The gut microbiome has been coined ‘the second brain’ - and research is now showing that phrases like “going with your gut” are more than just cute misnomers, but downright evidence based. The composition, quality and quantity of the bacteria in our guts have relatively recently been realised to have an enormous influence on individuals brains and overall health.

On ClinicalTrials.Gov alone there are currently over 1,400 investigations of the microbiome listed, approximately 63% of which are newly launched or currently recruiting study participants. One metagenomic study of the human microbiome demonstrated that there are 3.3 million unique genes in human gut, 150 times more genes than the human genome - basically we are more microbiome than we are human. With that in mind it seems retrospectively unsurprising that the microbiome has now been linked to a copious amount of indications including multiple sclerosis, diabetes, autism, AIDS and cancer and a potential key to personalised health diagnostics and treatments.  

The spotlight on the gut microbiome is drawing in a surge of interest from pharma, consumers and clinicians - each with their own set of priorities:

• Pharma set to benefit from scientific and biological advances to help segment populations and develop/discover drugs and personalised therapies which holds great allure in the face of critical R&D challenges being faced by the sector.

• Consumers are starting to pay attention to their own gut health accessing mail order microbiome assessments seeing it as an avenue where they could decode niggling health ailments and better understand their own self care and health management (prepare for skepticism on this one).

• Clinicians may be dealing with gut microbiome assessments as a way to more accurately diagnose and tailor treatment guidance for their patients sooner rather than later as these advances move beyond the lab into clinical care.

In this week’s HealthXL blog, we take a dive into the (somewhat overwhelmingly) flourishing microbiome space and digital interventions supporting its scale.

The Microbiome in Drug Discovery and Development

For pharma and life sciences, new understanding of the gut and its role in overall health means new treatment opportunities. Technological advancements are central in driving this insight from theory to practice.

Thanks to recent advances in advanced biostatistics, machine learning, and artificial intelligence we are beginning to be able to parse vast data sources to identify associations and interactions between the host–microbiome signalling targets for new diagnostics and therapeutics. Understanding how these interactions play out across populations is slowly revealing how these phenotypes can be integrated with other ‘omics’ data sets to enhance precision medicine. This need for diverse and comprehensive datasets is motivating the launch of efforts such as the  National Institutes of Health (NIH) All of Us Initiative to refine precision medicine biomarker discovery and comprehensive phenotypic profiling. The growing evidence linking the microbiome to human health highlights a need to closely consider the gut microbiome in precision medicine efforts.

Companies such as Symbiotix Biotherapies are now entering the market focused on championing emerging molecular therapeutics based on molecules derived from the human microbiome. Others, like Seres Therapeutics, are focused on leveraging advanced analytics and processing power to understand dysbiosis associated with certain conditions and diseases and from there design therapies to achieve a healthy microbiome and in turn address associated symptoms. In March 2019 Seres announced they were teaming up with AstraZeneca to explore whether microbiome therapeutics can increase the efficacy of cancer immunotherapies - AZ are not alone in getting in on the microbiome action. Other microbiome/Pharma investments and partnerships include:

• Pfizer and Adapsyn signed a $162M microbe-mining deal to identify promising drug candidates (2018)
• Celgene contributed to $50M investment in Evelo Biosciences (who started out by investigating how to use the microbiome to activate the immune system and treat cancer) to help push cancer and immuno-inflammatory drugs into phase 1
• Merck and SerImmune announced a drug discovery and development collaboration
• J&J and Day Two paired up for personalised microbiome analysis to guide diabetes nutrition
• Enterome have partnered with J&J, Takeda and BMS with a focus on gastrointestinal

AI advances at the intersection of the gut microbiome and treatment development also spans beyond drug candidate identification or potential applications in clinical trial population segmentation with the development of CRISPR gene editing technologies. SNIPR Biome are one next-gen example who are developing CRISPR-Based Microbiome Treatments where ‘bad bacteria’ are precisely targeted while maintaining the remaining microbiome intact. Welcome to the future. SNIPR's first port of call will be targeting infections that are challenging to treat and precision microbiome modulation in auto-immunity and cancer.

Direct to Consumer (DTC) Nutrigenomics & Microbiome based guidance: Sci Fi or Reality?

While some new emerging digital health companies are laser focused on delivering valuable evidence based microbiome insights to accelerate drug discovery and development, others have chosen to target the in vitro diagnostics (IVDs) direct to consumer market, promising everything from personalised nutrition plans to insights into which types of physical activity your body will respond best to. Sound questionable? Some of these offerings definitely seem to be a bit of a stretch (if not potentially more perilous). However, it’s hard to deny that there is a prime market at hand, where consumers are realising the importance of preventative health management and are more eager than ever to access their own data.

As Dr Eric Topol noted in a New York Times opinion piece in March ‘despite decades of diet fads and government-issued food pyramids, we know surprisingly little about the science of nutrition.’ due to the challenging nature of conducting randomised control trials with a long term regimented diet held steady. This has resulted in much of our guidance on what general diet works best to be largely based on observational studies which oftentimes put forward contradictory findings leading us to the conclusion that maybe there is no one size fits all?

Companies offering gut microbiome assessment and guidance are tapping into a consumer base that are facing this information overload and decision fatigue, something personalised microbiome guidance companies are aiming to address. Thryve is one example of such a company who are marrying their personalised gut assessment with a personalised probiotics [probiotics are surrounded by their own misinformation but that is another conversation]. Viome are another company offering DTC microbiome insights, but unlike Thryve, solely focus on nutritional and lifestyle insights to guide their consumers. Realising that the insights on what is compatible with an individual's physiology might not be enough to ignite change, Viome recently acquired Nutrigenomic company Habit to build out their nutritional guidance and behaviour modification offerings.

Companies positioning themselves as pharma companions and competitors in the drug discovery and development pipeline have been forthcoming with their research, but this remains a bit of a grey space when it comes to DTC microbiome companies who oftentimes (not always) appear to be more invested in their refined marketing collateral than convincing consumers of their clinical validity and proven ability to improve their health outcomes. Our suggestion to consumers? Collaborate with your provider to choose, decode and make a plan-of-action on your microbiome insights - uBiome is one example of a company offering a microbiome assessment and recommending this type of consumer-clinician interaction.

While many of the companies riding the microbiome wave are championing their CLIA approved labs, and depending on consumer stool samples and their self reported preferences to build their recommendations, FoodMarble diverge from this route in favor of looking at the gut microbiome in an aggregate way, by measuring the combined activity of a consumer in response to different foods, using breath analysis. The FoodMarble solution aggregates what foods result in rapid gaseous fermentation in each user’s unique microbiome. Users also track sleep, stress and the food they eat (which the app can translate into component-level data such as levels of lactose, inulin, etc.). The combination of this data helps give a strong indication of what is driving symptoms and how to best approach their self-management. This raises an important consideration for other microbiome offerings basing their recommendations on a cross-sectional insight of just one variable.  

"A major challenge is that the gut microbiome is not readily accessible and many bacterial species in faecal test samples are no longer living. Also, the ability to draw conclusions from the presence or absence of specific strains is still a rapidly evolving area of research. Fundamentally the microbiota act as a community in complex and hard to predict ways.

In general, it’s important for people to take a broad view of any data they gather and avoid looking at one element in isolation. Your microbiome and digestion are not simple systems and can be affected by many different factors."

Aonghus Shortt, CEO FoodMarble

A New Clinical Frontier

It’s not yet confirmed whether microbiome changes are causative or consequential in most pathophysiologies, however they might provide biomarkers for disease detection or management that will be able to be leveraged in clinical settings. The progress in the tech enabling these insights is signalling that microbiome analysis may soon span beyond infectious disease specialists and gastroenterologists towards standard primary care.

The role of the clinician will be pivotal in both mediating DTC companies listed above and delivering the projected future gazing drugs based on AI powered microbiome insights. But there is an additional opportunity for point of care diagnostics to shorten the time and expanding the insight diversity for clinical communities. Traditionally culture tests of patients gut samples was a slow process of waiting to hear back from labs. DNA Electronics is one example of a solution that is set to hit the market to assist clinicians deliver quick and reliable diagnostics from gut microbiome samples.

There are a number of clinical POC diagnostics emerging in this space, albeit slow and steady. In addition these tech interventions may support clinicians personalise their treatment recommendations for their patients based on their gut insights, administer of microbial cocktails and support lifestyle alterations and  behaviour change. The exact interplay of clinical practice and POC gut microbiome insights remains relatively unknown, particularly with regard to distribution of workload - however it is inevitable that a more diverse range of clinicians will be faced with the need to investigate the key role of the gut, potentially moving towards a more holistic clinical environment.

“I think the implications on the gut microbiome on neurobiology are still pretty unexplored. There are some interesting implications on whether we could tailor the microbiome to manage certain neurological processes. Bacteria in the gut metabolize certain compounds and these metabolites can have implications in the nervous system. I think this field will probably remain closely linked to gastroenterology given their expertise in the gut, however it seems other specialties may think about how they may leverage the microbiome at some point in the management of organ specific diseases.”

Peter R Chai MD MMS - Assistant Professor | Harvard Medical School and Scientific Advisory Board Member of uBiome

Things are Looking Fruitful

From our perspective it seems we are hurtling towards deep understanding of the links between the microbiome and human health, and actually seeing the first microbiome therapies entering the market.

But when it comes to consumers, beyond the validated science of these personalised microbiome guides if you are healthy and your preferences overrides the diet and exercise guidance provided by your microbiome assessment, is this new insight nothing more than a new source of information overload? It remains to be seen what conclusive long term gains can be made from DTC gut microbiome efforts, but it definitely seems like a move in the right direction away from the days one size fits all fad diets.

Additionally, Microbiome is just one (seemingly major) part of the puzzle - for consumer efforts we ultimately need to consider preference and behaviour change to action the insights, and conversely the associated environmental and biological factors leading to the presentation of symptoms. It’s not simple, it’s not solved, but it is undeniably promising.