This Probiota edition finally set foot in the country with the most effective regulation around probiotics, Canada, on 24-26 June 2019 in Vancouver!
NutraIngredients USA introduced the Wellness Program, proposing attendees to walk, run, practice yoga on a rooftop, and keep hydrated! The attendees were also treated with a DownTown cocktail and rooftop afterparty 😊
Matthew Otter, head of Consumer Health at Euromonitor, evaluated the possible scenarios for the probiotics market in the coming years. While the category was characterized by a strong growth, it has slowed down in the US since 2017, back to a 1-digit growth. Matthew hyptohesizes this could be due to category cannibalization of the supplement market from food-based probiotics, including kefir and kombucha. Future sales could follow different trends:
- Steady growth of about 4% till 2023
- Deeper drop down to 1-2% growth
- Rebound, on the back of scientific advance and innovation
- Market movement, with focus on areas with faster growth like Australia.
Matthew thinks a further drop is unlikely because the probiotics market shouldn’t become a commodity, having a lot of technicity and science behind. He rather expects a rebound, if the industry can engage with consumers in a new, better way and pass on the message of specificity, characterization and molecular pathways, that are not defined for most probiotics used in foods. Euromonitor envisions a short term decline followed by a category resurgence around new science and innovation: when consumers will understand probiotics are not just about digestion, but specific bacteria play a role in mental health, weight, cholesterol, allergy, etc. In parallel, other markets like Asia Pacific are growing at a rate of 20% per year!
From Lumina, regarding the online market for probiotics, Ewa Hudson reviewed the importance of this less visible market, currently growing 28% in Brazil and 22% in Australia. The online environment is where consumers search information on their symptoms and are influenced by articles, social media, brands, forums and product ratings. 72% of consumers will wait until they’ve read a review prior to buying. If your product scores below 4 stars, you’re in trouble, as it’s hard to compensate for poor reviews. Indications like skin health, constipation, UTI and brain health are highly ranked, showing consumers welcome innovation and science.
2. Microbiota science
Military rations impact on the microbiota
After a beautiful introductory poem by Stephen Daniells, Probiota started with the presentation of a study done in the US military. Dr. Ida Gisela Pantoja-Feliciano examined the influence of an acute change in diet on the gut microbiota, with 21 days on Meals Ready to Eat (MRE military rations), compared to a standard diet. MRE are processed foods with low diversity and not much fruit and vegetables, though they were complemented in this study with resistant starch. The impacts of MRE and starch on the microbiota composition are an increase in Dorea species, a decrease in Desulfuvibrio (related to inflammation, so its lowering could be a positive outcome), a decrease in Haemophilusparainfluenzae, an opportunistic pathogen, and a relative increase compared to the standard diet in Ruminococcus torques, Faecalibacterium prausnitziiand Eubacterium rectale. The MRE wasn’t found to substantially change community structure, though it could be exciting to complete this study with field stress, and to study probiotics in soldiers performance, though this population is quite inaccessible for scientists.
“Gut microbes eat our medication”
Najla Guthrie, President and CEO of KGK Science, reviewed evidence that prescription and OTC drugs – and not just antibiotics – have an effect on the microbiota and can compromise the efficacy of probiotic products on trial. With over half the Americans being on prescription meds and 75% also taking OTC drugs regularly, it’s important to take into account this source of bias in probiotics and microbiota studies. The article Extensive impact of non-antibiotic drugs on human gut bacteria, Maier et al., published last year in Nature, showed 24% of the 1000 drugs investigated had an impact on commensals. More precisely:
- Proton Pump Inhibitors (PPIs) increase Cdiff, Streptococcus and Staphylococcus, and make the stool microbiome look more like the mouth microbiome (logical, with less stomach acids to kill bugs)
- Antipsychotics and antidepressants tend to decrease diversity and richness (Valles-Colomer, 2019, Lukic et al., 2019)
- Contraceptives can create issues with immunity, especially if you’re a smoker
- Vitamin D increases richness and decreases Proteobacteria and Bacteroidetes – a priori a good outcome.
“Gut microbes eat our medication”Harvard put up as headline this year, challenging our understanding of what is healthy. Jessica Ter Haar gave a nice concluding comment “There’s a two way interaction: drugs impact bugs, and bugs impact drugs”. For all drugs that can reach the intestine, that is no more surprising than saying that the foods we eat affect our microbes.
3. Probiotics science
Some molecular mechanisms of action behind probiotics
Dr. Michiel Kleerebezem from Wageningen University deciphered for us molecular mechanisms of action of probiotics. Bacteria in yogurt produce beta-glactosidase which improves symptoms of lactose intolerance for example, but usually things are not so straightforward, and the knowledge gap limits the selection and production of improved probiotic products based on enhanced effector molecule expression.
Exemple 1: L. rhamnosus GG appears to stimulate barrier function and wound healing, mediated by culture supernatant, an effect lost when the preparation is treated with protein kinase, pointing to P40 and P75 contributing to epithelium integrity in vivo.
Example 2: L. plantarum WCFS1 activates alertness (increase immune responsiveness) by NFκB. Testing different cell wall components of the strain in Caco2 cells and NFκB, the research group identified lipoteichoic acid (LTA) and peptidoglycans (PG) as activators of this pathway.
However, the physiological consequence of a probiotic supplementation depends more on the starting point at the transcriptome level than on the arriving point, which could explain why probiotic research is so often confronted with non-responders.
Probiotics and health effects – the big picture
The broader vision regarding a health outcome linked to the microbiome is the Bristol Stool Scale, the best indicator of transit time in a cohort of over 5000 people. So don’t forget to check your poop consistency next time!
Christopher Martoni, Scientist at UAS Labs, gave the example of a systematic screening of Bile Salt Hydrolase (BSH) production in a number of bacteria, followed by optimization of the strains through growth components and clinical demonstration of efficacy showing the decrease of LDL cholesterol and C-reactive protein.
Similarly, Ralf Jaeger, Managing Member of Increnovo, reviewed clinical studies of probiotics in athletes and concludes 5 studies showed performance improvement, while 7 show benefits in immune health.
The panelists advised to look more at the small intestine microbiome – most of the food we eat doesn’t reach the colon but could have an impact earlier in our digestive tract – but this requires technologies that are not broadly accessible (IntelliCaps® being no longer produced).
Probiotics, prebiotics and cardiometabolic health
Jason Bush, Senior Scientist at MSPrebiotics, presented microbiome biomarkers related to cardiometabolic disease in a prebiotic supplementation clinical trial in which healthy individuals were supplemented with 30g per day of MSPrebiotic or placebo for 12 weeks. Bifidobacteria increased both in the 30-50 years age group and in the >70 years old, while insulin resistance decreased only in the older age group. Other positive outcomes in the seniors were a decrease in E. coli and an increase in butyrate production. It is likely that Bifidobacteria could have increased Lactobacilli, Firmicutes and butyrate producers by cross-feeding, altogether regulating insulin production in the pancreas. MSPrebiotic supplementation may therefore be part of an effective strategy to reduce insulin resistance in seniors.
Dr. Hana Koutnikova from Danone Nutricia Research evaluated the data available on the effects of probiotics in obesity, diabetes and Non-Alcoholic Fatty Liver Disease (NAFLD) in a meta-analysis covering 105 publications totalling 5188 subjects. On average, probiotics significantly reduced weight by 0,4 kg, with a robust effect estimate but a small size effect (below clinically meaningful threshold). Results on diabetes and NAFLD markers were similarly consistent and significant, but small. To target diabetes, supplementation should last at least 3 months, and 6 months for obesity. For future studies, Hana also recommends a follow-up after a washout period.
Probiotics can make a difference in Women’s Health
Dr. Johanna Maukonen, Global Health and Nutrition Science Leader at DuPont, reviewed evidence from the company regarding probiotics benefits in various aspects of women health:
- Vaginal health: selected probiotics are able to produce lactic acid, H2O2and bacteriocins and enter in competition with pathogens, as well as stimulate the mucosal immune system – with demonstrated clinical benefits in Bacterial Vaginosis and Candidiosis
- Weight management and metabolic health, with benefits regarding body mass, calories intake and promoted growth of beneficial bacteria like Akkermansia and Christensenellaceae
- Mind: rhamnosus HN001 in pregnancy showed lower post partum depression score than placebo;
Dr. Maukonen also highlighted the importance of better delivering the messages: a consumer study revealed that 80% consumers say they need more information on dosage levels and 69% declare themselves confused by the variety of probiotic products.
Probiotics in sports nutrition
Wen-Shiaw Lan from SynbioTech (Taiwan) shared the data on L. plantarum TWK10, a bacterium isolated from kimchi, on physical performance in sports. Germ free mice are exhausted sooner than mice with bacteria in their gut. Based on this observation, the company did research in humans:
- TWK10 increased endurance by 60% (21 instead of 14 minutes to exhaustion) when asking 16 males without professional training to run on a treadmill. They were supplemented either by TWK10 at 100 billion cfu daily, or a placebo, for 2 weeks.
- In a dose-effect second study involving 54 men and women supplemented for 6 weeks, TWK10 increased endurance by 20% when delivered at 30 billion cfu daily, and 40% when delivered at 90 billion daily.
4. New models and recommendations for better discovery and optimization in probiotics research
Emergent Intelligence, a new way to optimize probiotic selection
Dr. Anton Fliri from Systa Medic described how Emergent Intelligence (EI) as opposed to Artificial Intelligence, can identify molecules involved in different pathogeneses, create links with mechanisms of action, help find biomarkers and identify synergies and complementarities between strains through their mode of action. Ultimately, EI can support intelligent formulation with just the cost of analysis. For example, Systa Medic found that L. reuteri activates RAG2, ITCH, ceruplasmin and circuits involved in the regulation of autophagy and ferroptosis. Since these proceses are involved in neurodegeneration, it is advised not to add L. reuteria probiotic mix for Alzheimer products.
Best practices for probiotic clinical research
Joshua Baisley, VP at Nutrasource provided insights and advice regarding Good Clinical Practices when studying probiotics. An important one with respect to double blinding is that labels should prevent accidental unblinding: instead of A vs B, codes by randomization numbers are best. For probiotics specifically it also matters to trace what happens to the bacteria during the trial, with QC samples that accompany the real study samples, and check what was the overdose and does it align with the product label and end product. And, when microbiome variations are looked at and data represents a lot of info, data management becomes really important to then retrieve it during analysis.
Animal models to discover more about probiotics
Dr. Will Ludington from the Carnegie Institute for Science also looked at fitness, but in the fruit fly. Drosophila is a model system for reduced microbiome complexity, as the flies carry about 5 bacterial species (vs. about 1000 different ones in humans according to Senders, 2016). The researchers developed high-throughput single-fly inoculations into germ-free flies, and they conclude that:
- Colonization is stochastic (yes or no) and high counts of bacteria in the feeding don’t necessarily lead to colonization
- Colonization efficiency is highly strain specific
- Colonization is extremely complex: it requires inoculum, depends on growth, death, shedding, but also on random dimension and priority effects (precolonization with another bug), social interactions, etc.
And the historical contingency in colonization can impact the fitness (reproduction capacity) of the flies.
Daniel Ramon Vidal, VP of R&D at ADM Nutrition, mentioned another animal model that allows high-throughput and less ethical issues than working with mice: the small worm Caenorhabditis elegans.
C. elegans has 45% of genes in common with humans and mutations are available for each gene. In consequence, models of C. elegans are available to study obesity, aging, diabetes, cognition, oxidation, neurodegeneration, dermocosmetics, immunity…
For example, a screening was done for Danone to select bacteria with strong antioxidant effect. The researchers colonized the worms with E. coli and added the oxidative stress with H2O2, resulting in the identification of a strong anti-oxidant effect by L. rhamnosus CNCMI-3690. “What could be done in several years for 4 million euros in mice can now be achieved in less than 3 months for 100 000 €” says Dr. Vidal. The model can also help elucidate mechanisms of action and check multiple outcomes and formulations.
The research group is able to follow 50 000 worms per day and ran over 200 studies for clients, yielding 16 scientific articles and 9 patents.
5. The challenge of improving communication
Following the past year’s complicated relationship between probiotics and the Press, the organizers took a great initiative: they invited Dr. Brenda McArthur from the Alan Alda Center for Communicating Science to animate a session designed to help the many scientists in the room to focus on the importance of how they communicate their ideas and discoveries. Through small exercises, the audience learnt to connect with the people around, identify subjects their interlocutors lighted up about, relate to stories they know or care about, and make sure their auditors were ready to receive a message.
Scientists are taught to start with the background information and build a case for the information they will ultimately deliver. Trouble is: if the audience doesn’t have the same background, chances are they won’t be listening anymore when this key information will eventually be given. So depending on the audience it may have more sense to revert the scientific presentation standard and start with the important message. One can rethink the presentation title to grab attention, making it sound like an adventure movie or a call to action. The idea is to avoid just delivering the facts, but to say why this is important, exciting, how it might affect directly one’s audience, and although the data supports only a limited statement, explain what it could imply for healthcare, for patients, for the industry…
A panel discussion worked on the question of building consumer trust in pre- and probiotics in this context, and highlighted some misconceptions that still require better communication:
Misconception 1: the expectation of a permanent colonization. The objective of the probiotics supplementation is to modify a desequilibrium, not to permanently change the system. The transient nature is not linked with lack of efficacy.
Misconception 2: if a probiotic doesn’t work, probiotics don’t work. Dr. Kit Goldman, Director at the US Pharmacopeia, says: “People understand that if they take an antibiotic that doesn’t work, they may need to take another one. They need to understand the same applies to probiotics, and look at the species and strain.”Dr. Fumiki Aoki, business development director at Kaneka probiotic division, bounces back: “Consumers don’t always understand the difference between eating a yogurt and a studied strain”. This means there is room for a better definition and classification of probiotics.
Misconception 3: More is better. Meta-analyses on dose-effect are not able to confirm that higher dose means higher efficacy – except in Antibiotic Associated Diarrhea (in which the high dose was 10 billion). Implying that more is better harms the category, taking the attention away from strain specificity, and often tweaking labels to a cfu count “at manufacturing” which brings confusion and isn’t aligned with labelling recommendations.
Updates from the International Probiotics Association (IPA)
The IPA gave an update of the numerous activities conducted by the association. Kevin Mehring presented the output of the Manufacturing Committee, the Manufacturing Guidelines which are now available to all IPA members. These Guidelines will help new players improve their manufacturing conditions, and are also meant to help brand owners ask the right questions to select a probiotics partner.
Sandra Saville exposed the work of the Education and Communication Committee, a new IPA working group with transversal reach, that is improving the IPA website, organizing webinars and releasing infographics, and seeking opportunities to educate at all levels, from key influencers to healthcare professionals and consumers. The ECC looks to collaborate with associations, organizations and government bodies with the same objectives.
Jessica Ter Haar provided the Scientific Committee update and objectives. The Committee wants to publish a paper to explain that colonization is not necessary for efficacy, to tarp the current misconception. Jessica also works on posting blog articles, defining clinical trials tools to share the understanding of the best practices in microbiome and probiotics research, and on cross-pollinating with other committees, on the topics of a journalist webinar content, the taxonomy update, and the probiotics Wikipedia update for example. In short, IPA Scientific Committee aims to interact more with scientists in the community and in the membership.
Solange Henoud, of the Regulatory Affairs Committee, explained the 5 objectives of this working group:
- Assist the membership to understand regulation
- Recommend regulation improvement
- Protect – consumers and the industry, to deliver safe, efficacious and compliant probiotics.
The IPA Regulatory Affairs Committee provided experts insights to ANVISA in Brazil, DSHEA in US, member States in EU, etc. A meeting is also planned for Health Canada to provide guidance in China.
6. Pan-Americas regulatory upate
ANVISA, the Brazilian Health Surveillance Agency, represented by Ana Claudia Marquim Firmo de Araujo, recently updated requirements for probiotics used in foods, based on 3 pillars:
- Identification at strain level
- Safety: history of safe use, literature, in silico, in vitro, animal and clinical testing, and post market surveillance
- Benefits, still at strain level – though not therapeutic, otherwise the product should be regisered as a medicine
The guideline 21/2019 lists acceptable studies for the authorities: well-designed human studies, systematic reviews, meta-analyses and cohort studies. The document is in force but open to contributions until March 2020.
Health canada, through Michael Steller, indicated that the Natural and Non-prescription Health Products Directorate (NNHPD) probiotic monograph is updated since March 2019. It can be found online and also ensures strain-specific identity, safety and efficacy evaluation, with different levels of evidence expected for the different classes of risk category. It applies to 53 different species of probiotics and lists 51 health claims.
Dr. Susana Fattori presented the framework for probiotics as defined by Argentina guidelines. Argentina has taken up the work of harmonization of probiotics framework around the globe and works on the Codex for probiotics with rules similar to their guidelines.
Ivan Wasserman, Managing Partner at Amin Talati Wasserman, looked at the situation in the US with a few words on the different product categories concerned by probiotics – drugs, cosmetics, foods and dietary supplements. Interestingly, the draft guidance now plans for declaration in cfu and not just mg, and the State of California introduced a Bill on probiotics requiring cfu labelling.
Regarding the expected change in Lactobacillus taxonomy, only Health Canada gave a comment, with the recommendation to adapt labelling within 3 years or the next label change.
7. Panel on the future
Nobuhisa Oe from Morinaga sees the major new trend in the rapid growth of Japanese e-commerce, and the increase in consumer to consumer recommendations.
GrowthWays Managing Partner Michael Bush observes a decline in food supplements and a surge in foods and beverages – this is true at least for the US as shown by Euromonitor.
Susan Mitmesser from Pharmavite looks ahead to the challenges to be taken for a better communication of the findings to create value, when the lines between food and pharma are increasingly blurred.
George Paraskevakos, executive director of the IPA, reminded that everything is linked from science to market and regulatory, and that harmonized guidelines will be key for filling the gaps in regulation and improving the market in the coming years.
On the science side, there will likely be a more evident focus on the reasons why probiotics research sees responders and non-responders, to allow a more holitistic and personalized, effective approach to nutrition, supplementation and medical treatments.
Stephen Daniells concluded the event showing brilliantly the challenges and opportunities ahead, with the clinical and microbiome research best practices being better defined, with much evolution going on in regulation, and with sciecne expansion leading to new questions. Look ahead also for the expected taxonomy change, which has the potential to increase confusion but also great power to catch media coverage and be a foot-in-the-door reason to better explain bacteria to the public.