TI-1: The Microbiome as a Modifier of Immune-modulatory Therapies

Coordinators: J. Baines (CAU, MPI), P. Rosenstiel (CAU), C. Sadik (UzL)

In TI-1, the members systematically investigate whether and how the microbiome, i.e. the totality of microorganisms colonizing the skin or intestine, for example, influences the individual respond to therapy in chronic inflammatory diseases. This is being investigated using the example of inflammatory bowel disease (IBD) and bullous pemphigoid (BP). The results could help provide personalized treatment recommendations and develop microbiome-based therapies to optimize the treatment of chronic inflammatory diseases.

In recent years, more and more research has provided evidence that at the site of inflammation in all chronic inflammatory barrier diseases (CIBD), the microbiome is out of balance. In inflammatory bowel disease (IBD), the phenomenon was initially attributed to the direct effect of local inflammation leading to gross alterations in the properties of the intestinal mucosa. However, recent evidence has shown that the gut microbiome is actually disrupted in many CIBDs, including rheumatoid arthritis and even skin diseases. It remains unclear whether this dysbiosis arises from the over-activated host cytokine network that actively shapes the gut microbiome, or was present prior to the primary disease, making patients more susceptible to it. Nonetheless, recent cancer therapy studies have shown that in these cases the microbiome can help predict or account for individual therapy response. The efficacy of the immunomodulatory anticancer drug cyclophosphamide depends on the composition of the gut microbiota and its recognition by the innate immune receptor NOD2. Other studies have shown that patients undergoing anti-PD-1 immunotherapy for the treatment of melanoma can be easily classified into responders and non-responders based on their gut microbiome, and have demonstrated the causal contribution to treatment response by fecal microbiota transplantation (FMT) into germ-free mice. Participants in TI-1 suggest that the gut (and skin) microbiome influences individual response to targeted therapies in CIBD as well.

TI-1 has the following main objectives:

Perform multi-omics profiling of the microbiome during the course of treatment for IBD and BP diseases.
Identify taxonomic and functional metagenomic indicators of responders vs. non-responders for individual treatments.
Validate the impact of indicators of responders vs. non-responders in preclinical studies using humanized gnotobiotic mouse models.
Develop algorithms for individualized microbiome-based treatment recommendations.
Investigate microbiome-based interventional approaches (e.g., postbiotics) to optimize treatment.

The project has the potential to demonstrate that the microbiome influences the response to CIBD therapy. To date, this relationship has only been demonstrated in a few exemplary diseases. This will significantly advance knowledge of these diseases and provide the basis for translation into the clinic.

The results of TI-1 will allow to determine individual therapeutic decisions based on the microbiome of individual patients.

TI-1 will work closely with RTF X and CD-1 to access material from patients and prospective cohorts. The preclinical animal models will be performed in collaboration with RTF IV.

What does this research area's work build on?

What are the main research objectives?

What makes this research area special?

What does the research area contribute to precision medicine in chronic inflammation?

Cooperation with other research areas in the cluster

Members