Why does medication work ‘like magic’ for some but cause side effects for others? The secret might lie in our gut. The individual composition of bacterial communities shapes how we respond to drugs, making each person’s experience with medication different.
Such individual variability in drug response has been a key issue in medical research for decades. While the human genome has been identified as a major contributor, the success of such pharmacogenomics varies between drugs and is not sufficient on its own to explain response variability. The microorganisms living in our guts, such as bacteria, viruses, and archaea, have a collective genome and metabolome (meaning their metabolic products) that exceeds that of the human host. Additionally, there is evidence that mitochondria in human cells are of bacterial origin, with a significant overlap in genes and proteins. Unsurprisingly, then, it can be more precise in explaining variability, as we have shown in previous work. In fact, the gut microbiome can explain both response and side effect profiles – or adverse drug reactions – across a range of drugs. This is particularly relevant in cancer, where large response variability exists for immunotherapy such as anti-PD1 therapy. It is also expandable to drugs that act across various organ systems, e.g. GLP-1 in diabetes, proton-pump-inhibitors used in acid reflux, or Levodopa which is a Parkinson’s Disease therapy. Fully understanding and, importantly, knowing how to modulate these effects will unlock better treatments for everyone. This is our central mission at BioCorteX: right drug, first time, for al
So what exactly is happening between drugs and bacteria?
The interactions between drugs and the microbiome are bidirectional, meaning that bacteria affect the processing of a drug and that these drugs change the composition and function of the gut microbiome.
Lab research has shown that bacteria directly modulate drug metabolism by:
- Biotransformation: bacteria can enzymatically convert compounds into active, inactive, or even toxic metabolites.
- Enzymatic degradation: bacterial enzymes can degrade or otherwise metabolise the active ingredient, reducing concentration and impacting systemic circulation.
- Bioaccumulation: bacteria absorb and accumulate the active ingredients and alter their concentration.
- Competition for a required metabolic enzyme: bacteria can compete with active ingredients for enzymes that are required for metabolism, thereby reducing the processing of the drug.
- Drug target modification: bacteria can directly modify drug targets or mimic host enzymes to influence drug action.
The varying frequency of these mechanisms due to different compositions of the gut microbiome across people can mean that there is a higher or lower concentration of the active ingredient – or even toxic metabolites. Together with indirect effects of the gut microbiome, such as modulation of the immune system or gut barrier functions, this gives rise to variations in drug effects.
Types of direct bacteria-drug interactions. Created with biorender.com
Similarly, the therapeutic drug can affect the concentration and function of the gut bacteria. Active ingredients can inhibit bacterial growth or even kill beneficial bacteria, change the environment, like the pH, or the permeability of the intestinal barrier. Not only does this affect which bacteria can thrive and which die, thereby changing the composition of the microbiome. It can also affect the metabolites produced and how many of them can enter circulation, affecting host physiology. These effects can contribute to the effect of medication as is the case with Metformin, where changing bacterial composition supports the glucose-lowering effects of the medication. However, they can also contribute to side effects, particularly gastrointestinal symptoms or increased susceptibility to infections.
While gut bacteria tend to be the first point of contact for medication that is ingested, bacteria in other body sites can also impact the therapeutic effect. For example, the bacteria on and within cancerous tumours can affect the efficacy of cancer therapy, as we have shown previously.
Together, these bidirectional effects show the central role that bacteria play in medication processing and that they directly and indirectly contribute to individual variability in drug response.
Figure from Weersma et al. (2020) showing the bidirectional nature of drug-bacteria interactions.
Why this matters
Apart from supporting a clinical effect like in Metformin, or reducing side effects, these drug-bacteria interactions could drastically impact cancer survival. As mentioned above, interactions stemming from gut or tumour bacteria play an important role in determining the efficacy of immunotherapy in various cancers. Immunotherapy is the most powerful treatment we have for many cancers such as breast, skin, or colorectal cancers. In fact, it is sometimes capable of curing metastatic cancers, which are especially hard to treat and have a median survival time of only 10 months. Being able to adjust a major factor determining immunotherapy success could thus be groundbreaking for patients and their families.
Mitigating drug-bacterial interactions is also crucial to optimise clinical trials: It is estimated that drug-bacteria interactions contribute to over 243 billion USD in Research & Development costs and could be responsible for decades of failed clinical trials. This means that many potentially helpful treatment candidates do not reach patients as the benefits are obscured by high variability in response, driven by bacterial differences.
We can change this.
Our Solution
At BioCorteX, we not only recognise the importance of these hidden drug-bacteria interactions, we can predict and act upon them. While it is possible to study these effects in the lab, e.g. with artificial gut systems and other in vitro systems, it is not possible to scale such experiments to the number of repetitions needed, say, to predict a clinical trial outcome. Our foundational biology emulator, Carbon Mirror, can.
Our unique Carbon Mirror platform can model and understand bacterial effects in drug metabolism, as well as knock-on effects on host health. This is a best-in-class capability built to the highest international standards leveraging the latest techniques in software development and engineering. It enables us to fully understand how bacteria can impact a specific medication and how to mitigate these effects.
We have already successfully collaborated with multinational pharmaceutical companies to help them identify the contribution of bacteria to the side effect profiles of key assets. We have also shown with our approach that gut bacteria explain differences in trial outcomes between Japan and the USA.
If you want to learn more about potential use cases, you can contact us here.
We are convinced that uncovering these hidden drug-bacteria interactions can unlock variable drug effects, revolutionising clinical trial planning and asset success. Right drug, first time, for all.
