Bugs as drugs, and drugs from bugs

Jakob Begun studied for his MPhil in biochemistry at the University of Cambridge, and his MD and PhD in genetics at Harvard Medical School. He completed his advanced training in gastroenterology and inflammatory bowel disease (IBD) at Massachusetts General Hospital. He moved to Australia in 2014 to research clinical and translational IBD and gut health. He is the Director of IBD at the Mater Hospital in Brisbane, IBD Group leader at the Mater Research Institute, and an Associate Professor at the School of Medicine, The University of Queensland. He leads a laboratory at the Australian Translational Research Institute, investigating the interaction between the innate immune system and the gut microbiome, as well as genetic contributions to disease.

What inspired your grant application?

Globally, the number of cases of inflammatory bowel disease (IBD) is around 30 per 100,000 people — similar to the incidence of type 1 diabetes. IBD is a chronic, debilitating disease that is often diagnosed in the second or third decade of life, and consists of two main conditions: ulcerative colitis and Crohn’s disease. About 30% of patients do not respond to existing therapies, so many people need surgery and there is high morbidity. There is also growing recognition of the role of gut bacteria and how they interact with the immune system. This interaction probably contributes to IBD, and to immune mediated diseases in general, such as rheumatoid arthritis, as well as autoimmune conditions, like lupus or thyroid disease.

What is the main goal of your project?

In IBD, there is an inappropriate immune response directed towards resident bacteria in the gut. It appears there is a breakdown in the innate immune system, and how it responds to gut bacteria. Our multidisciplinary team have been looking at the proteins and other metabolic products from bacteria, and examining how these molecules interact with and modulate the immune system, and how the immune system responds. This allows us to probe how gut microbiota can set the tone of the immune system, and how it might break down and end up with inflammatory conditions like IBD.

In this specific project, we will explore how bacteria in the gut can produce immunomodulatory molecules that affect a specific inflammatory pathway: the IL-23 pathway. We hope to identify how gut bacteria target that pathway and how the status quo might be disturbed in Crohn’s disease and ulcerative colitis. We will look specifically at how the bacteria function, and whether we can enhance beneficial bacterial activity so that a patient’s system returns to a more balanced, healthier state.

Why has this not been studied before?

One reason that these interactions have been overlooked is that they have been incredibly hard to study, largely because it has been difficult to culture and analyse gut bacteria at scale. The genomics revolution has given us unprecedented insights into the communities that exist inside the gut and the body as a whole. Now that we have newer techniques in bacterial culturing, including anaerobic growth chambers and specialized culture media, we can grow many more bacteria to study their function and discover how they modulate the host immune system. These technologies have revolutionized microbial research.

What steps will your project take?

We already have a collection of bacteria isolated from stool samples from healthy individuals. We have selected bacteria of interest and cultured them. Using these monocultures, we can then use cell-based assays to examine how these bacteria interact with immune cells and, more specifically, the IL-23 pathway. We will use our high-tech metabolomics platform to isolate particular compounds the bacteria produce that are responsible for this immunological activity. We will then explore what aspects of the compounds we’ve identified actually trigger and modulate that activity, and that’s the first step down the road towards novel drug development.

We will use animal models to validate that these bacterial components modulate immune responses. We will also investigate whether these bacterial products can affect immune signalling in human-derived samples from our IBD cohort. Within the timeframe of this project, I’m hoping to identify specific candidates from our library of bacteria that could be used to inform potential therapies.

What might be the practical applications of your project?

There are two overarching philosophies. One approach is ‘bugs as drugs’— you take the bacteria that you have identified, and you develop them as super probiotics. We have the opportunity to personalize therapy here. A collection of, for example, 20 bacteria that can quell inflammatory activity might be tested on a patient’s blood sample. The actual therapy would then consist of the six most effective bacterial strains for that person’s immune system. We may soon be able to take a decision-based approach to probiotic therapy.

The second approach is ‘drugs from bugs’, where we would use the bacterial compounds we identify to design drugs with high affinity and activity against IL-23. Both approaches have the potential to reach beyond IBD, and might prove valuable for other immune-mediated health conditions.

What hobbies do you have?

I have an interest in sailing, which is an activity I often do with my parents. I am an avid skier; often conferences are close to ski areas and I enjoy getting together with colleagues on the slopes. I’m a keen cyclist and I’m involved in lots of activities with my children.

What advice would you give other researchers who might wish to apply for the Gut Health grant?

It is important to propose a project that is achievable within a short timescale, yet has the potential for big impacts in the field. Microbiome research as a whole is a vital focus, especially as we learn more about the ‘holobiont’ that is a human being, because it covers so much of how we function as organisms. After all, our DNA shows we are more microbial than human.