Research project Gut microbes and chemotherapy efficacy and toxicity in vitro and in vivo
We investigate how bacteria in the gut microbiota influence the efficacy and toxicity of chemotherapy in vitro and in vivo – both in experimental models and in patients.
Effective treatment-regimens with chemotherapy have significantly reduced cancer mortality, also for pediatric patients with acute lymphoblastic leukemia (ALL). Still, chemotherapy has a range of harmful side effects that include mucosal injury and inflammation in the gut and long-term depletion of lymphocyte subsets and protective antibodies. This immunological insufficiency could be life threatening to ALL survivors also after clinical remission.
We aim to understand how the microbiota contributes to chemotherapy efficacy and toxicity as well as to the recovery of immune functions after cancer treatment. We perform cellular and molecular experimental studies in vitro with mammalian cells, bacteria and viruses, complemented by in vivo studies in experimental models and work with human clinical samples.
Project description
In recent years, the gut microbiota composition has been highlighted as an important component during cancer treatment for various kinds of cancers, including hematologic malignancies. The chemotherapy-microbiota cross talk is probably bidirectional meaning that our gut microbiota is affected by chemotherapy but also in turn defines the efficacy and toxicity of chemotherapy (as well as other drugs). Our group focus on cancer in the pediatric population, in particular children with acute lymphoblastic leukemia (ALL). How immune recovery occurs in children following completed chemotherapy-treatment after ALL is still relatively unexplored (1-2).
In our work we have previously investigated how secondary lymphoid tissues are affected by chemotherapy. We found a diminished memory and IgG+ B cell population and reduced total and booster vaccine-specific IgG producing memory B cells in the spleens of macaques with past doxorubicin exposure (3). In contrast, the lymph node B cell population seemed unaffected by chemotherapy, as was the T cell population in both compartments. Also, doxorubicin alters the secretory profile of human primary bone marrow mesenchymal stromal cells (BMMSCs) and thereby their ability to support antibody-producing cells. We found that regardless of age, doxorubicin divergently altered BMMSC release of previously described survival factors CXCL12 and IL-6, as well as the less acknowledged GDF-15. Surprisingly, higher IgG-producing cell numbers were recovered from co-cultures with drug-exposed BMMSCs, and removal of IL-6, but not GDF-15, lead to partial lowering of IgG-producing cell ratios (4).
In this project we continue to study how conventional chemotherapy influence inflammatory responses gut epithelial and myeloid cells in vitro and in experimental in vivo models. The studies are performed in the absence and presence of different microbes and/or microbial compounds. We will also investigate how chemotherapy-treatment of children affect the gut microbiota composition and immunologic functions.