Our Aim
Our plan is to use engineered probiotics that can respond to specific triggers in the gut to treat mental diseases like depression.
This can be achieved in multiple ways. We are focusing on two main effectors that have an impact on the pathways involved in the brain-gut axis.
- Tryptophan regulation
Our first target is tryptophan metabolism which we are going to control by:
- inserting an antisense tryptophanase gene into E. coli to repress the expression of tryptophanase. This enzyme is present in most bacterial cells and degrades tryptophan which is the precursor of serotonin. Controlling tryptophanase output would allow accumulation of tryptophan in the cells and thus an increase in serotonin levels which could be a useful target for depression as many patients with depression have low serotonin levels.
- using the enzyme TPH1 which converts tryptophan to a precursor of serotonin. In a similar way as above this could be a mechanism to elevate the levels of serotonin in people with naturally low levels of this neurotransmitter.
- inserting the KAT gene (Kynurenine aminotransferase) into E. coli. This enzyme is necessary for the synthesis of kynurenic acid, a metabolite of tryptophan. This enzyme has been linked to schizophrenia and is being considered as a possible target for treatment.
- Neurotransmitters
The second part of our project involves the production of neurotransmitters that target the same problems.
Hence, we are using genes expressing the following neurotransmitters:
- GABA (gamma-Aminobutyric acid)
- Acetylcholine
These neurotransmitters are naturally produced by some gut microbes. We want to make them dependent on stimuli present in people with mental health issues.
In order to be viable as a treatment for mental disorders like depression the output of neuroactive compounds by bacteria needs to be specific to triggers that are caused by depression in the gut and decrease output when no signals for depression are present. We are therefore testing different promoters in combination with our effectors that could be relevant in this context which includes an adrenaline-sensitive promoter, a nitric-oxide sensing promoter, osmoregulated promoter, and pH-sensitive promoter.