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Why responders and non-responders may not be the holy grail for biotics

/in ISAPP Science Blog /by KC

By Prof. Dan Merenstein MD, Georgetown University Medical Center, USA

In September the New York Times published an article titled “What Obesity Drugs and Antidepressants Have in Common“. It was written by a physician who had personally struggled with weight issues and depression. In his personal journey with these health challenges, he hesitates to undergo any treatments. But he eventually does and experiences much relief from them. Why would a practicing physician hesitate to use approved drugs?

The article opens with this viewpoint: “We like to think we understand the drugs we take, especially after rigorous trials have proved their efficacy and safety. But sometimes, we know only that medications work; we just don’t know why.” He goes on to discuss selective serotonin reuptake inhibitors (SSRIs) and  the recently approved weight loss drugs, such as glucagon-like peptide-1 (GLP-1) receptor agonists. The former have been widely used for over 40 years, while the weight loss drugs are more recent. For both classes of drugs, we have some ideas how they work but the exact mechanisms have not been elucidated. While this knowledge gap has not prevented wide usage, the author of the article was skeptical about using the drugs if he did not know exactly how they worked. 

When I started studying probiotics 15 years ago, I began to interact with a different group of scientists than I was used to. My new collaborators were basic and applied scientists, not just clinicians. I had opportunities to attend conferences that covered bench science more than clinical evidence.  My perspective as a clinical researcher was different from most of the others in attendance. I was somewhat surprised to learn how much emphasis those scientists placed on understanding mechanisms. On the one hand, intuitively it makes sense. If you know how something functions, you have a lot more confidence that it will do what you expect it to do, and more assured that it can be used safely. You also have a sense that it should work for you. But on the other hand, knowing an intervention is effective is more important than knowing how it achieves its effectiveness.

This emphasis on understanding mechanisms of action for interventions reminds me of the development of beta-blockers, a class of medicines that block epinephrine, and cause the heart to beat slower and with less force. One of the most common test questions I was asked when I was a medical student and resident is: What class of blood pressure medicines are never permissible for a patient with congestive heart failure (CHF)? Well it was obvious to all of us that the answer was clearly beta-blockers, as you wouldn’t want to slow the heart rate and reduce the force of the heart in a patient already suffering from a poorly performing heart. Yet after clinical trials were completed, beta-blockers were shown to be effective treatment for CHF patients and are now a mainstay of CHF treatment. This was counterintuitive considering the drug’s mechanism of action. So in fact, a drug’s mechanism of action does not always lead in a straightforward way to knowledge about which conditions can be treated or which individuals will respond.

Beyond mechanisms of action and individual response

In clinical medicine, we use two important statistics to capture efficacy and safety of an intervention: number needed to treat (NNT) and number needed to harm (NNH). NNT is the number of patients that need to be treated in order to have an impact on one person, while the NNH is the number of patients who must be treated with an intervention before one patient is harmed.  All interventions have both an NNT and NNH. Obviously, the goal is  a very low NNT and a high NNH. But we are rarely so fortunate. Take for example statins, a medicine many of us take. In patients at low risk of cardiovascular disease, the NNT is 217, which means 1 person out of 217 avoided a nonfatal heart attack by taking statins. Meanwhile, NNH for muscle pain is 21 and for developing diabetes is 204.

NNT and NNH are rarely considered in the biotics field. Yet I commonly encounter discussions about the importance of identifying responders versus non responders to biotic intervention and the need to elucidate the mechanism(s) of action for biotic substances. I believe this is because many of the scientists doing research in biotics come not from a clinical background but more bench research, where the questions really are those of mechanism. Many seem to believe that such knowledge is the Holy Grail of biotics – if only scientists could have such a good grasp of mechanism that they could figure out why certain people responded while others do not. There is nothing inherently wrong with wanting to identify reasons for differences in individual response. It is what we do in clinical practice every day. When I give someone blood pressure medicine and they don’t respond to it, I wonder – Is it a compliance issue? Is the patient’s blood pressure caused by something that the medicine does not impact? Is the patient taking the medication at the wrong time, with the wrong diet, or with other interfering medicines?  Clinicians always must think about who is responding and who is not responding. However, NNT and NNH for biotics are worth prioritizing.

Data have shown that certain probiotics can get people better from an upper respiratory tract infection 26 hours earlier, or can treat infantile colic, or improve irritable bowel syndrome symptoms with a NNT respectively of 20, 15 and 100, while having a very high NNH. These are great products. But instead what I often hear at conferences is that we need to figure out why some people respond to the probiotics and others do not. I agree, go ahead and figure it out. But have realistic expectations. If two of the most widely used medicines, SSRIs and GLP-1 agonists, have an unclear mechanism, and if statins have an NNT of 217, be realistic about the impact of your probiotic. When a doc prescribes you Lipitor, he doesn’t say, “Good luck –  I hope you are the 0.4% in which it helps and aren’t the 5% that gets muscle cramps.” The hope is that for you, the NNT is 1. And when your strain or product does have an impact, feel free to find ways to improve efficacy but celebrate the impact it has. If possible, maybe compare your NNTs to standard of care, or if no comparison look at your NNT versus NNH to really better understand what your biotic can do.

Inaugural nominations open for ISAPP Award: The Sanders Award for Advancing Biotic Science

/in News /by KC

With this year’s retirement of ISAPP’s longtime Executive Science Officer, Dr. Mary Ellen Sanders PhD, the ISAPP board of directors sought a suitable way to honor her contributions in advancing scientific development in the fields of probiotics, prebiotics, synbiotics, postbiotics and fermented foods. Many scientists in these fields have commended Mary Ellen’s leadership, initiative, collaboration, and communication over the last 20 years.

Board members decided to launch a new award in Mary Ellen’s honor: The Sanders Award for Advancing Biotic Science. This award aims to promote excellence in the biotic field and recognize exceptional achievement across a range of potential endeavours including research, scientific communication and stakeholder engagement. A cash grant and travel to the ISAPP meeting will be awarded to the annual recipient starting in 2024.

Prof. Gregor Reid PhD, ISAPP co-founder and former board member, who championed the award, says: “What better way to applaud leadership and someone who has placed honesty, stewardship and evidence-based progress above all else, than to have an annual celebration of advancement in these critically important fields.”

The ISAPP board invited members of the ISAPP community to donate to a special endowment fund in order to sustain the Sanders Award over the long term, and this fund received over $34,000 of donations.

ISAPP President, Prof. Dan Merenstein MD, says: “We have really appreciated and been touched by the generous individual and company donations. But none of that is surprising because Mary Ellen has been a positive force in this field since the beginning and everyone who works with her respects and enjoys working with her.”

The award was launched in August, 2023 and nominations are open through to November, 2023.

Find out more about the award here.

Clarifying the role of metabolites in the postbiotic definition

/in ISAPP Science Blog /by KC

By Dr. Gabriel Vinderola PhD, Instituto de Lactología Industrial (CONICET-UNL), Faculty of Chemical Engineering, National University of Litoral, Santa Fe, Argentina and and Prof. Colin Hill PhD, School of Microbiology and APC Microbiome Ireland, University College Cork, Cork, Ireland

ISAPP published a definition for the term postbiotics in 2021 that states that “a postbiotic is a preparation of inanimate microorganisms and/or their components that confers a health benefit on the host” (Salminen et al., 2021). This 19-word definition had to distill the content of the accompanying article that ran to over 9,000 words (not including references) and so obviously a lot of nuance was lost. A reading of the full paper should dispel any misconceptions, but we thought it might be timely to discuss what is perhaps the most common misunderstanding.

Some of the previous definitions included metabolites (purified or semi-purified) under the postbiotic concept. We did not agree with this interpretation. For us, the term postbiotics refers to preparations that consist largely of intact microbial cells, or preparations that retain some or all of the microbial biomass contained in microbial cells. This latter concept was captured in the phrase “and/or their components” The first column of page 3 of Salminen et al., 2021 elaborates on this; “The word ‘components’ was included because intact microorganisms might not be required for health effects, and any effects might be mediated by microbial cell components, including pili, cell wall components or other structures. The presence of microbial metabolites or end products of growth on the specified matrix produced during growth and/or fermentation is also anticipated in some postbiotic preparations, although the definition would not include substantially purified metabolites in the absence of cellular biomass. Such purified molecules should instead be named using existing, clear chemical nomenclature, for example, butyric acid or lactic acid”. So, taken in context, the scope of the ISAPP definition covers inanimate, dead, non-viable microbes; either as intact whole dead cells or in the form of “their components”. We do not consider microbial metabolites to be postbiotics. Such an interpretation would, for example, make butyrate or other end-products of fermentation postbiotics (once shown to have a health benefit). The ISAPP definition does not exclude the likelihood that microbial metabolites will be present in a postbiotic preparation, but it does require that dead microbes or microbial cell fragments or structures should be present to qualify as a postbiotic.

Why did the ISAPP definition exclude purified or semi-purified metabolites in the absence of cellular components? We fully accept that metabolites or other microbe-generated functional ingredients such as lactate, butyrate, bacteriocins, defensins, neurotransmitters, and similar compounds can be present in a postbiotic preparation. But as you can see from this list, these compounds already have names that are clearly understood. The ISAPP definition of postbiotics focuses on the beneficial role of inanimate microbes and/or their components, a category that did not have a clear definition. Postbiotics are simply one category of substances that provide microbe-associated health benefits. In terms of semantics, dictionaries define the prefix ‘post’ as meaning ‘after’ and the word ‘biotic’ as meaning ‘living things’, and so a postbiotic in that context is something that was living and is now after-life, or inanimate. Metabolites are derived from living things, but never had an independent ‘life’ of their own. As a thought experiment, let us imagine a microbe that has been shown to have a health benefit and therefore qualifies as a probiotic. If the same microbe is inactivated and continues to show a health benefit, this new formulation is no longer a probiotic and qualifies as a postbiotic. If this postbiotic preparation can be further purified and it is shown that a metabolite or metabolites in the absence of cells or their components can provide the same health benefit it ceases to be a postbiotic and becomes a health-promoting metabolite. We could imagine microbially-produced vitamins as an example.

Ideally, definitions should be clear without supplemental explanation. But short, simply worded definitions that describe complex concepts must be read in a context. There is a background, they have a scope, there are things that are covered by that definition and things that are not, and of course definitions have their limitations. It would be hard, if not impossible, to include the scope, the background, the coverage and the limitations in a 19-word definition. For instance, the 15-word probiotic definition is “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” (Hill et al, 2014). This does not include the idea that probiotics are strain-dependent, a fact that is widely accepted by the field. Other criteria for probiotics not stated in the definition include the fact that that they may be of any regulatory category, that their health benefits must be demonstrated in well-controlled trials in the target host, and that they must be safe (Binda et al. 2020).

In closing, we believe that the postbiotic concept can be an incredibly important scientific, regulatory and commercial concept. That is why we spent the time and effort to arrive at what we hope is a workable definition. We accept that the definition is not perfect but we do think it is useful, and we urge those interested in the future of this important field to read the accompanying paper carefully and to place the definition in its proper context.

See ISAPP’s Postbiotics infographic here.

 

Biotics in animal and human nutrition

Episode 22: Biotics in animal and human nutrition

/in Podcast, Season Two /by Laura

Biotics in animal and human nutrition

 

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The Science, Microbes & Health Podcast 

This podcast covers emerging topics and challenges in the science of probiotics, prebiotics, synbiotics, postbiotics and fermented foods. This is the podcast of The International Scientific Association for Probiotics and Prebiotics (ISAPP), a nonprofit scientific organization dedicated to advancing the science of these fields.

Biotics in animal and human nutrition, with Prof. Kelly Swanson

Episode summary:

In this episode, the ISAPP podcast hosts join guest Prof. Kelly Swanson PhD from University of Illinois at Urbana-Champaign, to discuss the role of biotics in animal and human nutrition. They review the criteria for prebiotics and synbiotics, then discuss how we gain knowledge about nutrition and the role of biotics in animals compared to humans.

Key topics from this episode:

  • A good argument can be made that biotics are essential for our diet; they are beneficial even if efficacy is sometimes difficult to prove.
  • Nutrients have an impact on the host’s health and simultaneously on the host-associated microbes.
  • Health benefits are essential to the FDA definition of fiber.
  • Antibiotics’ effect on the microbiota: short-term effects may be minor, but we still don’t know the long-term effects.
  • The synbiotics definition, criteria for products to meet this definition, and the health outcomes from using these biotic substances.
  • The difference between complementary and synergistic synbiotics.
  • When studying biotics in companion animals (cats and dogs), can results from one host be extrapolated to another host? Final studies should be in the target host.
  • Biotics are important in veterinary medicine and a popular topic of study.
  • Predictions about the future of nutrition science as informed by the microbiome.

Episode links:

Additional resources:

About Prof. Kelly Swanson:

Kelly Swanson is the Kraft Heinz Company Endowed Professor in Human Nutrition at the University of Illinois at Urbana-Champaign. His laboratory studies the effects of nutritional interventions, identifying how diet impacts host physiology and gut microbiota. His lab’s primary emphasis is on gastrointestinal health and obesity in dogs, cats, and humans. Much of his work has focused on dietary fibers and ‘biotics’. Kelly has trained over 40 graduate students and postdocs, published over 235 peer-reviewed manuscripts, and given over 150 invited lectures at scientific conferences. He is an active instructor, teaching 3-4 nutrition courses annually, and has been named to the university’s ‘List of Teachers Ranked as Excellent by Their Students’ 30 times. He serves on advisory boards for many companies in the human and pet food industries and non-profit organizations, including the Institute for the Advancement of Food and Nutrition Sciences and International Scientific Association for Probiotics and Prebiotics.