Human microbiome therapy

The microbiota is composed of unique communities of microorganisms include bacteria, archaea, protists, fungi and viruses. These communities live on and within the human body, mainly in the gut, in the oral cavity, and on the skin. Quantitatively, for each human cell in the human body we have about 10 bacterial cells, and the total weight of all the microorganisms in adult's body is about 3 kg.

In the last decade, research in the field of microbiome is gaining momentum. Experiments show it has a huge potential, and an equally important role to genetics in influencing on the differences between humans, health and disease states, cognition, emotions etc. 

The initial composition of the microbiota is inherited from the mother to the newborn at birth and can be changed during the life. It is affected by a variety of internal and environmental factors such as: genetics, hygiene, nutrition, medication, living area, life partners, and stressful situations. Shifts in the composition of the microbiota are associated with the pathogenesis of obesity, diabetes, heart and liver diseases, chronic inflammatory bowel diseases, and gastrointestinal cancer, as well as autism and stress.

Through microbiome engineering, the unbalanced microbiome will be rebalanced, and the ecosystems will be restored to their balanced states or even improved, leading to enhanced phenotypes. A breakthrough in this field is a fecal microbiota transplant (FMT), a process of transferring fecal bacteria and other microbes from a healthy individual into another individual, to rebuild the patient's microbiota. This method was proven as an effective treatment for Clostridioides difficile infection (CDI).

By using our software tool, it will be possible to engineer the microbiome by causing a desired gene to be expressed in a specific population and through this changing the bacterial composition.

 

Some examples for applications are presented below:

Anti-cancer treatment:

The gut is bidirectionally connected to the nervous system through what is known as the “gut-brain axis” (GBA). As such, the gut serves as a complex interface between the resident bateria in the gut microbiome and the rest of the human body, with the gut functioning as the communication gatekeeper between the host’s GBA and the resident bacteria in the gut microbiome.

Unsurprisingly (considering the extensive crosstalk between the host and its gut microbiota), certain microbes in the human gut microbiome have been shown to secrete certain molecules and metabolites that have been shown to help the host fight tumors and prevent tumorigenesis in several ways. In addition, it has also been shown that certain other types of bacteria secrete effectors that have pro-tumoral effects and promote cancer cancer development.

Using our solution, it would be possible to selectively engineer the anti-tumoral bacteria to increase effector secretion and/or protect them from hostile factors reducing their population, thus improving their anti-cancer capabilities, and simultaneously engineer pro-tumoral bacteria to reduce secretion of pro-tumoral effectors and/or reduce their population — all in a safe and efficient manner.

Source: Vivarelli, Silvia et al. “Gut Microbiota and Cancer: From Pathogenesis to Therapy.” Cancers vol. 11,1 38. 3 Jan. 2019, doi:10.3390/cancers11010038

 

Urea cycle disorders:

Urea cycle disorders (UCD) are inherited metabolic disturbances caused by deficiency in enzymes required to transfer nitrogen from ammonia to urea, which is created in the metabolism of proteins. Current treatment for UCDs focuses on dietary manipulations, ammonia-scavenging medication, and liver transplantation.

Recently, administration of an engineered ammonia hyperconsuming strain of Lactobacillus plantarum was found to reduce ammonia levels and mortality in rodents with hyperammonemia (a form of UCD). In addition, an orally-delivered E. coli probiotic which has been engineered to convert ammonia into arginine was found to effectively reduce systemic ammonia levels and improve survivability in hyperammonemia mouse models.

Using our solution, the risk of lateral gene transfer that arises from the incorporation of foreign engineered bacteria into the microbiome would be eliminated, as it would be possible to selectively engineer bacteria that are already present in the microbiome to reduce ammonia levels, thus reducing the disturbance to the delicate microbiome, as no external bacteria would be introduced.

Source: Leandro R Soria, Nicholas Ah Mew, Nicola Brunetti-Pierri, Progress and challenges in development of new therapies for urea cycle disorders, Human Molecular Genetics, Volume 28, Issue R1, October 2019, Pages R42–R48, https://doi.org/10.1093/hmg/ddz140