LIMIT
Background
The exact number of patients with Long COVID in the Netherlands is unknown, but it was estimated that ~450.000 persons suffered from Long COVID in March 2023, of which ~90.000 patients have very severe complains (https://www.c-support.nu/over-long-covid/ and Maatschappelijke gevolgen van long covid – Maatschappelijk Impact Team - 19 juni 2023 ). Long COVID is defined by the WHO as complaints that start within 3 months of the initial COVID-19 illness and last at least 2 months (Post COVID-19 condition (long COVID)). Approximately 10% of COVID-19 survivors suffers from complaints three months after infection.
The care for patients with Long COVID is still not sufficient. There is no clear diagnostic tool and treatment options are still limited and often experimental. In November 2024, the first post COVID outpatient clinics were opened in the Netherlands with the aim to optimize care for the patients. The clinics collaborate closely together and scientific research is integrated into the outpatient clinics. Understanding the characteristics of the patient (phenotypes) and underlying mechanisms (endotypes) are needed to find effective treatment options as a one-size-fits-all approach is unlikely to be effective against the heterogenous complaints. The LIMIT project is one of the studies that will be conducted in the outpatient clinics.
In the LIMIT project (Long COVID Microbiome and Inflammation Trial), we are studying the effect of a microbiome intervention on complaints and microbiome composition in patients with Long COVID.
The microbiome consists of all microbes in our body. The reported numbers vary, but we might even have ten times as many microbes in and at our body than human cells. Research on the microbiome has shown that a healthy composition of the microbiome can have a great positive impact on our health. One of the mechanisms by which microbes can influence our health, is by the production of metabolites from the food we digest. Those metabolites can travel through the blood and have an effect on many cells in the body. It is also known that the composition of the microbiome of people with certain diseases differs from healthy individuals. This also seems to be the case in persons with Long COVID. Six months after infection, COVID-19 patients that did not have complaints anymore at 6 months had a microbiome composition that was recovered and comparable to healthy controls, whereas the microbiome of people with post-acute COVID-19 syndrome (PACS, also named Long COVID) was still different from healthy controls (Liu et al.). A placebo controlled clinical trial was performed in Hong Kong to test the effect of a microbiome intervention on complaints of Long COVID. This study showed that several complains of Long COVID could be reduced (Lau et al.).
In patients with Long COVID from the P4O2 COVID cohort we recently discovered two distinct microbiome profiles, which were associated with differences in complaints and lung function (Blankestijn et al.). The microbiome of persons in one of the two groups contained less butyrate producing bacteria and this was the group of persons with more complaints. In the LIMIT trial we aim to correct this disbalance by providing persons with Long COVID a food supplement that contains butyrate producing bacteria.
Study procedures
A total number of 150 patients will be recruited from the post COVID clinics in the Netherlands. After a careful investigation to rule out other diseases, the participants can be included in the trial and will be assigned to taking a specific food supplement for six months or to taking a placebo control intervention. The participants can only join the study if they did not use a probiotic/prebiotic/symbiotic product or antibiotics in the last 6 months. Also, persons that use steroids or immunosuppressive drugs cannot participate.
At the first visit the participant will perform a lung function assessment, will complete questionnaires and biological samples will be collected (see figure). Additionally, we will take nasal and blood samples to test the in vitro effects of an inhibitor of a target we found in the nasal transcriptome. After six months the same measurements are repeated. In the months in between the two visits, questionnaires on severity of complaints will be completed. The primary endpoints in this study are related to the severity of long-COVID, and include symptom severity and frequency and questionnaires describing the impact of long-COVID on aspects such as quality of life, societal participation and fatigue. The secondary endpoints include the changes in the microbiome, pulmonary function in patients, the effects of the synbiotic in vitro and the characterization of the microbiome over time through AI image analysis.
We expect to start recruiting patients in May 2025. The findings are expected to be reported in May 2027.
Collaborators
In P4O2, collaboration between researchers of universities and companies is stimulated. We believe this will optimize innovation.
LIMIT is a project within the P4O2 consortium, which is co-financed by Health~Holland.
UMCG is coordinator of the study. Patients are recruited in the post COVID clinics in Amsterdam UMC, LUMC, Erasmus MC, and UMCG.
VITAKRUID provides the synbiotic and the placebo intervention aiming to explore how the product can be further developed to better support patients with Long COVID. Through this collaboration, the company seeks to gain deeper insights into its potential benefits and applications.
TNO will further develop their in vitro assay that predicts effect of interventions on personal microbiome samples. For over 20 years, the microbiology group at TNO has been at the forefront of developing innovative platforms to explore the function and composition of the gut microbiota. One of their main tools is the i-screen method—a high-throughput system that empowers food and pharmaceutical companies to test their products on individual microbiome samples. In this project, TNO is set to further enhance this in vitro assay, the i-screen platform, to predict the effects of interventions on personal microbiome samples. This development is particularly important for Long COVID patients, who exhibit a wide range of symptoms and may not respond uniformly to treatments. By leveraging the i-screen platform, we can test microbiome-targeted therapies on individual samples before proceeding to human trials, significantly reducing the burden on patients and paving the way for personalized medicine.
HORAIZON contributes to the project by making available their MicrobeLink technology available, which is detect changes in microbiome composition based on imaging of fecal smears
NOVARTIS provides an inhibitor to test the effect of the medication on the inflammatory responses in vitro.
LIMIT is a project under the P4O2 program
P4O2 contains projects that focus on prevention and early detection of lung disease by applying personalized medicine approaches. To do so, collaboration between academia and industry is essential. Interested in other P4O2 Long COVID projects? Please visit Publications | P4O2 for a list of publications. Interested in collaborating? Please contact us via p4o2@amsterdamumc.nl
