Little organisms, big impact: how microbes help us battle chronic Inflammatory Bowel Disease.
MIMOSA project reviewed.
October 17, 2023
In 2019 the MIMOSA project, funded by the VIB Grand Challenges Program, was kicked off. The goal was to alleviate Inflammatory Bowel Diseases (IBD) using the intestinal microbiome. Together with partners at KU Leuven, UZ Leuven, and the Imelda Hospital in Bonheiden, some great progress has been made. Time for an overview of the past 4 years. What are the achievements? And which further investigations are envisioned?
What’s it about?
This strange thing called IBD
Inflammatory bowel diseases are chronic inflammatory diseases of the intestines, of which Crohn’s disease and ulcerative colitis are the most common. Symptoms generally emerge during young adulthood and last a lifetime. The exact cause of the disease is still unknown, and the clinical course of patients remains elusive and unpredictable. Previous research suggests that lifestyle and environment may play an important role in causing IBD. In rapidly industrializing countries in Asia, the Middle East, and Latin America, steep rises in IBD incidences are seen. In North America and Western Europe, the prevalence has stabilized at around 1% of the population. This means Europe alone counts for more than 3 million people with some form of IBD, leading to a staggering direct healthcare cost of 5 billion euros annually. Apart from the financial aspect, there is an incalculable impact on the physical and emotional life of the patients. Current treatments focus on reducing the symptoms by targeting the inflammatory pathways that maintain the disease rather than addressing the cause of the disease. As a result, the remission rates - meaning a reduction of the symptoms - stay around 30%. IBD has a strong impact on the quality of life of the patients. Around 25% of people with ulcerative colitis and more than 50% of people with Crohn’s disease will need to undergo surgery to remove (often large) parts of their small intestine or colon.
Tackling IBD from different sides
When a patient is treated for IBD, current therapies target only the intestinal inflammation symptoms by administration of agents suppressing the immune response. In recent years, scientists found that the gut microbiota also plays an important role in IBD. The disturbance in the gut ecosystem, which we call dysbiosis, is triggering and/or worsening the inflammation in the intestine, suggesting that targeting the microbiome might also be part of the possible routes for treating IBD. The MIMOSA project does exactly that. The team led by Jeroen Raes from VIB-KU Leuven Center for Microbiology aims to tackle the disease with the help of our very own gut flora. This is done in three different ways:
- Fecal microbial transplantation in the ‘RESTORE’ multicenter randomized controlled trial: In this method the gut flora of a healthy person is transplanted into a patient with IBD. The goal is to restore the natural balance in the patient’s intestinal microbiome.
- Development of novel probiotics and improving existing probiotics: Probiotics are beneficial bacteria that can be used as therapeutic agents. Novel probiotics can be generated by creating bacterial cocktails in which different beneficial bacteria are combined. This ecosystem can restore the intestinal microbiota composition and as such bring the disease in remission and maintain it. It is also possible to improve existing probiotics to make them more efficient for the treatment of IBD. For the MIMOSA project, the researchers are investigating ways to improve certain yeast strains.
- Repurposing existing medicine in the ‘REMIDY’ trial: For the third and final approach, an existing medicine that is used to treat other diseases is explored for potential IBD treatment, so-called repurposing. These medicines have already been proven to be safe for human use, meaning they can be deployed quickly and safely.
The strength of this project resides in the fact that we are tackling one and the same problem from different angles. We don’t know which of these methods will succeed and show the best results, but by trying these strategies in parallel we hope to develop new therapies successfully. - Jeroen Raes, VIB-KU Leuven Center for Microbiology
What progress has been made?
RESTORE: challenges and perspectives
For the RESTORE trial patients with ulcerative colitis received a fecal microbial transplant (FMT) treatment with microbiota from either super donors stored in optimal conditions and handled with care to cause as little disruption as possible, or their own stools (placebo). Unfortunately, the clinical trial did not show a clear difference between patients treated with FMT from super donors and the placebo group, so the trial was terminated.
Although the outcomes were not as expected, data were further analyzed to investigate why the FMT treatment did not lead to the desired positive effects. One particularly interesting observation was that FMT had a positive effect on the dysbiosis seen in the patients before the treatment, hence restoring the microbiome balance. Whether this restoration of the dysbiosis by FMT leads to changes in the future disease course (less severe disease for instance) is not yet clear.
When a clinical trial does not have the desired effect, it is often terminated early and labeled a futility trial. On the one hand, this protects patients from unnecessary further treatment, on the other hand, it strongly limits the amount of data the scientists can get out of the trial. Therefore, the FMT data are currently too limited to really pinpoint the reasons why no strong effects of FMT treatment were noticed or what causes the positive effect on dysbiosis. The team from Jeroen Raes stays militant, however. “There is something there,” Jeroen Raes says. “I think we have to continue collecting data on an international scale, with large multi-center trials. Only then can we collect enough data and get to the bottom of it.”
Advancements in probiotics
The work on probiotics shows promising progress with the improvement of Saccharomyces boulardii (cfr. Enterol). This is a strain of yeasts currently used as a probiotic for relatively harmless intestinal problems like antibiotic induced diarrhea. For its improvement, the team worked together with Dr. Johan Thevelein, managing director of the company NovelYeast. The newly engineered S. boulardii strain combines two advantages: a high capacity to produce acetic acid together with a good tolerance for acidic environments. The latter is important for the survival of the stomach passage, while acetic acids have been proven to be beneficial for multiple reasons. They exhibit anti-inflammatory effects, stimulate growth-depleted beneficial bacterial species, and bolster the displacement of harmful bacteria.
First studies in cell models and laboratory animals showed a positive effect of oral S. boulardii administration on IBD symptom development. Further safety and efficacy studies were done to investigate the effect of acetic acid on normal gut cells, with positive results. The positive results have sparked the interest of Lallemand, a company specializing in probiotic strains. They are currently using -through licensing- the engineered S. boulardii strain for animal nutrition purposes.
Repurposing Statins: the REMIDY trial
Statins are a group of drugs used to lower blood cholesterol levels and reduce the risk of illnesses linked to atherosclerosis. Clinical trials are being set up to see if statins can be repurposed for use as medication against IBD. The Delta Hospital of Roeselare (Belgium) joined the patient recruitment, together with the partners in Leuven and Bonheiden. The trial is currently ongoing, while data are being collected and analyzed.
The value of this project consists in the close collaboration between clinicians and researchers. We can pose our clinical questions to the VIB researchers, and together start working on solutions. These solutions have the potential that they can be implemented quickly in the clinic to help our patients – Severine Vermeire, KU Leuven – UZ Leuven
It’s the goal of MIMOSA to improve the quality of life of IBD patients. The collaboration of academic centers and hospitals with established clinical research facilities is crucial in this regard – Peter Bossuyt, Imelda Hospital – Bonheiden”
Something is moving in the field
What can we expect?
One of the goals of this project is to develop microbial cocktails based on the knowledge gained from the MIMOSA project. The aim is to combine different beneficial bacteria in order to generate a new ecosystem. This can be used as a drug to restore the intestinal microbiota and cure the disease.
It is safe to say that things are moving in the field of gut microbiome research. Expertise is being gained, clinical trials are being conducted and promising data are being collected, all for a better insight both in the disease and in potential treatments. Hopefully, with the relentless work of scientists, we will soon be able to improve the life quality of patients with IBD drastically.