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07 October 2021
Jan Majta
Jan Majta

Gut microbiota’s road to clinical utilization. From bathroom to bedside.

A surge of biotech ventures in the field of microbiome research is gaining momentum. The last ten years showed  a rapid increase in interest in microbiome research, which can be seen in a variety of sources – from  PubMed to Google Trends. Scientific groups worldwide are constantly uncovering new  associations between microbial communities and various health conditions. New publications are being written on the topic every day, and yet it seems there is still much to be discovered about the microbiome. But in the end, what really matters is that  these findings are applied to improve human health.

Microbiome-based diagnostics

The most straightforward way to utilize basic research discoveries is to design a diagnostic solution. A number of companies offer basic microbiome profiling services. We all know the story of uBiome and 23andMe for the microbiome. But after the collapse of the pioneer, a similar kit can be ordered from myBioma or Viome. For the price of roughly $150, one can purchase a kit for stool self-sampling that must be shipped back for sequencing and afterwards, the composition of one’s gut microbiota is  provided on a website. However, the discovery of various bacteria species in the sample is only the beginning of this story. Most consumers are curious and ask what each bacteria taxa says about their health and how this knowledge can be used. Although the microbiome-profiling services include some basic interpretation and suggestions on how one can “improve” the composition of their microbiome, this is not medical advice.

However, two ventures aim at providing true microbiome-based diagnostic tests. The first one comes from the previously mentioned brand Viome, which tops their Gut Intelligence test with an AI-based test for oral and throat cancer prediction from metagenomic sequencing. The second test comes from Prescient Metabiomics, which provides  early stage detection of colon polyps and cancers. Both technologies achieved FDA breakthrough designation and are on the last lap before being available on  the market.

Microbiome-based therapies

Although  diagnostic tests are very useful for identifying various health concerns, they are a rather small step on the road to improving your health. The more profound question to ask is whether we can use the microbiome to manage health conditions by developing microbiome-derived therapeutic products.

Not surprisingly, the potential of the gut microbiome, while still a novelty to the western civilization, was already applied in ancient Chinese medicine. Left with no major success, it had to wait almost two millennia until 1950s’ when Fecal Microbiota Transplantation (FMT) was applied to treat antibiotic-associated diarrhea.

Around the same time, German bacteriologist Werner Kollath defined the term ‘probiotics’ , which describes quite a different approach to human gut health as opposed to FMT’s. Instead of a rather rudimentary transplantation of whole fecal matter, the probiotics method involves precisely selecting bacterial strains with beneficial potential. The modern understanding of probiotics emerged at the beginning of XX century with the work of Ilya Mechnikov on the topic of lactic acid bacteria. The application of so-called “Bulgarian Bacillus” came into popularity after the observation of the longevity of yoghurt-drinking inhabitants from the Balkan peninsula.

For years, the introduction and manufacturing of beneficial bacterial strains was no different than that process. Novel strains were discovered in food – mainly dairy and fermented products and utilized as food additives or supplements.

Figure1. https://tiny.pl/9rk6k
Used under CC BY-NC-ND 4.0

It wasn’t until the 1980s’ when modern techniques in molecular biology – most notably PCR and DNA sequencing – enabled scientists to get a deeper, fuller understanding of microbial communities. These advances led to the discovery of a number of potentially health-promoting novel strains whose functions are yet to be fully understood.

Modern microbiome therapies

The history of the application of bacteria in medicine has shaped the way people think about novel microbiome-derived products. Having in mind FMT and probiotic models, we could observe two distinct, yet overlapping paths.

The first one, following a top-down development approach, relied on the observed beneficial effect of fecal bacteria transplantation. The key idea behind the process is to understand the transplanted material and to narrow down the consortium.

A number of players in the microbiome industry follow this product development scenario. Some key companies like Seres Therapeutics, Rebiotix or MaaT Pharma are achieving successes by developing their products with full fecal consortia as a starting point.

The fundamental advantage of this approach is that it significantly accelerates the research. Starting with an already working product – FMT – you can incrementally add the value by refining the consortium that the product is made of. What is more, when developing a novel product, using FMT in an initial phase of R&D allows to quickly and cost-effectively evaluate the applicability of microbiome-derived intervention.

On the other hand, it must be underlined that the microbiome is an extremely complex ecosystem. It takes a lot of research (and a large budget!) to fully understand the relationships between numerous strains in the community. After an initially successful development of basic products, it requires much effort to transform the FMT into a well-understood, fully controlled therapeutic with a described mode of action (MoA).

Alternatively, another approach for the utilisation of the gut microbiome’s potential in therapeutics has been developed. With the bottom-up approach, companies like Enterome, Senda Biosciences or 4D Pharma are leveraging the very specific mechanisms identified in the microbial samples. These companies spent a significant amount of time upfront to identify the potentially key activity of the microbiome and then develop a product based on that information.

Within this approach, we can distinguish two main modalities investigated by researchers. The first one relies on identified immunostimulatory molecules present in or produced by bacteria. This is the key path for companies such as Enterome and Everimmune. To reach this point, it is crucial to understand both the human immune system and the gut microbiome. Another strategy is to utilize bacterial metabolites (postbiotics) that are identified as effectors. This is what SFA Therapeutics, Axial Therapeutics and Kaleido Biosciences aim for. Moreover, a number of ventures exploit those mechanisms indirectly by altering the bacterial growth conditions with pro- or antibiotics.

Contrary to the top-down approach, this one is highly precise – the entire therapeutics development process starts with a defined MoA. It can stem from either a well-studied hypothesis or even a clinically observed difference. However, the challenge for this product development strategy is rather similar to the top-down procedure – the complexity of the microbial system. Due to this, one cannot be sure that such a mechanism of action will benefit patients, as it may not be compatible with the distinct composition of gut microbiota they have.

Where’s the sweet spot?

Knowing all the pros and cons of the aforementioned processes, other companies, like Vedanta Biosciences, aim at a third, hybrid, method. The solution for the shortcomings of both approaches seems to be a rationally designed consortium that is intended to be a synergy of a number of precise mechanisms.

It is achieved by creating a bacterial consortium of a limited number of strains that retains crucial functions of a whole microbial community, but is scrapped of its unnecessary, and potentially harmful members. Such a product combines the precise definition known from the classic drug development process with an ecosystem context that is a fundamental factor in the microbiome area.

Conclusions

Knowing all the possibilities and limitations in the field of microbiome product development, we can see that the crucial step which defines all the steps is the identification of key processes that are present in the “good microbiome”. Whether we want to refine an FMT-derived product or precisely select a postbiotic-factory strain, we need to know which biological processes are the proper ones.

At Ardigen, we are aware of the significance of those challenges. Therefore, we made the discovery of actionable signatures the primary focus of our AI Microbiome Translational Platform. If you would like to learn more about the platform, reach out to us at https://ardigen.com/microbiome/

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