On 24 September 2020, it was BaseClear’s 3rd Human Microbiome Experts Meeting with discussing the association of microbiome to health & disease. It was an open event with 60 participants, chaired by Dr. Radhika Bongoni and Dr. Derek Butler.

The event was conducted in 2 sections: the morning session which focussed on Diseases and Pharmaceutical aspects of microbiome, while the afternoon session focussed on Next Generation Probiotics, clinical trials and regulations.

The speakers included industry thought leaders and key players:

  • Dr. Kristin Wannerberger, Director of R&D Alliance Management at Ferring Pharmaceuticals
  • Dr. Klaasens, Product Manager Clinical Microbiome at BaseClear
  • Dr. Assaf Oran, Chief Business Officer for BiomX
  • Dr. Adam Baker, Director of Science at Chr. Hansen
  • Dr. Arthur Ouwehand, R&D Group Manager of DuPont Nutrition & Biosciences
  • Dr. Margaret Haldeman, Senior Scientific Leader of i-Health Global R&D at DSM

HIGHLIGHTS

The meeting focussed on trying to understand the status of human gut microbiome research and its link health and disease. Traditionally and until most recently, oral probiotics (specifically (lactic acid or bifidos or saccharomyces) and prebiotics have been the common ways to modulate the gut microbiome, thus the human health.

The industry has by far been evolving and the direction of research and applications have become varied.

  1. Feaces as representative of gut microbiome: Gut microbiome composition is not only dynamic but also different at different regions of digestive track. In case of humans, small intestine and colon are the region most populated by microbes, including fermentation and nutrient absorption. Samples collected from this region of the GI tract will include Anaerobes however not in faecal samples. Despite, faeces is the representative sample one can have for studying microbial composition. Though incomplete, digestive models have been a big aided to increase our understanding on microbiome in the GI.
    Organoids are the other upcoming alternatives, also to give a perspective to study host-microbe interactions with (meta)transcriptomics & metabolomics approaches.
  2. Human models: The interactions between all factors influencing the microbiome are hard to track in human models. Other animal models, such as mouse, have been used to control for factors and find answers to basic questions. However, translating the findings to humans is still a hardship. It is important to remember that findings from non-human models should be considered as exploratory findings to be confirmed in future studies.
  3. Next generation probiotics: Our gut inhabits a range of microbes and Next Generation Probiotics represent our gut. Saying so, because of their nature of survivability,  isolation, safety, production and distribution are a challenge and a number of pioneering R&D institutes & companies are excelling to produce a quality but safe product!
    Toxicology and safety studies with clinical data these days are an crucial piece of  dossier filing on new probiotic registrations and marketing.
  4. Multiomics analysis: A multi domain approach is vital to get a full understanding on mechanism and mode of actions of microbiome for health & disease. Example, metabolites, proteome, metagenomics, metranscriptomics. Integrating metagenomics-transcriptomics data with metabolites is challenging and hard to establish, however will be the key to establish the mode of actions as well as understanding ‘gut-brain’ axis.
  5. Multiple stable states: Many studies do not consider that one host’s “normal” microbial composition travels through its own cloud of normality. In other words, each host has more than one stable microbial state. A future understanding of what is normal and abnormal for one host may shed light on the types of differences we can expect to see in our data.
  6. Guilds: Studies report results in higher-level taxonomic levels (e.g. Phylum) but do not have identical species being reported from the samples. The removal of species specific  information makes comparing studies very difficult. More, the members of one taxa do not have the same functions. One possible solution is to use study functional guilds. Members of one guild participate in similar functions, and one species only belongs to one guild. In this way, species can be grouped together in a meaningful way.
  7. Microbiome data is compositional: It is important to understand that when one bacterial abundance increases, others must decrease.
  8. Resistance in phages & claims: Resistance in phage cocktails has not yet been reported, but participants questioned how to best prepare for this possibility. In addition, Dietary supplements are not intended to diagnose, cure, or treat disease. For this reason, phages used to treat disease would be classified as drugs, not dietary supplements.
  9. Regulation: There is a lack of harmony between markets. Dietary supplements, for example, are referred to as different terms and regulated by various governing bodies. There have been initiatives to harmonize the markets, but information is not yet available.

SESSION 1: MICROBIOME AS PROSPECTIVE BIOMARKERS

Dr. Kristin Wannerberger, the Director of R&D Alliance Management at Ferring Pharmaceuticals, opened the first session of the experts meeting with her talk, “Microbiome in Health and Disease”. The presentation began with an overview of the human microbiome, which includes bacteria, viruses, bacteriophages, yeasts, and fungi.

Metabolites produced by bacteria can interact with human digestive, hormonal, neural, and immune systems. The types of metabolites produced, however, can be by-products of host diet. For example, a high fiber diet will feed bacteria that produce short chain fatty acids, which in turn, can inhibit inflammation. Aside from the host diet, a number of factors (e.g. parental microbiomes/health/lifestyle, environment, host health) can influence the microbiota during conception, pregnancy, childbirth, childhood, etc. Dr. Wannerberger remarked on the complexity of the interactions between our microbiome and the world at every stage of our lives. To get a better grasp on these complexities, Dr. Wannerberger heads a number of research initiatives that stretch from basic science exploration to innovative therapies, such as using bacteriophage cocktails. One study explored the relationship between microbial diversity and stem cell transplant-related mortality rates. They collected fecal samples from patients prior to stem cell transplant and tracked patient mortality rates. The results, published in Blood, suggest that a pre-transplant diverse microbiota (measured by inverse Shannon index) is linked to a lower stem cell transplant related mortality rate (Taur et al. 2014). These results can be translated to preventative measures that may reduce mortality rates in transplant procedures.

Dr. Eline Klaasens continued the first session by discussing the importance of host diet for the microbiome. Dr. Klaasens is a Product Manager Clinical Microbiome at BaseClear and her talk was titled, “Macro-nutrient ratio effects on the microbiome”. Emphasizing the idea of interconnection, Dr. Klassens explained that a change in diet is sufficient to drive change in the microbiome and thus, have an impact on host physiology. Studying the role of the diet in effecting change, however, comes with many challenges. These include finding an informative way to track diet among participants and taking into consideration that other factors (such as host genome, behaviour, environment, etc.) have effects on the microbiome. Controlling human diet is not ethical, so Dr. Klassens explained a controlled diet study that was done in mice. To study the effects of energy density on the microbiome, mice were place on 25 different carbohydrate: protein: fat ratio diets. At 15 months, amplicon sequencing was done using cecum samples. Findings suggest that cecum microbial compositions clustered based on diet, and alpha diversity was highest in the lowest calorie diet group. Moreover, it was discovered that specific bacterial taxa react differently to energy dense diets. As a whole, Firmicutes thrive in high energy density diets. When looking at specific members in the group, however, different preferences were found. A diet lower in protein was found to increase the presence of microbes that metabolize host mucin and promote intestinal function. These findings may help to suggest diet types for patients undergoing microbial dysfunction.

Dr. Assaf Oran closed the first session with his talk, “Phage therapy for Inflammatory Bowel Disease (IBD)”. Dr. Oran is the Chief Business Officer for BiomX, whose mission is to develop phage cocktails as a precision medicine that targets chronic disease-causing bacteria. As opposed to using a single phage, phage cocktails are used to target multiple receptors on the bacteria and prevent resistance. BiomX is currently working on phage therapy for four conditions: acne, IBD, a liver disease, and colorectal cancer. Klebsiella strains are targeted in their IDB phage cocktail, as higher abundances of the bacteria are found to be proinflammatory. Thus far, they’ve found higher abundances of Klebsiella in patients undergoing an IBD flare and generally higher abundances in patients with IBD than in healthy patients. To find the effects of the phage cocktail in a mouse model, the phage is given orally and stool is tested for bacterial load. The initial phage cocktail was temporarily beneficial but showed a formed resistance. After adding additional phages to the cocktail, however, the results show a lower fecal bacterial load. Next steps for BiomX include further testing in human participants.

SESSION 2: NEXT-GENERATION MICROBIOMICS

The keynote speaker began the second session of the expert meeting. “The Science of Probiotics in the Microbiome Era” was presented by Dr. Adam Baker, the Director of Science at Chr. Hansen. Again, the idea of the microbiome and health being connected throughout stages of human life was emphasized. Chr. Hansen develops probiotics, which they believe are integral to support the human microbiome ecosystem. The presentation outlined what is important to the company: safety at every step of the production process. Whole genome sequencing at multiple time points allows them to ensure safety by tracking strain changes in their products. Dr. Baker went on to describe the company’s pipeline in developing a new product. In one example, a screening program was initiated to identify a Bifidobacterium that may prevent intestinal damage. In vivo, they profiled 127 strains for acid and bile tolerance, intestinal permeability, mucus adhesion, and immune modulation. Five strains were chosen to test in mice, where inflammation was chemically induced. Lastly, one strain was tested in humans and suggested to lower levels of intestinal damage. These results, like others reported in this meeting, may be helpful in treating patients with microbial dysfunction and the resulting symptoms.

Dr. Arthur Ouwehand, the R&D Group Manager of DuPont Nutrition & Biosciences spoke on “Fecal Recovery of Probiotics Administered as a Multi-Strain Formulation during Antibiotic Treatment”. Howaru Restore is a probiotic product manufactured by DuPont and contain four strains of bacteria in equal numbers. The safety has been evaluated for antibiotic resistance, genomic risk factors, and acute toxicity. The safety evaluation reports that patients receiving a high dose of Howaru experience a reduced incidence of antibiotic associated diarrhea (AAD). When AAD does occur, the duration (in days) is shorter than in patients on a lower dose of Howaru or in placebo groups. A follow-up study with 400 patients tested the use of antibiotics concurrently with Howaru. The probiotic and antibiotic were started at the same time and the probiotic was continued for one week after the completion of the antibiotic. Fecal samples were collected at several time points to test probiotic bacterial loads. After recruiting 250 patients and finding that only four had reported AAD, the group terminated the trial based on low statistical power. Dr. Ouwehand, however, did not want to waste the collected samples. Their new research question asked whether probiotics survived during antibiotic consumption in 250 patients. The findings suggest that probiotics are found in fecal samples, but the four strains differ in levels of recovery and detection. Compared to the placebo group, the probiotic group had significantly more probiotics recovered. Also noteworthy, both probiotic and placebo groups returned to baseline abundance levels of probiotic strain after being treated with antibiotic. Overall, Dr. Ouwehand was able to conclude that probiotics are found in stool when consuming antibiotics.

The last speaker of the meeting was Dr. Margaret Haldeman, the Senior Scientific Leader of i-Health Global R&D at DSM. This presentation was titled, “Claims in Foods and Supplements- Supportable, Allowable, Compelling”. A claim, simply put, is a message to the consumer. Some claims may be “For adults including pregnant women”, “Convenient daily capsule”, or “#1 Pharmacist recommended”. Dr. Haldeman outlined the claims process: brainstorming, researching, and revising until the final list of claims has been approved by the collaborative team (e.g. Marketing, Product Development, Scientific Affairs, Regulatory Affairs, Quality, and Legal teams working together). The final list of claims includes science-based claims, formulation claims, content claims, and marketing claims. Most importantly, the final list of claims cannot intend to diagnose, cure or prevent disease and must follow current guidelines. In the US, dietary supplements are under the authority of the FDA, although this varies by market. To connect to the other presentations, Dr. Haldeman discussed probiotics. “Probiotic” is a dietary supplement claim and thus, requires that the product meets specific requirements. Specifically, the product must have experimentally and clinically demonstrated health benefits that are shown through randomized, double-blind, placebo control clinical trials. Clinical outcomes, such as “reducing GI upset” or “increasing  Bifidobacteria abundance”, are then translated to allowable claims, “helps with occasional digestive upset” and “may contribute to a healthy microbiota”. In the end, these are the claims that consumers use to choose products in the marketplace. Presenting claims that best represent your product will allow for a clear communication channel with the consumer.

Thanks to the work of all presenters and participants for a highly interactive day.

UPCOMING EXPERTS MEETINGS

BaseClear routinely organises experts meeting and this meeting will have a follow edition. We look forward to see what progress will have been made. For the complete overview of BaseClear’s Experts Meetings, visit https://www.baseclear.com/experts-meetings/ and follow us on LinkedIn (https://www.linkedin.com/company/baseclear) to keep up to date.

Acknowledgement:

Ms. Jolanta Szkodon, University of Amsterdam and Vrije University for contribution via notes.

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