Antibiotic resistant bacteria – can the microbiome provide an answer?

Author: Colin Hill, APC Microbiome Ireland
Date: 6th June, 2019

Antibiotics are amazing. They are the most successful medical discovery of all time. Used appropriately, they are life-savers. They control life threatening infections, they permit surgeons to perform operations, they have added over 20 years to average life expectancy wherever they are readily available. We need antibiotics, and we cannot risk a return to the pre-antibiotic era.

Bacteria are amazing. They have been evolving for over three and half billion years and occupy every exposed surface on the planet, including every surface of the human body. Most are located on our ‘inner’ surface –the gut. Humans contain as many bacterial cells as human cells and each one of us has a unique constellation of bacteria that accompanies us through life – our microbiomes. Most scientists are convinced that these bacterial partners play a significant role in human health, acting as a kind of microbial ‘organ’ similar in weight to the liver. As humans evolved into this microbial world we adopted the same chemical signalling molecules and so we ‘speak’ the same language as our microbial fellow travellers. If you want to know how important microbes are to human health, just consider that every mother produces milk which contains hundreds of sugars which her baby cannot digest – the mother is producing these to ensure the right kinds of microbes grow in the newborn gut to give her baby the very best chance of a healthy start to life.

But what has this to do with antibiotics? When antibiotics are used to treat an infection, or to prevent infection, they are usually broad spectrum. This means they kill as many bacteria as possible, including the problematic bacteria causing disease. In many instances the doctor simply doesn’t have the time to establish the identity of the infectious bacterium and so the broader the spectrum the better. Of course, the antibiotic does not ‘know’ which bacteria are dangerous, and which are valuable members of our microbiome and so there can be significant collateral damage. If you have a serious infection this is a price worth paying. Once the infection is treated you can expect your microbiome to recover, and to gradually return to a pre-treatment state.

But there is another cost. As stated earlier, bacteria are the most evolved biological entities on Earth, and they didn’t survive this length of time by shirking a challenge. Firstly, many antibiotics like penicillin are produced by microbes in the first instance, so bacteria have encountered these agents in the past and have developed strategies to defend themselves. Secondly, because microbes can multiply in minutes rather than years they can evolve very quickly to overcome a new challenge. And so, inevitably, bacteria have become resistant to antibiotics. As every new antibiotic hit the market it was followed by the emergence of ‘superbugs’ capable of resisting it. This is inevitable. If you create a situation where a bacterium faces extinction, you will force it to evolve to survive. This would be bad enough if the antibiotic was only killing the infectious bacterium, but in reality every member of the microbiome is exposed to the antibiotic, and they are all forced to evolve and survive. A harmless bacterium can become resistant, and then transfer this resistance to other bacteria, and so antibiotic resistance itself acts like an infection, spreading through the microbiome.

Of course, we have not helped this situation by our inappropriate use of antibiotics. The have been used extensively in animal husbandry, they are used to treat viral infections (where they cannot work), they have been pumped into our rivers and our environments. If the development of antibiotics represents the greatest discovery in science, then our reckless abuse of this invaluable resource and our flagrant disregard for the wellbeing of future generations is only matched by our attitude to climate change.

So, what is the answer, and can the microbiome play a part? We know that the individual bacteria within the microbiome are in intense competition with one another, and so they have developed means of killing one another, and keeping the microbiome in balance. Very often these strategies are narrow spectrum, because a bacterium in the microbiome is only interested in killing competitors for the same nutrient or niche. Here in APC Microbiome Ireland we have been mining the microbiome for novel antimicrobials and have developed a bank of effective, microbiome based, narrow spectrum weapons for combatting infectious bacteria. We have even tested these strategies (probiotics, bacteriocins, bacteriophages) in animals with some spectacular successes.

My proposal is quite simple. Humans are ecosystems composed of our human and microbial partners, and so we need to treat infection as a disruption of this ecosystem. Antibiotics are currently used with the ambition of eliminating the infectious bacterium. If successful, in the short term this represents a win for the patient, a loss for the infectious bacterium, and a loss for the microbiome. In the longer term antibiotic resistance is likely to occur, another loss. Narrow spectrum strategies derived from the microbiome could be used to simply bring the infectious bacterium under control, not eliminate it. If you can reduce the numbers to levels which do not cause disease, very often the microbiome will be able prevent the infection from returning. Reducing rather than eliminating would also reduce the pressure on the bacterium to become resistant in a process referred to as a ‘refuge strategy’ – this is based on the fact that if the infectious bacterium does not face extinction, it is under much less pressure to become resistant. At the same time of course, the other members of the microbiome will also not be driven to develop resistance. This would be a win (patient), win (infectious bacterium), win (microbiome), win (preventing antibiotic resistance) scenario.

I am not suggesting that microbiome strategies should replace antibiotics, or prevent us from developing new ones. Far from it, because antibiotics are a vital part of modern medicine. But I do think there are many situations where an ecosystem based approach could be just as effective in controlling infection, but without the associated burden of antibiotic resistance.