The next weapons in our ongoing fight against disease may come from an unexpected source
Bacteria may be humanity’s greatest enemy. They are directly responsible for three of the top 10 causes of death worldwide (respiratory infections, tuberculosis and diarrhoeal diseases), and contribute to several others, including chronic obstructive pulmonary disease, lung cancers and stroke.
Since 1928, when Alexander Fleming discovered penicillin, medical researchers have been in a constant ‘race to the top’ against bacteria. For every new antibiotic we develop, we discover a new bacterial resistance mechanism to counteract it. We are even now seeing deaths from bacteria resistant to every available antibiotic, which is causing less alarm than it perhaps deserves. Were such bacteria to become widespread, we would have nothing with which to treat patients. It is a constant war — "drugs against bugs” — that will likely continue for as long as we have modern medicine.
It would be a bit harsh, however, to characterise bacteria simply as villains in this story. Populations of bacteria reside inside our digestive tracts in a mutually beneficial relationship, aiding digestion, providing nutrients, shaping the immune response and preventing infection by other pathogenic bacteria.
Several factors determine why some bacteria are beneficial and others harmful. In the simplest scenario, a bacterial species can become dangerous due to numbers alone. For instance, Clostridium difficile can be comfortably tolerated in the colon, as resident ‘good’ bacteria keep its growth in check. However, antibiotics may eliminate much of a person’s healthy microbiome, allowing the C. difficile population to rapidly expand and cause recurring colitis that is very difficult to treat.
In some cases, the harm-benefit relationship is determined by what the bacteria can produce. Many strains of Escherichia coli form a normal part of the healthy microbiome in the gut, but a small number of strains produce the destructive shiga toxin, or produce specific molecules to help them adhere to host cells, causing disease. In other cases, the difference between a hero and villain bacteria is its location. Staphylococcus aureus is found on the skin of practically every person, and can even live without issue in the upper respiratory tract. However, if it enters the lungs and inhabits the lower respiratory tract, it can cause life-threatening pneumonia.
Fortunately, we’re beginning to develop new ways to use the microbiome. There is even now a 'microbiome cook book', which has a variety of meals that are meant to improve the microbiome (think less meat, and more potatoes, vegetables, grains and legumes).
Sally Marchini, an accredited dietitian who has worked with people with chronic disease for six years, is regularly asked about the microbiome in her work. She points to the need for consistency. “As each of us has a unique and constantly changing microbiome, it is thought that we’re better off feeding the good ones with prebiotics — resistant starch does this job — so we can be our individual best,” says Marchini. “These good guys need to be fed every day as the composition can change in less than 24 hours.”
The problem is that these diets can only nourish the bacteria already living there. If you have lost the good bacteria through antibiotics or poor diet, improving what you eat will only have a limited effect. One way around this problem is a faecal microbiota transplant. In this procedure, faeces are collected from a healthy donor (often a close relative or partner), mixed with sterile saline, and the bacteria separated from other bulk material through a strainer. The resulting solution can then be introduced to a patient’s gastrointestinal tract during a colonoscopy, via enema or through a nasal tube, depending on the target location. In some cases, a pre-treatment with antibiotics is recommended to remove competitive pathogens and make it easier for beneficial microbes to effectively colonise the host. A few rounds of faecal transplants, coupled with the proper diet, and the good bacteria should start to gain a foothold.
In some cases, such as C. difficile infection, faecal transplants are remarkably safe and highly effective at preventing relapse. Other, more palatable approaches include the wide variety of commercially available probiotics, which supply a selection of beneficial bacteria in a capsule to improve gastrointestinal health.
Other studies have discovered just what ‘good’ bacteria produce to help us, things like short chain fatty acids or tryptophan metabolites, leading to speculation that directly providing these nutrients could prevent diseases like asthma, arthritis and cardiovascular disease.
So we know bacteria can be good or bad, we know (partly) how to tell the difference, and we’re starting to understand how we can use these good bacteria to treat or prevent disease. The latest work suggests that it may be possible to turn these enemies of humanity, these nasty disease-causing bugs, into friends.
Helicobacter pylori was famously proven to cause stomach ulcers when Nobel prize winner Barry Marshall drank a vial of it and then cured himself with antibiotics. Clearly, developing stomach ulcers is not ideal, and H. pylori has also been associated with increased risk of chronic obstructive pulmonary disease, a complex lung condition often called emphysema. On the other hand, these same bacteria may help to prevent the development of asthma through a complex gut-lung-microbiome connection. It turns out that certain strains of H. pylori are quite good at prompting our body to produce regulatory T cells (a specific type of immune cell that turns off inflammation once an insult is cleared), which may prevent the chronic inflammation necessary for development of asthma.
Discoveries like this force us to consider how we can use these bacteria for their health benefits and can complicate our ‘hero or villain’ question. H. pylori is obviously not your conventional good guy, but, if it were found in someone predisposed to getting asthma, it might be considered protective. The best solution is to determine which mechanisms of H. pylori cause this protective effect and use them in isolation without causing illness, letting patients have their cake and eat it, too.
Work like this has already been done with other bacterial species. The vaccines Prevenar and Pneumovax contain components from the capsule of the bacteria Streptococcus pneumoniae, and were originally developed to help build up immune responses to protect against infections. However, these vaccines can also increase the number of regulatory T cells in the lungs and alleviate symptoms of asthma. Similar findings have been found using deactivated Mycobacterium vaccae. Of course, we have long known that vaccines containing bacterial parts are useful in protecting against infections, but we now know they can be used to treat or prevent non-infectious diseases, as well. Interestingly, the microbiome also plays a role in our response to vaccines, adding to an equation an extra function for ‘good’ bacteria.
So there are many options out there for transforming bacterial villains into heroes, pushing the frontiers of medical research to turn infections into cures. But there are still many questions to answer before the field is fully established. For example, we’ve identified over a thousand species of bacteria from the guts of healthy people, but not every person will have every bug. There are huge differences between seemingly healthy individuals, based on age, sex, diet and environment, so it isn’t always clear exactly which parts of the microbiome need to be altered. As we deepen our knowledge of the specific functions of the microbiome and enter the era of personalised medicine, we can match our microbiome to our own specific disease risks.
Similarly, while microbiome treatments may be approved clinically, and many probiotics are available over the counter, the long-term effects are still being studied. The gut microbiome is linked to practically every body function and every disease, from mental health to cancer. While most treatments appear relatively safe, it is important to gather information about the long-term consequences. The western diet has already disrupted our collective microbiome and is likely a big part of the increasing incidence of allergies and autoimmune diseases. If microbiome treatments and probiotics are to become widely used to combat these diseases, robust research is required to ensure we do not create a different sort of problem in the future.
The other limitations of harnessing bacteria are more practical. Often, the early stages of research are performed in ‘optimal settings’; researchers either use genetically identical animals with strictly regulated diets, or have a well-defined human study group with ways of measuring compliance to the protocol. These are effective ways of doing science, but the real world is often messy: people forget to take their probiotic, patients don’t want a faecal transplant, or a special diet is thrown out the window for a hamburger and Coke. Even some of the more effective treatments, such as vaccines, may have different effectiveness based on various biological and lifestyle factors. Whether microbiome treatments will work in everyday life is a question that will only be answered as these treatments gain widespread acceptance and use in the community.
As with the case of any new medicine, how do we decide if the reward is worth the risk? Last year, I attended the Falk Symposium in Brisbane, where this very question was debated for faecal transplants. Our current situation was best summed up in a closing statement by University of Newcastle gastroenterologist Nick Talley: “If you were a person who had tried everything and nothing had worked, would you be willing to say this therapy is ready? I think yes.” Microbiome research may still have unanswered questions, but we know enough to say these treatments are ready. There will always be room to improve, but for now there are many suffering patients who could benefit from targeting the microbiome.
Bacteria are always going to pose problems, particularly as antibiotic resistance worsens. However, as we move beyond thinking of them purely as our enemies, we can begin to make them our friends. The use of probiotics and microbiome modification is increasingly accepted in the community, with many exciting prospects on the horizon. Sometimes, all it takes is a researcher crazy enough to look for a little friend amongst all our microscopic enemies.
Edited by Andrew Katsis and Duncan Bell