about trustworthy sources to read scientific-based but “easy-to-understand” material, posing specific questions about their gut feelings, where to get these probiotics and prebiotics or how to make fermented foods in a safe manner. Fortunately, the ISAPP infographics on probiotics and prebiotics were already available in Spanish, translated by Miguel Gueimonde (Spain) and me, and these were a welcome resource. Yet people still wanted more information, and asked more and more specific questions.

Spurred by such widespread interest, I contacted a local lawyer-turned-chef, Ana Milena Giacomini, who left behind her professional law career to open a small restaurant with a menu heavily based on fermented foods. She features such delights as home-made yoghurt, chucrut, kimchi, sugary kefir, fermented hummus, sourdough bread, pancakes made out of fermented rice flour, kombucha, kvass and a gasified drink from fermented ginger. With her, we organized 4-hour workshops, which are currently on hold due to COVID-19. These workshops feature Ana preparing some of these fermented foods live, followed by tasting, while I explain the science and microbiology behind them. I share factors related to the identity, safety, stability, and potential health effects of these products. I emphasize the differences between fermented foods and probiotics, while discussing the potential value of incorporating fermented foods, probiotics and prebiotics to the daily diet as a way to promote gut health. I provide more specific information on health effects for which robust meta-analyses are available to support the microbes’ use, such as prevention of antibiotic-associated diarrhea in children, treatment of infant colic, prevention of allergies, and downregulation of intestinal inflammation. Other workshops with different chefs from different locations in Argentina are in line for when the coronavirus pandemic ends.

Part of the four-course dinner containing fermented foods prepared by chef Martin Russo. The starter consisted of fermented carrots and hummus, served on sourdough bread (pictured).

These workshops are expected to be attended by 30-35 people each time. Nutritionists are interested in giving sound responses to their clients, who hear about these topics in the media or in social networks. But also, people come who want to learn how to make fermented foods, where to find probiotics and prebiotics, or to gain clear guidance on how to incorporate live bacteria to their diets. Other health professionals (gastroenterologists, pediatricians), educators and even people from the industry also attend.

 

The dessert was ice cream balls covered by the mother of vinegar (transparent circle on the top), rinsed and sweetened.

Most people interested in attending these workshops have narrow experience with fermented foods, only being familiar with such things as yoghurt, cheese, wine or beer. Some of them do not know that these foods are indeed fermented, or do not have a clear idea what fermentation is about. Most of them also have a very limited awareness, or even misinformation, about probiotics and prebiotics. These workshops offer the possibility for the curious to learn and to taste new foods, to get insights on the science behind fermented foods, probiotics and prebiotics, and to learn the differences between them in a science-based manner in an “easy-to-follow language”. These encounters are a great way to expand the interest by the general public on the invisible world inside and around us.

The Horses: Daily Routines in the COVID-19 Era

By Gregor Reid BSc (Hons), PhD, MBA, ARM CCM, Dr HS, FCAHS, FRSC

It’s dawn and as per every day, I put on my mask. It’s not the type of mask you might think in these anxious times. It’s to prepare hay bags for our two horses. Hay, filled with the dust and mold particles that frankly my lungs despise.

After preparing the hay, I then begin my walk. Our faithful dog by my side in between racing after a ball that ejects from a plastic thrower in my right hand. All around, the sounds of birds starting their day in song, zooming in to find a spot on a feeder filled with sunflower seeds and nuts. The air is cool, but it opens my lungs.

 

In half an hour, I will go back to our house and open up a computer screen that counts the dead and the ill from around the world. That sends me a litany of messages outlining new rules and procedures. The temptation to check savings has long passed. Not that they don’t matter. It’s just that we have to cope whatever they do.

As I walk past bare trees standing tall, itching to come alive, I think of frontline workers at hospitals being asked to check incoming sickness. Surely, managers, teachers or others could take over this public-facing role? We need to protect front-line health workers, or we won’t have them by our bedside. I know of one case where a super-highly qualified nurse was thrust into the cold air without protective gear and told to check incoming. The managers hadn’t fully understood what a virus is, how it infects and what is needed to stop it, and despite advance warning from other countries they had left the hospital and staff unprepared. The nurse had to demand personal protective equipment. Thankfully, awareness is growing. The messaging is now full-on.

Isn’t it easy to fathom what we’re all scared of? The cough, the sore throat, the fever then lungs that can’t seem to get enough air into our body? The fear of our calls not being answered, of not getting tested, and where we sit on the priority list when the ventilators are all taken? The fear of not seeing your mother again because planes won’t take you there and she’s too old to be saved.

It’s the first day of spring, so the leaves have not yet shuttered the sounds of motor vehicles on nearby roads, except today that constant hum is muted. It’s quiet outside. Humanity behind curtains. As it should be, even though we could never have imagined it.

I sit down for breakfast. Oatmeal, a probiotic milk drink that has data on fighting the flu, on top of frozen fruit melted in the microwave. A tablespoon of sunflower seeds and almonds the birds didn’t get. I pop my favourite probiotic along with a multi-vitamin perhaps only to sanctify my mind. Plus, a cup of tea, of course.

I re-read what my colleague in Britain, Glenn Gibson, has compiled. A brilliant piece on why probiotics may help us fight this coronavirus. I also wrote a commentary, well-intentioned but already met with cynicism via Twitter, that communication tool that never allows enough space to say what needs to be said, and is never enough for the addicted users.

Whatever we do to fight this miniscule blob looking only to live and multiply like the rest of us, we must do it with hope. For hope is our salvation. It is what we aspire to find. And if our time here has come to an end when we least expected it, we can still leave hope for others and tell them we tried our best to shine a light in the darkness. A light that will be their future. And if more time is given to us, then surely with every ounce of energy we will welcome the horses and the blessings of Mother Nature and pass our multitude of gifts to make the world a better place.

 

When I was at high school, our English teacher from the highlands had us read a poem written around the year I was born (1955) by a famous Scot, Edwin Muir. It’s called The Horses and I will leave it for you to read (substitute ‘fathers’ for ‘parents’). For Muir, these beautiful animals were creatures closest to his God. Animals to bring hope through the hours of sadness and fear.

Barely a twelvemonth after
The seven days war that put the world to sleep,
Late in the evening the strange horses came.

By then we had made our covenant with silence,
But in the first few days it was so still
We listened to our breathing and were afraid.

On the second day
The radios failed; we turned the knobs; no answer.
On the third day a warship passed us, heading north,
Dead bodies piled on the deck. On the sixth day
A plane plunged over us into the sea. Thereafter
Nothing. The radios dumb;

And still they stand in corners of our kitchens,
And stand, perhaps, turned on, in a million rooms
All over the world. But now if they should speak,
If on a sudden they should speak again,
If on the stroke of noon, a voice should speak,
We would not listen, we would not let it bring
That old bad world that swallowed its children quick

At one great gulp. We would not have it again.

Sometimes we think of the nations lying asleep,
Curled blindly in impenetrable sorrow,
And then the thought confounds us with its strangeness.

The tractors lie about our fields; at evening
They look like dank sea-monsters couched and waiting.
We leave them where they are and let them rust:
‘They’ll molder away and be like other loam.’

We make our oxen drag our rusty plows,
Long laid aside. We have gone back
Far past our fathers’ land.

And then, that evening
Late in the summer the strange horses came.

We heard a distant tapping on the road,
A deepening drumming; it stopped, went on again
And at the corner changed to hollow thunder.

We saw the heads
Like a wild wave charging and were afraid.
We had sold our horses in our fathers’ time
To buy new tractors. Now they were strange to us
As fabulous steeds set on an ancient shield.
Or illustrations in a book of knights.

We did not dare go near them. Yet they waited,
Stubborn and shy, as if they had been sent
By an old command to find our whereabouts
And that long-lost archaic companionship.

In the first moment we had never a thought
That they were creatures to be owned and used.
Among them were some half a dozen colts
Dropped in some wilderness of the broken world,
Yet new as if they had come from their own Eden.

Since then they have pulled our plows and borne our loads
But that free servitude still can pierce our hearts.

Our life is changed; their coming our beginning.

-Edwin Muir

The science on gut microbiota and intestinal gas: Everything you wanted to know but didn’t want to ask

By Kristina Campbell, science and medical writer

Even on the days when you don’t eat a large meal of Boston baked beans, the inside of your intestines is a gas-generating factory. This serves a valuable purpose for the body when everything is working as it should, with gases being produced and eliminated through a complex set of physiological processes. But sometimes gas becomes a problem—and this is when it’s valuable to know not only what contributes to intestinal gas symptoms, but also how dietary adjustments can alleviate some of the problems.

Dr. Fernando Azpiroz, Chief of Gastrointestinal Research at the Vall d’Hebron Research Institute and Professor of Medicine, Autonomous University of Barcelona (Spain), is an expert in both the pathophysiology of the gas produced in the digestive tract and the clinical problems related to intestinal gas. Dr. Azpiroz is the author of a chapter on intestinal gas in the well-known textbook, Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, which is now in its 10th edition. And for more than 20 years he has been conducting research on digestive tract function, intestinal gas, and the contributions of the gut microbiota.

ISAPP caught up with Dr. Azpiroz to ask him about everything you wanted to know—where intestinal gas comes from, when it becomes a problem, and the latest research on the dietary changes that can reduce symptoms of intestinal gas while keeping the gut microbiota intact.

In different parts of the digestive tract, where does intestinal gas come from?

For the most part, the gas in the digestive system comes from metabolic activities of the colonic microbiota.

In addition, some air enters the stomach during swallowing. Most of this air is eliminated by eructation (i.e. burping), so there is a homeostasis. There is a small air chamber in the stomach of about 20 mLs, and this is pure atmospheric air, or CO2 after recent consumption of carbonated drinks.

In the small intestine, the neutralization of acids and alkali can theoretically produce large amounts of CO2. However, it’s more in theory than measured in experimental conditions.

Other gases originate from the metabolism of the gut microbiota. The residues of the diet that are not absorbed in the small bowel pass into the colon. These are the parts of the diets that we, as humans, cannot use. These pass into the colon, and in the colon serve as substrates for colonic microbiota. Gas is produced during this process of colonic fermentation.

What types of gases are produced in the digestive tract?

The composition of intestinal gas depends on where in the gut it is produced.

In the stomach, the gas is virtually all atmospheric air or CO2.

In the small bowel, theoretically it should be CO2, although the hard data are very scarce.

And in the colon, the largest component is likely hydrogen and CO2. But the data on that are very limited, and it is not known for sure that these theories are really true. The measurements of gas composition, in the colon or even in the gas eliminated per anus are still uncertain but so far the main concept is that most of the gas is hydrogen and CO2, and methane in subjects that have a methanogenic microbiota.

How does this gas normally get eliminated?

Throughout the GI tract, particularly the colon, about 80% of the gases produced are absorbed through the mucosa, pass into the blood, and are eliminated by breath. So only about 20-25% of the volume of gases produced, particularly in the colon, are eliminated per anus.

What influences the amount of gas produced?

The amount of gas produced in different subjects depends on two factors: one is the diet—the amount of residues (i.e. fiber) in the diet—and the second is the type of microbiota, which is very individual. It varies a lot from one subject to another.

How much intestinal gas is ‘too much’?

From the point of view of patients, of symptoms, what might be relevant is the volume of gases produced, and possibly the type of gases. One evolving idea is that some gases, which are produced in very small quantities, might serve as neurotransmitters, might play a role, but so far the information we have about the role of these gases is very limited so we cannot extrapolate that to clinical use.

Very recent data indicate that symptoms occur when the GI tract has a poor tolerance to its contents, and particularly to gas.

So what is the factor that makes gas produce symptoms? Well there are two factors. One is the amount of gas, and the other one is the tolerance of the subject.

In healthy subjects, it will typically take a large amount of gas to develop symptoms, if at all.

But even small amounts of gas in patients that have a hypersensitivity of the gut and poor tolerance to contents might contribute to their symptoms. This can be seen because, if we reduce the amount of flatulogenic substances in their diet, the symptoms reduce.

This is if we just take into consideration the volume of gas produced, but there is also another factor.

If we give a high flatulogenic diet or a high-residue diet, we know, because we have measured, that we increase the volume of gas produced into the colon. However, we also increase the amount of the fecal content in the colon. So it could be that these diets produce symptoms because they increase the amount of gas, but also because other non-gaseous components, the fecal content of the colon, also are poorly tolerated.

How can someone manipulate their diet to change the amount of intestinal gas that’s produced?

A ‘challenge’ diet, or a high flatulogenic diet in healthy subjects, makes them sick. They go from being symptom-free to having some symptoms, particularly flatulence and bloating.

In patients, the effect of the diet is more accentuated. If patients consume a diet with high residues they get very symptomatic, and if these patients will reduce residues in the diet, they see quite an improvement.

What are the options for dietary change when someone has IBS or wants to reduce gas symptoms?

One thing that has been shown recently is that the effect of a low-residue diet is similar regardless of the type of diet. In the past ten years or so there’s been a major trend with the use of low-FODMAP fermentable oligo-, di-, mono-saccharides and polyols diets.

However, the effect of these complex diets is not better than the effect of any sensible and simple low-residue diet. So if you reduce legumes, veggies from the diet, and fruits, you get a similar improvement.

The problem with low-residue diets, in particular the low-FODMAP diet, is that they introduce a restriction of the substrates for the feeding of the microbiota, and this is deleterious to the microbiota. The microbiota is impoverished.

The other limitation of low-residue diet is that the moment that the patient returns to a normal diet, the symptoms come back.

There is an alternative that has been shown in the past few years, which is to use some type of prebiotics that initially—because they are fermented—produce symptoms, but after a few days they induce an adaptation of the microbiota towards a microbiota that produces less gas with normal fermentation. And down the road, these prebiotics have a positive effect on symptoms in patients. As a matter of fact, the effect on symptoms is similar to a restrictive diet. The advantage of the prebiotics is that, after interruption, …the effect is sustained at least over a few weeks. And this is because it has been shown that prebiotics serve as substrates for microbiota and induce a proliferation of beneficial organisms.

There is also some preliminary evidence that some probiotics reduce the volume of gas production and reduce digestive symptoms in patients.

Is it a good idea to test your gut microbiota when you have IBS or gas symptoms?

There are different companies that claim that by analyzing microbiota they can diagnose some functional conditions, for instance IBS. The practical application of this technology has not been demonstrated. Usually they are expensive techniques and of no value.

It’s important to understand the real value of these methodologies and take the myth out of ‘wonder’ techniques that make a diagnosis from the microbiota and claim it explains everything.

Hopefully, this might be true in the future, but not right now. And actually many of the technologies that are used for this type of analysis are suboptimal.

 A previous blog post by Dr. Bob Hutkins on diet, gut microbiota, and intestinal gas is ISAPP’s most-read blog post of all time. Read it here.

The past decade of probiotics and prebiotics research: ISAPP board members share their perspectives.

By ISAPP board members, compiled by Kristina Campbell

Scientific progress in the field of probiotics and prebiotics, as in any other field, often seems to occur one tiny step at a time. Yet over the course of several years, these tiny steps can add up to significant progress.

Current members of the ISAPP board of directors hold academic positions across North America, and Europe, representing some of the experts at the forefront of scientific innovation in probiotics and prebiotics. Their collective experience encompasses functional foods, fermentations, microbial ecology, microbial genetics, immunology, and clinical medicine, including pediatrics, family medicine and gastroenterology. As we enter into 2020 and a new decade, these board members have taken a moment to reflect on how far they and their colleagues have come over the past ten years, by answering the question: What changes have occurred in the domains of research, applications, and awareness about probiotics and prebiotics?

ISAPP board members, 2019 annual meeting

Available scientific methods and tools

The change that stood out the most to the ISAPP board members over the past decade was the rapid expansion of available scientific methods and tools – from gene sequencing technology to CRISPR-Cas to bioinformatic approaches. These exciting developments have enabled scientists to obtain more information, and to do it both quickly and economically. In the words of the board members:

“Advances in sequencing technology [have] revolutionized our ability to understand the gene repertoire of each individual probiotic strain (whole genome sequencing) and the interplay with the microbiome (metagenomics). This has been really energizing to the field, but has also meant that competence in bioinformatics has become an essential tool for probiotic and prebiotic scientists.”

“A decade ago, human studies on prebiotics would look at changes in the gut microbiota using fairly laborious procedures. Nowadays, the analysis is much more extensive and straightforward to do, and probably more accurate… The biggest change has been the capability to assess not only composition of the microbiota but also its functionality. So, today, the trials include metabonomics as well as assessments of health effects (through changes in particular symptoms and /or biomarkers such as blood lipids, microbial products, immune and inflammatory status). That way, we get a far better picture of what prebiotics can do.”

“In 2010 we only had DGGE to characterize the genome and were trying to figure out how to implement 16S amplicon sequencing. Now we are implementing shotgun & shallow shotgun sequencing for similar prices. In 2010, we did only work on 3-4 probiotic lactobacilli for molecular research, now we work on 400-500 lactobacilli. We do comparative genomics and functional analyses at much larger scale. And in 2010, we paid almost 10000 euro just to sequence one genome of lactobacilli, with limited analysis, now a few hundred euro for sequencing.”

Probiotics and prebiotics for microbiome modulation

Because of the rapid advancements in scientific tools and techniques during the past decade, as mentioned above, many more research groups are endeavoring to study the microbial communities that relate to probiotics and prebiotics. Gut microbiota are of great interest—not least because, among the strategies for microbiome modulation, probiotics and prebiotics are two of the leading candidates. Moreover, microbiome data can help researchers understand the context of probiotics and prebiotics in the gut and in different environments. In particular, many clinical trials of probiotics and prebiotics now include a microbiota-related measure. Novel species and strains for food use may be identified from gut microbiota studies, although safety and efficacy assessment will form challenges for regulatory bodies. Board members said:

“My collaborators and I initiated our first human clinical trials with prebiotics in 2008 and published several papers in 2010 and 2011. These early papers were among the first in which high throughput 16S DNA sequencing was used to assess how the human gut microbiota was affected by the prebiotic, GOS. Although this is now a routine method in the field, in 2008, having a Roche 454 pyrosequencer in the lab was very special, and we were astounded to be able to identify and measure abundances of the main members of the gut microbiota. Having these large data sets also led us to realize the importance of what was at the time the “new” field of bioinformatics that was critical in analyzing and reporting the data. This research showed that GOS was bifidogenic (with high specificity) in healthy adults, but was also subject-dependent. Thus, the results clearly showed there were prebiotic responders and non-responders. This remains an important area of research for my group.”

“The decade started with general excitement that ‘dysbiosis’ of the gut microbiota is involved in just about every human health problem, and has turned into re-remembering that correlation is not causation and microbiota patterns are often driven more by random factors or factors unrelated to disease than by microbiology.”

“It’s worth noting that in 2020, the well-controlled probiotic studies showing health benefits in humans are still more convincing and valuable than the studies showing any ‘beneficial’ effects on the human microbiota.”

“Over the past decade we have witnessed a tremendous explosion in our understanding of the microbiome and its interactions with us, its host. Progress in translating this knowledge into new treatments has been slower but glimmers of encouragement have appeared and we look forward to the next decade when interventions that modulate the microbiome to benefit our health will be based on a true understanding of how they act and will be selected to the maximal benefit of each individual.”

Probiotic mechanisms of action

Probiotic mechanisms of action are a perennial hot topic within the scientific community—and many had hoped that the new suite of scientific tools at scientists’ disposal would significantly advance this area of research during the past decade. But according to one ISAPP board member:

“In 2010 I would have confidently predicted that by 2020 we would have much more of a mechanistic understanding of probiotic mechanisms [and] the importance of strain effects… But this simply has not happened.  The field has become more biologically and computationally complex and many millions have been spent on research, but I still don’t think we can answer the fundamental question we faced in 2010, and in 2000, and in 1990 – what makes one a strain a probiotic, while another is not?”

But in the views of other board members:

“Through genomic and metabolomic studies we are identifying differences between strains that function at different sites and what properties are important for their probiotic function.”

“Identify[ing] the key effector molecules turned out to be more complex [than] we thought 10 years ago. It has become clear to me that probiotic mechanisms of action are per definition complex and multifactorial, because they are living microbes having thousands of molecules that all play a role. Yet, there is clearly an hierarchy of effector molecules.”

Probiotic and prebiotic applications

In general, microbiome studies of the past decade have led to a better appreciation of the ubiquity and complexity of microbial communities—not just those associated with different human body sites, but also those occupying every possible niche on Earth. ISAPP board members reflect:

“In 2010, I was mainly studying probiotics for the gut and vagina, now we have explored probiotics for the skin, respiratory tract, animals, plants, isolates from fermented vegetables that can boost vegan probiotic formulations etc., and other areas.”

“Two areas of research I am doing I’d never have imagined in 2010 are in honey bees and Chinook salmon and against environmental chemicals, administering probiotics.”

Public awareness of probiotics and prebiotics

Numerous studies and surveys show the general public has more awareness than ever of probiotics – and increasingly, of prebiotics too. Individuals receive their information through many different channels, both digital (e.g. blogs, websites) and non-digital (e.g. magazines, product packaging). The past decade also saw the creation of valuable evidence-based resources, such as the Clinical Guides available in the US and Canada, and resources from World Gastroenterology Organisation and from ESPGHAN (probiotics for pediatric acute gastroenteritispediatric nosocomial diarrheapreterm infants, and pediatric AAD). These resources have been enabled by a critical mass of studies that have examined the efficacy of various probiotic strains for certain indications. One board member says:

“From a clinical perspective, the biggest change for us has been that the general public knows so much about probiotics; now we are doing a lot less educating of docs and patients about the concepts behind our probiotic studies.”

But there’s still work to be done:

“The term probiotic is now widely known, but still too often people are misinterpreting what it means, or generalizing the whole field instead of recognizing strain and product differences. We need to continue to educate and clarify to keep the messaging on track.”

“There is still lack of knowledge that not all probiotics are equal. The clinical effects and safety of any single probiotic or combination of probiotics should not be extrapolated to other probiotics. The same applies to prebiotics.”

“Choosing a probiotic continues to be a major hurdle for the consumer – for every probiotic strain that is well characterized, studied in detail in appropriate disease models, and shown to be effective in clinical trials there are hundreds that would fail to pass even the most basic tests of quality control. We must help the consumer to make informed choices.”

 

It seems that, while the past decade has been a fruitful time for probiotics and prebiotics research and public awareness, scientists still have a lot of work to do. In the 2020s they will use the tools available to them, and continue to develop new ones, to gain more detailed and multi-faceted information about probiotic strains and prebiotic compounds—and about the context in which they operate (for instance, the gut microbiome), to ultimately confer benefits on human health.

Probiotics, Prebiotics and Globobiotics!

By Prof. Colin Hill, PhD, APC Microbiome Ireland, University College Cork, Ireland

Growing up I could not imagine what the world would look like in 2020, but I was convinced it would be amazing. The future was exciting, new planets and solar systems would be explored, diseases would be cured, and everyone would have sufficient food and shelter.  I sometimes think my generation may have been born at the most perfect time in human history (for someone brought up in a first world country at any rate).  We avoided the major world wars which our parents and grandparents endured, we had the benefits of cheap airfares so we could travel the world as tourists, not as armies. Oil was cheap and plentiful. Access to education was widely available. We benefited from antibiotics while they were still effective.  Gender inequalities and racism began to be addressed, even though there is still a long way to go. Computers became commonplace and the internet provided access to almost unlimited sources of information.

But here we are in 2020, and now things do not look so promising. Perhaps cynicism is a natural by-product of getting older, but now the future seems to be presented in apocalyptic terms. Climate change, antibiotic resistance, ageing populations, the paradoxes of increasing obesity and increasing hunger, exploding populations, depletion of natural resources and pollution of our oceans. Watching nature programmes hosted by the incomparable David Attenborough has changed from generating a sense of awe at the wonders of the natural world to a sense of despair as to what we are doing to it. Australia is literally on fire as I write this!  Can our planet survive the onslaught of the projected 10 billion humans by 2050 – each one hungry for a share of finite resources?  Is this really going to be the legacy from my generation to the next – a dystopian future without hope and optimism?

But it’s a New Year and a new decade, and I really want to be hopeful. I am encouraged by the fact that we are gradually beginning to come to grips with this new reality. The UN Sustainable Development Goals provide a roadmap guiding societies and individuals as to how to make a contribution. Attitudes are changing.  Too slowly for sure, but we do seem to be at a tipping point.

But what has this tirade have to do with prebiotics and probiotics, you may ask? Well, everything of course. One of the things that really gives me hope is our growing understanding of how humans are simply occupying space in a microbial world. If we squander our opportunity and destroy our planet in terms of human habitation, microbes will carry on for billions of years to come. We should remember that we can only live on Earth because all of the oxygen we breathe is the result of billions of years of microbial metabolism, that most of the carbon cycling on earth is due to microbes, and that every natural system on Earth depends on microbes. Of course we are also inhabited by a vast ecosystem of microbes (our microbiomes) that are required for our health and wellbeing, and we live in environments shaped by microbes. Understanding this will help us to live in harmony with our microbial world, rather than constantly forcing our poor planet to deliver our short term needs.

How can microbes help us to achieve sustainability and restore a healthy ecosystem? I believe that there are many opportunities. By 2050 I predict that we will be using microbes to restore productivity to land damaged by excessive use and pollution.  We will be using microbes to clean our oceans of plastic waste. We will improve food production without using chemicals, and we will have certainly reduced food waste (it is estimated that one third of all the food we produce on earth is lost to spoilage, much of it caused by microbes). We will have reduced methane emissions by manipulating the rumen microbiome in domesticated ruminants. We can look forward to a world where we can work with microbes to restore and replenish our atmosphere by unlocking the enormous potential of microbes to scavenge and store carbon. We will have reduced our reliance on antibiotics and will have found microbiome-friendly solutions to prevent and treat infection. We will have developed probiotics and prebiotics that will help us to address metabolic diseases, we will be using bacteriophage to sculpt microbiomes, while psychobiotics will be helping to prevent age related loss of brain function.

Given that the world is a microbial ecosystem, I propose that in the same way we can treat our human ecosystems with prebiotics and probiotics to improve or restore health, we can think in terms of developing microbial solutions to improve or restore planetary health. Because we haven’t had one in at least a month, I propose yet another new term; globobiotics. Globobiotics would be defined as “live microorganisms, microbial products or substrates selectively utilized by microorganisms, that are used in a manner that contributes to the sustainability of our planet”.

We’ve had the Stone Age, the Iron Age, the Oil Age, the Atomic Age and the Information Age, welcome to the Microbial Age!