Identifying Cross Sectoral Opportunities, Challenges and Needs for Effective UK Microbiome Related Technology Exploitation July 2018 Organised by:

Knowledge Transfer Network Supported by:

The Microbiology Society

*The Red Arrows made a flypast during the meeting to celebrate 100 years of the RAF

Workshop Leaders: Dr Yvonne Armitage, Dr Dana Heldt, Dr Charles Vander Broek, Dr Bryan Hanley (KTN), Dr Wendy Russell (Rowett Research Institute, University of Aberdeen).

Executive Summary

Microbiomes are an essential feature of living systems. They comprise a community of microorganisms, together with the habitat or host they exist within or upon. The characteristics of a microbiome are dependent upon three important factors:

• The microorganisms and the interactions between them, • The environment and factors within that environment that impact upon the

microbiome and vice versa and • External factors that may either support and stabilise or change the microbiome.

While there are some examples of very stable microbiomes, most are constantly in a state of flux and transition. This then leads to the obvious question of what do you measure in order to assess the stability and efficiency of microbiomes and are such measurements consistent across different microbiomes in different environments?

This workshop brought together practitioners from across the UK research and industrial bases to identify cross sectoral as well as sector specific opportunities and challenges in commercialising microbiome targeted products and to ensure the UK stays competitive in this emerging area.

Priorities for moving to translation of microbiome research and innovation included:

• Continued efforts in basic science for greater understanding of microbiomes • Better collaboration and funding to foster interdisciplinary work • Skills matching and upskilling • “Microbiome friendly” regulations underpinned by research and • Scale up manufacturing facilities infrastructure

Recommendations were made in order to move this largely emerging sector forward, which might include the formation of a special interest group as a focal point for cross-sector and cross-discipline, commercially focussed community-based activities

It was concluded that microbiome research and innovation remains in a state of flux, with disparity in research and commercial activity, regulatory and standards depending on the application. There is certainly a growing awareness of the importance of cross-sectoral interactions and also of a need to focus both on mechanistic based studies and on having a greater emphasis on microbial function and not just on identification of populations. There was an implicit awareness of the importance of homeostasis and how to maintain it in microbiomes, however this was not explored explicitly.

Introduction “I then most always saw, with great wonder, that in the said matter there were many very little living animalcules, very prettily a-moving”. Antonie van Leeuwenhoek (1632–1723).

“Every living thing on this planet has a microbiome … associated microbes that maintain health and well-being.” Liita Proctor (The Human Microbiome: Diet and Health, Workshop Report, Institute of Medicine, 2013).

Microbiomes are an essential feature of living systems. A microbiome has been defined in various ways but the definitions have certain common features.

First of all, a microbiome comprises a community of microorganisms together with the habitat, or host, they exist within or upon. Single strain microbiomes are an anomaly generally only found within the confines of a research lab or in extreme environments where few organisms can survive and unique adaptation characteristics have evolved.

The characteristics of a microbiome are dependent upon three crucial factors – the microorganisms and the interplay between them, the environment and factors within that environment that impact upon the microbiome and vice versa and external factors that may either support and stabilise the microbiome or may perturb it such that it changes in response to the external stimuli.

While there are some examples of very stable microbiomes, for example those that exist in extreme environments, most microbiomes are constantly in a state of flux and transition. However recent studies suggest that in many cases – in human, animal and ecological systems – there is a core microbiome that is mutually autoregulatory and which confers homeostasis on the system. That then leads to the obvious question of what do you measure in order to assess the stability and efficiency of microbiomes and are such measurements consistent across different microbiomes in different environments?

The first and simplest way to measure the characteristics of a microbiome is to identify and enumerate all the microorganisms that are present. This can be done either using traditional culture techniques or 16s rRNA analysis. The disadvantage of the former is that, if the culture conditions adopted are not appropriate for growth ‘ e.g. nutrition or presence of oxygen, then some species that are present, may not grow and are therefore not counted. In addition 16s rRNA does not take into account viability or spore formers, which when taken outside of their natural environment have the potential to become metabolically active again once favourable conditions occur. Using genomic and metagenomic techniques (i.e. identification of DNA characteristics of a certain species), a larger proportion of bacteria and other microorganisms in a microbiome can be identified. However, all of these techniques have one thing in common – they are measuring what is there, not what those organisms are doing. They also fail to provide insight into the

external factors (e.g. the host or the environment) that can both affect the microbiome and be affected by it.

There has been increasing interest in studying microbiomes in situ and in looking at how the different microorganisms contribute to the characteristics of the system. Methods to perform this analysis include transcriptomics, metatranscriptomics (i.e. what genes are actually expressed and what genes are present and therefore have the potential to be expressed) and metabolomics. One of the problems with such approaches is the sheer volume of data that is created and its interpretation. The second problem has its roots also in the inherent complexity of the system. Once you get beyond simple observation and are attempting to develop ways to positively affect the system then the numbers of confounders and interfering components in the system make it difficult to determine the effects of specific interventions in a measurable way. This is a particular problem when we need to measure the effects of changes and not simply the plethora of interconnected changes themselves.

Against this complex background, KTN, in conjunction with the Microbiology Society, organised a workshop to debate some of the issues surrounding the microbiome area with a view to identifying technological challenges and solutions that could result in increased understanding and impact in exploiting microbiomes. The workshop was oriented towards industry, two thirds of attendees were from different industry sectors, but also included a number of key academics and other thought leaders whose role was to introduce fresh ideas and different ways of thinking and representatives from UK Research & Innovation.

Background

The area of microbiome research has been substantially mined over the past years. Despite this there have been few success stories and examples of products getting to market – particularly in the human health area.

The strength of the R&D in the area is reflected in the substantial numbers of papers published on the microbiome (Table 1).

Table 1: Publications on the microbiome (From Lloyd Price et al, Genome Medicine 2016, 8:51)

Terms All Publications Publications 2011-2016

Gut, Colon, Intestine 17,546 10,707

Oral, Mouth, Tongue etc. 4,843 2,089

Urogenital, vaginal, penile 1,477 706

Skin, cutaneous 1,372 754

Airway, lung 764 524

Placenta, breast milk 702 426

Ocular, eye 152 82

Despite this significant research effort, the numbers of success stories remains stubbornly low. Some of the notable opportunities and difficulties previously described are shown below as examples of where traction has been achieved.

AgriFood

Probiotics

Manipulation of the microbiome in the agri-food space is currently being used in a commercial setting. Probiotics in animals have been used to reduce pathogen disease problems in commercial animals and to improve feed conversion rates and improve animal growth rates. The Food and Agriculture Organisation have reviewed the use of probiotics in agriculture (FAO. 2016; Probiotics in animal nutrition – Production, impact and regulation, by Yadav S. Bajagai, Athol V. Klieve, Peter J. Dart and Wayne L. Bryden. Editor Harinder P.S. Makkar. FAO Animal Production and Health Paper No. 179. Rome) and concluded “Several probiotics have been found effective in improving animal performance and preventing disease and the spread of the enteric pathogens in both monogastric and ruminant livestock industries.” However, they also acknowledged that information on the detailed mechanism of action is not available and that there are a number of areas where further investigation is warranted. These include a better understanding of whether probiotics administered to animals enter the human food chain and what the consequences of that might be, reproducibility of effects, regulation in different countries and the presence of acquired antimicrobial resistance genes in probiotic species. Overall the FAO called for international guidelines for the production, marketing and use of probiotics in animal nutrition. The situation with ‘crop probiotics’ is less established, however the use of legumes to enrich nitrogen content using co-existing bacteria is very well known. Other uses of probiotics are less well understood. A number of academic studies have suggested that bacteria can increase crop yield and quality and help plants to grow more effectively and be more resistant to stress. Commercialisation of these products is still at an early stage.

Probiotics have also been used as a feed additive for horses and benefits have been claimed for horses recovering from conditions such as colic. There are a number of probiotic preparations that have been recommended for cats and dogs. The target for most of these, are gastrointestinal well being and an enhanced immune system; similar claims to those that have been made in humans. The bacterial content of these probiotics has included Bifidobacteria and Lactobacillus strains that are generally found in healthy dogs and cats.

Prebiotics

Various definitions have been used for prebiotics, since the original description by Gibson and Roberfroid (Gibson RG, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Appl Bacteriol. 1995;125(6):1401–1412). These include the original definition: “Non-digested food components that, through stimulation of growth and/or activity of a single type or a limited amount of microorganisms residing in the gastrointestinal tract, improve the health condition of a host” and more recently “A substrate that is selectively utilized by host microorganisms conferring a health benefit” (Gibson GR, Hutkins R, et al. The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol. 2017;14(8):491–502).

The use of prebiotics in animals has become more important since the ban on the use of antibiotic growth promoters in the EU in 2006. The possibility of using prebiotics or a mixture of pro and prebiotics in animal feed as a replacement for growth promoters remains a possibility however further work is needed to determine optimal types and dosages of both. The particular advantage of prebiotics in animal feed is that they can be added to animal feed without losing their efficacy during the heat treatment of feed processing. The majority of prebiotics are targeted towards poultry, pig, ruminant and aquaculture markets with a total market value in excess of $150M in 2016 for these four segments. Some studies have suggested that prebiotics may be of value to cats and dogs however definitive data is still lacking and further work will be necessary to define both the best prebiotics and how they might be combined with probiotics (synbiotics) for the benefit of the companion animal microbiome.

Internal Health

Internal health includes all of the parts of the body that are not directly exposed to the external environment. For the purposes of this workshop, oral health was included as part of the internal health system. Other parts of the internal health system that have, or appear to have, a microbiome include those noted in Table 1. In addition, there have been some indications that a blood microbiome exists with red blood cells containing the higest levels of bacteria and most of these are Proteobacterium but Actinobacteria, Firmicutes and Bacteroidetes have also been detected through 16S rDNA detection after PCR (Paisse et al, Transfusion, 56, 1138, 2016). It has been suggested that many of the blood microbiome organisms derive from the gut or from the oral cavity and are in a dormant state in blood (Potgieter et al, FEMS Microbiol Rev., 39, 567, 2015). The physiological significance of such bacterial populations is unclear and their definition as a ‘microbiome’ when they are in a non-proliferative state is questionable. There have been a small number of articles and some reports of the existence of a brain microbiome however rigorous scientific studies are lacking and most research has been carried out on the gut:brain axis. Studies have demonstrated the presence of viruses in human brains (particularly HIV and HSV) and also some fungi, which have been associated with pathological conditions. The olfactory nerve has been proposed to be a route of entry to the central nervous system for both viruses and bacteria. Attempts to modulate the oral microbiome either directly by addition of probiotic bacteria or by altering the environment has met with mixed success. Addition of arginine will raise the pH and leads to increasing amounts of Streptococcus sanguinis and to a reduction in levels of acid forming S. mutans. (Zheng et al, Nature Scientific Reports, 7206, 2017). A number of commercial preparations that claim to reduce gum disease by direct administration of a probiotic are on sale however the effects are generally temporary and shifting the balance of the oral microbial population on a permanent basis is difficult (Allaker and Stephen, Curr Oral Health Reports, 4, 309, 2107).

Modulation of the gastro-intestinal (GI) microbiome to promote gut and systemic health has been well documented however there are few verifiable claims. Indeed, up until late 2017, despite there being 129 claims for health benefits of probiotics registered with the European Food Safety Authority (EFSA), not a single claim had been approved. One example is that of Seres Therapeutics and their lead development candidate, SER-109. This was an investigational oral microbiome therapeutic for the prevention of recurrent Clostridium difficile infection (CDI) in adults who have had three or more occurrences within a nine-month period. The Food and Drug Authority designated SER-109 as a Breakthrough Therapy. The company claimed that SER-109 was a patient-friendly, single-dose capsule that may repair the underlying cause of recurrent CDI—dysbiosis, which is a disrupted state of the gut microbiome. SER-109 was developed using computational design insights suggesting that a complex spore ecology includes keystone organisms that could address the underlying dysbiosis and return the gut microbiome to a healthy state. SER-109 was an ecology of bacterial spores enriched and purified from healthy, screened human donors. However, as was noted in a market report “Seres Therapeutics raised an impressive $134M in its IPO, on top of massive deals like the €1.7Bn collaboration with Nestlé. It also had the most advanced therapy in the field, consisting of bacterial spores (SER-109) for the treatment of recurrent Clostridium difficile infections. The results of SER-109 Phase II trials (Ecospor) are giving a hard time for the company and the Microbiome field. In the 8-week study, SER-109 failed to beat placebo. This happens after promising Phase I data, when 29 out of 30 patients were cured of recurring infections. Seres deemed the results as ‘inconsistent with expectations’ and will review the data to make a decision about the program. Following the announcement, its share price fell by 70%. This is similar to the worst recent clinical failures in Biotech.

External Health

The definition of ‘external health’ that was adopted for the workshop includes skin, eyes, hair and all other non-internal targets. These are important both from a personal care/cosmetic and a health standpoint. The skin microbiome has been studied for a number of reasons including trying to find potential microbial triggers for skin diseases. Manipulation of skin microbial communities is one approach that may offer some opportunities. However, despite the issue of accessibility to the microbiome environment being simpler for external health than for much of internal health, there has tended to be a focus on 16SrRNA sequencing to identify types of bacteria rather than efforts to determine how functioning microbial communities work together. This was shown in articles such as ‘The skin microbiome: potential for novel diagnostic and therapeutic approaches to cutaneous disease (EA Grice, Seminars in Cutaneous Medicine and Surgery, 2014, 33(2) 98) which reviewed the use of genomic technologies to help identify and characterize microbial communities on skin. She concluded that although knowledge of the skin microbiome is increasing, including with respect to disease, in order to apply this insight into diagnostic, prognostic, and therapeutic applications, ‘further research is necessary to understand beneficial and harmful microorganisms and their mechanism’.

This lack of a functional emphasis and the lack of significant funding when compared to internal microbiome studies means that progress in external health has been slower than might have been anticipated, although there are a number of both brands and biotech companies actively selling products based on their understanding of the skin microbiome. A BBSRC funded collaborative project carried at York University and Oxford University, with support from Unilever has been investigating the role of microbes in body odour production

(Minhas et al, eLifesciences, Structural Basis of Malodour Precursor Transport in the Human Axilla, July 2018), which has identified the key protein in Staphylococcus hominis responsible for transporting S-Cys-Gly-3M3SH which is then converted to the thioalcohol, 3-methyl-3-sulfanylhexan-1-ol (3M3SH) which is responsible for the malodour associated with BO.

Others

Microbiomes are present in a number of other circumstances and environments and these are not always seen as beneficial, but can be problematic. For example in the oil and gas industries, the flourishing of microbiomes and the growth of bacteria and fungi cause a range of problems, including pipe fouling and corrosion. Some of these were described and needs to address the problems mooted in an earlier workshop on biofilms. Microbiomes also impact on the water industry, on the construction and built environment and in food and other manufacturing facilities. Many of these have similar issues and problems but they also have some unique challenges and opportunities. As noted in a recent review “Buildings represent habitats for microorganisms that can have direct or indirect effects on the quality of our living spaces, health, and well-being. Over the last ten years, new research has employed sophisticated tools, including DNA sequencing-based approaches, to study microbes found in buildings and the overall built environment. These investigations have catalysed new insights into and questions about the microbes that surround us in our daily lives. The emergence of the “microbiology of the built environment” field has required bridging disciplines, including microbiology, ecology, building science, architecture, and engineering.” (Adams et al, Building and Environment 109 (2016) 224-234). In the case of water treatment and use, micro organisms have an important role to play in the process. In addition to domestic use, it is also important that water used for industrial processes (e.g. in fermentation, pharmaceutical manufacture, cosmetics etc.) is of a sufficiently purity to be fit for purpose as microbiomes can cause issues in pipes and other infrastructure resulting in blockages and downtime. However, at the opposite end of the supply chain microbiomes – or microbial communities – are used very effectively for waste water treatment and a reduction in impurities as well as the removal of xenobiotic compounds.

Purpose

The workshop was carried out in order to engage industry from across several sectors, together with key academic/technology providers to identify what is needed to stimulate translation of microbiome research into commercial reality and ensure the UK stays competitive in this emerging area. In the workshop major industry challenges and needs: technical, regulatory, infrastructure, skills and models for collaborative work to expedite delivery of commercial solutions were explored.

Aims The aims of the workshop were to identify and prioritise key areas and actions that need to be addressed by industry, academia, funders and regulators. By carrying out this exercise, it was the intention that this complex and, at times, confused area would be easier to navigate and innovate within its auspices. As part of this process, we would identify key challenges, blockages and opportunities.

Topic areas included:

• Key market areas • Industry challenges - technical, regulatory, funding, infrastructure, skills etc. • Why should the UK be particularly involved? This leads into a review of UK strengths

and weaknesses. • What needs to be done to create progress? • Who are the key players who need to be involved?

A secondary aim was to explore if one potential route to progress might be the setting up of a cross-sectoral, cross-disciplinary Special Interest Group to develop a cohesive community that will advance the area through collaboration shared understanding and to facilitate the bringing of products to market. Such an approach has previously been used by Innovate UK and KTN, to create or consolidate disparate communities, with the aim of developing added and synergistic value.

A list of contributing organisations to this workshop is given in Appendix 2.

Format

The format of the workshop was a combination of presentations (scene setting) and small group working using the ‘world café’ format whereby groups circulated around the different topics. The thematic subjects were - Agri Food; Internal Health: External Health; Others. A period of time was set aside for participants to make short ‘elevator pitches’ outlining their own expertise and suggesting potential solutions or particular requirements.

In addition to these outputs, and at the request of the MRC, we also asked workshop participants to provide a snapshot of facility needs.

Workshop Structure

Part 1

Scene setting with presentations from:

• Professor Glenn Gibson, (University of Reading), overview and thought leadership • Paul Richards (the Microbiology Society) on their recent Microbiome Report and • Dr Karen Finney (Medical Research Council gave overview of the MRC and its

approach to work on the microbiome.

Part 2

The workshop was split into groups to discuss key issues relating to the microbiome across these 4 sub groups:

1. Agri-Food 2. Internal Health 3. External Health 4. Others.

Each sub-group examined 4 key questions

• Opportunities • What needs to be done • Who needs to do it • Why should the UK be taking a major role?

Part 3

The workshop participants reassembled and offered a summary of their priorities for each of the 4 sub-groups. At this stage participants were also invited to give a brief pitch to the others and to present any ideas they might have around specific technologies and approaches.

Part 4

Each of the four sub-groups then produced a list of up to five priority needs that were then voted on by all of the participants.

In the final part of the workshop participants were asked to write down any infrastructure needs that they identified. These were also captured and are shown below.

Results There was an excellent range of delegate expertise, both technical and sector specific, with market relevance and experience involved in the workshop, which helped to identify the most important factors to aid commercialisation, as well as the short term needs and priorities for success. The collated outputs from each of the sub groups are shown in Appendix 1 for reference.

Prioritisation

The participants voted for the priorities they found most compelling. The top priorities derived from each sub group are shown in Table 2. A second, open prioritisation exercise resulted in the same priorities being identified in more than one group and the scores have therefore been aggregated and shown in Table 3.

Infrastructure

The workshop group identified a number of specific requirements for both physical and virtual, with associated capabilities:

• Improved, centralised high performance computer cluster like the MRC Cambridge facility but with larger storage (pentabyte or more).

• Manufacturing infrastructure. There is no facility in the UK for freeze drying live microbes at a large scale commercial level and this is a key activity in probiotic production

• Nutrition Trial Unit. Infrastructure to trial and test foods and diets. • Academic:industrial steering group on the skin and oral microbiome • Support for microbial community culture collections. Essential for mechanistic and

functional research • Bioinformatics training and continuous professional development to accelerate up-

skilling in critical bottleneck skills • UK skin microbiome institute “Quadram for skin”. Can be a virtual institute.

Table 2: Challenges/Priorities per Sub Group Area

AgriFood Internal Health External Health Other

Skills matching including setting up

of a forum, directory and info

portal

Continued basic science support

including: microbiology, biochemistry, informatics,

genomics

Market areas clearly defined

Opportunities for natural products

from microbiomes, industrial

exploitation in the built environment

health & safety and optimal

environment Upskilling in both

industry and research base-

especially informatics and

statistics

Better collaborative funding to foster interdisciplinary

work with industry

Classical microbiology capability and

culture collection development

Challenge of data collection and

analytics, scale up manufacture and access to strains and microbiomes

Microbiome friendly regulations,

underpinned by research

Biological inference: ‘So what?’ data

collection. Funding needed

Needs include large grant funding,

multidisciplinary skills, dedicated

ecosystems (a ‘hub’) for the microbiome

Scale up manufacture

especially non-fermentable spores

and subsequent lyophilisation

Interpersonal /interdisciplinary

diversity

+/- Individual research centres

with industry across sectors

Table 3: Top grouped and ranked priorities across all groups

Priority Number of Votes

Basic science 17

Better collaboration and funding to

foster interdisciplinary

work

16

Skills matching and upskilling 15

Microbiome friendly regulation

underpinned by research

9

Scale up Manufacturing 8

Discussion and Conclusions

Microbiome research and innovation remains in a state of flux, with disparity in research and commercial activity, regulatory and standards depending on the application. There is certainly a growing awareness of the importance of cross-sectoral interactions and also the need to focus both on mechanistic based studies and on having a greater emphasis on microbial function and not just on identification of populations. There was an implicit awareness of the importance of homeostasis and how to maintain it in microbiomes, however this was not explored explicitly.

Apart from the prioritised needs identified above, there were some underlying issues that were also brought to the surface. These included the following:

• There was a perceived lack of synergy between research institutes and between public research and industry. In some cases and in some areas, this has led to a lack of critical mass and the realisation that the UK lags behind the US and Scandinavia in some key aspects. This lack of joined up thinking extends to the use of clinical data generated by the NHS and the need to have a critical mass of such data in order that it can be both interpreted and used as a tool for predictive modelling of the effects of interventions on the microbiome.

• Several groups pointed to data handling as both a strength and a weakness in the UK. This was reflected in the comment about infrastructure needs. Linked to this was the need to identify the strains and their functional characteristics under different conditions. In addition, there needs to be standardisation for data collection and storage including microbiome meta data. The need for standardised methodology extends to measurements of efficacy and effects, outputs of systems and analytical techniques.

• A number of specific solutions and technologies were identified including phage production and a greater understanding of biofilms. The latter of these is clearly relevant to the Biofilm Innovation Knowledge Centre and to the workshop on biofilms that was held by Innovate UK and KTN earlier in 2018.

• Finally, it was noted by several groups that consumer awareness and understanding is key for the successful commercialisation of products and solutions. This in turn impacts upon the regulatory climate and on investment both by industry and by the public purse. However deriving a sensible cost:benefit analysis is still challenging. Coupled to this is the difficulty in obtaining microbiome-specific funding. Often funding, particularly from public sources, is based on functional outcomes related to overall health rather than on developing a better understanding of microbiome-derived benefits.

Recommendations Based upon the inputs and the prioritisation list shown above, the following recommendations can be derived:

1. There is a continual need for microbiome specific basic science. This includes measurement of functional endpoints and better ways of measuring efficacy. A review of R&I gaps and the potential to make use of non-traditional technology (e.g. sensors, new and better model systems, more systems biology) to circumvent challenges is a key step in the further development of the microbiome as a commercial and health endpoint reality.

2. There is a need for more collaborative work both from a scientific and a commercial standpoint to better understand the opportunities. Cross disciplinary and cross-sectoral priorities must be established in order that there is an underpinning body of evidence for products coming to market and a clear timetable for introduction of products in different sectors. A detailed review of the TRL for the microbiome in different sectors is a key requirement. Areas at a higher TRL should be prioritised, even if they have not been in the past. Novel and innovative approaches are required to overcome some longstanding blockages that prevent technologies in some target sectors from progressing to products. This may mean temporarily abandoning research in some sectors and areas.

3. Successful adoption of microbiome-based approaches and their translation into products requires matching of skills to needs and, where necessary, upskilling. At a basic level, this means at a production and practical processing level however it also means upskilling health professionals and others whose knowledge of microbiomes and their potential impact may be weak. At line and near line training is a prime requirement in all sectors. This may use something like the AgriFood Training Partnership model as a way of accessing industry training however such training has to be both vocational and sufficiently adaptable to enable a flexible and efficient workforce to be created and retained. In some areas the use of microbiome related products is not understood and that means that their use is limited. There is a need for upskilling of primary users of microbiome related manipulation techniques to understand their potential and limitations. This includes health care professionals, nutritionists and dieticians, farmers, personal care professionals and others. A programme of training should be initiated that is specific to the needs of each group.

4. Microbiome products can only succeed in the market if the regulatory framework governing their use is clear and unambiguous. The use of pharmaceutical type regulations is not fit for purpose in most cases since it requires the use of very large intervention cohort sizes in order to be able to measure relatively small (or long term) effects. The whole area of microbiome modulated effects needs to be considered separately from other diet:health effects. Acceptable tests should include demonstration of the modulation of the microbiome, the replacement or control of pathogenic organisms and the increased stability of a healthy homeostasis. Clinical endpoints may not be necessary and this should be investigated.

5. As in many other manufacturing areas, scale up is an essential component of taking products to market. There is a need for an improved set of scale up procedures and a closer examination of requirements including mixed microbial stability, maintenance of functional efficacy and shelf life. There is a need to review the key aspects of scale up related to manipulation of the microbiome. These should be accompanied by a review of current relevant, or future potential, UK facilities and the identification of key gaps.

Many of the conclusions and recommendations could be approached through the setting up a Special Interest Group with representation from the key sectoral and disciplinary stakeholders, with a focus on developing cross-sectoral community-based activities that benefit several sectors simultaneously. In a follow up to the workshop participants will be asked if they see this as a realistic and desirable outcome.

The three key aspects will be –

• Is a Special Interest Group something that the group feel would be useful? • What should the remit of such a group encompass? • Who should be involved (i.e. are there others who were not at the workshop who

should be encouraged to contribute)?

Appendix 1 Outputs from the four individual sub groups

Agrifood

Challenges

Regulation:

• European claims process delays progress and Europe lags behind North America, Asia etc. So, consumers are not able to access appropriate information.

• Different regulatory environments – preventing animal/human cases. • Why the lack of harmonization in animal/human evolution? • Prebiotics – can we be creative about novel prebiotics? • GMO is a challenge in showing proof • Scale up and production • IP – big issue – can’t patent single bug • Production issues – anaerobes • High throughput scale up of anaerobes Skills Gap/ Skills Merging:

• Need mechanism level understanding • Lack of proof • Cross-over with Biofilms IKC • Inability to grow all microbes • Bioinformatics lacking • Cross-discipline collaboration/working • Funders are ‘forcing’ silos • Human and animal • Mindset contributing to silos

Funding:

• Lack of pre-farmgate research and funding for it • Lack of funding on universal technology instead of asking specific question • Human/animal • Reproducability in scale up and fundamental research • Need standard techniques/methods • Animal models not being leveraged • Delivery to appropriate site of action

Why the UK?

• Strength in aquaculture • Ruminant microbiology • Environmental microbiology • Plant microbiome • Expertise exists and is limited by….?? • Food/nutrition • Rumen microbiome driving growth in this area • People don’t want to report negative studies

What are the key market areas?

• Reduction in antibiotics usage • Biofertilisers • Soil health • Pesticide producers • Vet medicine • Animal/bird gut microbiome – pathogen exclusion • Personalised microbiota responses to dietary interventions • Increased shelf life – food production • Husbandry can impact final product (milk) and methane production • Use of ‘waste products’ in functional foods • Kombucha Kefir • Fermented foods • Increased shelf life – consumer handling and use • Alternatives to chemical fertilisers • Antimicrobial resistance key driver • Impact of bird microbiome on human microbiome – positive and negative • Bio-energy • Pro, pre, synbiotics

Who needs to do it?

• Interaction of UKRI/Academia/Industry – facilitation – cross-discipline of ….. areas • Better articulation of funding for microbiome – consistent and correct timing • Skills merging across sectors, but how?

o CPD courses o Industry role o Appropriate skills

• Can research councils help drive standards? • Standard format for more microbiome meta-data • Network in microbiome – like NIBB – Database? • More human/animal studies • Use of relevant models

External Health

Challenges

• Investment in high risk projects • Investment in skills research base but not enough of it • Data missing • What species? • Which genes? • Infrastructure focus on diseases/health – funding in consumer products needed • Regulatory status of probiotics? • Bioinformatics statistics • Lab set up

o Fermented o Scale up facilities missing

• Regulatory/consumer perception of GM strains • Define external needs • Full economics costing models in collaborative research is hindering collaborations

between academics and industry • Need bigger and better data sets available • Early stage financing (VC) – general not microbiome specific • Metabolics more important than microbiome

Why the UK?

• Population density • Funding… towards… not just treatment • NHS data • Critical mass • On-going co-host group • Academic infrastructure and size • Excellent academic infrastructure • Momentum for microbiome initiatives • NHS/All Party Parliamentary Group in microbiome • Funding for cosmetic science – recognised as health benefit (invest in health through

to ‘feel good factor’)

What are the key market areas?

• Reduce impact of aging • Device related health impact • Improve appearance/feel of skin • Probiotics for the environment eg hospitals and buildings • Biofilms around wounds and ulcers and bedsores • Caries • Gingivitis • Periodontitis • Malodour • Infant microbiome • Improve skin health • Maintain skin health • Antimicrobial resistance • Skin allergies • Ocular health • Vaginal microbiome • Acne wounds • Health treatment v health prevention

Who needs to solve these challenges? How? • Science/evidence to support regulations claims • Industry-academic partnerships • Government • Academia structure, cost too high for collaboration with industry (overheads)

Infrastructure needed in the UK • Improved, central high performance computer cluster like MRC CLIMB but with large

storage – pentabyte or more • Nutrition trial unit – infrastructure to trial and test foods and diets • Academic-industry-government steering group on skin and oral microbiomes • Manufacturing infrastructure • There is nothing in the UK for freeze-drying live microbes at commercial level – and

this is a key activity in probiotic activity • UK Skin Microbiome Institute “Quadrum Institute for Skin” can be a virtual institute • Support for culture collections – essential for functional and basic research • Bioinformatics training and continuing professional development to accelerate up is

critical

Internal Health Challenges • More basic mechanistic understanding • Hypothesis driven mechanisms • Generate body of knowledge/evidence • Basic to translation to commercialisation • What do we need to know? Appropriate level • Chronic/sub clinical conditions • What is healthy? • Functional end points • Reproducibility • Complexity • Bioinformatics • Big gap in bioinformatics • Response – stratification required? • Creation, reproducibility and interpretation of data • Pseudo science • IP

• Therapeutic targets • Functional targets • Prebiotics • Lysins • Bactericidal and bacteristatic chemicals • Complexity of immune system – model systems needed • Regulatory pathway evaluation • We need a different trial design than the usual ‘clinical’ model • Scale up manufacture • Identification of ‘new’ small molecules from environmental/human/animal

microbiomes • Integrating skills and expertise • Translating from PO to commercial • Identify microbiome interested companies Why the UK? • Rowett • Cost/benefit UK universities • Quadram Institute • Strain collections – which are the most beneficial? • Getting everyone to collaborate • Innovate UK and KTN is a big help and science in UK generally • UK too expensive • Full economic costing (and where does it go) variability in ability to deliver for the

funds available • Size of UK for meetings (low travel time) • MHRA lost focus on novel dosage development due to rationalisation and impact of

Brexit What are the key market areas? • Clostridium difficile infection research • Prebiotics less than £3bn PA globally • Synbiotics • Probiotics • Ageing population • COPD cystic fibrosis • Biomarkers/diagnostics/community profiling • Gut health IBS? IBD? CRC? NAFLD? • Obesity metabolism

• Immune system • Paediatrics infant nutrition developmental diseases • Oral microbiota – can food influence a ‘healthy mouth’? • Appetite regulation • Nervous System • Stress/cognitive function Who needs to solve these challenges? How? • Identifying the (microbial) target • Regulatory o Context specific, food, MRC, Cosmetic, “holistic” o How is whole body eg Gut/brain regulated

• Clinicians (end users) dentists etc • Signpost interdisciplinary opportunities • National Institute for Biological Standards and Control (NIBSC) etc. to help standards

development • Industry/academia • Regulators – different ones depending on target area • All Party Parliamentary Group • UKRI – create infrastructure eg AMR forum • Funding trial infrastructure • University courses not fit for purpose for microbiome research • Identify non-normal interactions • Service based bioinformatics

Other Challenges

• Lack of computational resources • Analytical testing – not sensitive enough and resolution for sub strain identification • Technology development and commercial realisation eg. Oxford Nanopore • Screening for valuable small molecules • Improved meta data • Genomic data availability and meta data • GMP manufacturing of microbes and compounds (infrastructure lacking) • GMP scale up • Fermentation and scaling up (strength) • Changing regulatory framework • Need more info on microbiomes – lots of unknown in soil – need strain and wet data

• No one funds long term culture collections • Strain banks • New strains as chassis for protein production • Dedicated databank needed • Timely deposition of genomic data • Strain banks with related data • Access to sample cohorts

Why the UK? • Business scale up difficult in UK • Healthcare cost analysis (Technical justification for therapies) • Collaboration with public bodies (weakness) • Good computational and genomics (in academia only) • Oil industry interest in microbiome • Strain repository • Pharma high value manufacture • Good microbiology base • No synergy between research centres

What are the key market areas?

• Functional biofilms • Find new strains for new small molecule products • Phage and phage enzyme production • Biofuels from microbes – from waste materials • APIs • Flavours &fragrances • Fine chemicals • Microbiome and pollution control eg microbes to clean air • Bio-degradation (eg plastics) • Forensics • Built environmental microbiome • How does environment and cleaning products impact on microbiome • Sterilisation and surface microbiomes • Climate change

What needs to be done? Who needs to do it?

• BIG funding – more RCUK and industry – for large scale sample collection • Need more funding into ‘institutes’. Partners get first refusal on IP • Funded by industry • Philanthropic funding

• Resources regulatory to open up new studies • Research expensive and therefore an issue • Developing faster/broader analytics and screening • Chemistry – IT – biology nexus • Need for consumer input and acceptability • Cut through the hype • Evidence • Scandinavia/US much more advanced than UK • Hubs/ecosystems • Encourage spin-outs • Not critical mass in UK – yet

Priorities Agrifood

• Skills matching Agrifood o Forum o Directory o Information portal

• Up-skilling merging o Target research and industry o Priority – bioinformatics statistics o Agri Food Training Partnership (AFTP)

External Health

• Industry wants/needs (market area) • Skin

o Oral o Vaginal o Medical o Cosmological o Cosmetic

• Funding for collaborations • Cross-sector collaborations

o Academic – industry collaboration • Lack of funding

o Large scale funding needed

• Classical microbiology • Culture collections that are “relevant” • Hubs of consumer companies and pharma companies 5/8 globally • Biological inference “so what”? • Data collection – but needs more funding for large scale data • Interpersonal diversity • Training • Informative statistics • Continuous training • Undergrad microbiome programmes

Internal Health • Basic Science o Microbiology o Biochemistry o Informatics o Genomics • Better Collaborative funding o Foster interdisciplinary work with industry • Microbiome friendly regulation underpinned by research • Scale-up manufacturing Other

• Opportunities o Industrial products from microbiomes o Environment/industrial exploit microbes o Built environment H&S

• Challenges o Data collection and analytics o Scale up manufacturing o Access to strains

• Needs o Funding (Government, Large genome project o Multidisciplinary skilled workforce/researchers o Dedicated ecosystem for microbiome (hubs)

• +/- o Individual research centres and industry sectors

Appendix 2

Contributing Organisations

Abbott Alphabiomics BBSRC Biocatalysts Ltd Campden BRI Chain Biotech Croda Enterobiotix Ltd Folium Research Food Standards Agency IBM Research IFST Imperial College London Innovate UK Kings College London LA Brewery Landcatch Natural Selection Lifebit Biotech Ltd Medical Research Council Microbiology Society Moy Park Ltd National Biofilms Innovation Centre Probiotics International Ltd (Protexin) Quadram Institute Quay Pharma Rowett Instutute Seventure Unilever University of Aberdeen University of Cambridge University of Reading University of Southampton

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