We study the cellular, molecular and genetic mechanisms that facilitate proper communications between the gut microbiota and the intestinal epithelial, immunological and neuronal systems. Our aim is to understand how these intercellular communication networks control immunological decision-making processes, manage local and systemic inflammation or facilitate immunological tolerance. Our efforts are devoted to developing a microbiome-based, personalized therapy for human autoimmune and chronic inflammatory diseases, as well as for boosting cancer therapy. For these purposes, microscopy, next-generation genomics and molecular biology methods are used in combination with a unique gut organ culture system that we developed (Yissachar et al., Cell, 2017). This 3D system preserves the physiologic tissue structure and cellular complexity, yet allows tight experimental control. This advantage facilitates experimentations which cannot be reliably performed in vivo, and led us to discover some unexpected roles for enteric neurons in mediating microbiota-induced effector and regulatory T-cells development (Yissachar et al., Cell, 2017; Duscha et al., Cell, 2020). We utilize this ex vivo system to investigate how changes to gut microbiome composition control enteric neuro-immune communication in a range of healthy and pathological conditions, including neonatal host-microbiota interactions, autoimmune disorders such as multiple sclerosis, chronic inflammation such as inflammatory bowel diseases and cancer.
Specific research projects include:
The infant gut undergoes massive microbial colonization at birth, which is vital for proper development of intestinal and systemic immunity. Alterations to gut microbiota composition in early life (for example due to cesarean-section delivery or antibiotics administration), are linked to disease development (i.e. allergy, asthma and autoimmune disorders) in later stages. However, the molecular mechanisms that facilitate proper host-microbiota interactions at birth remain mostly unknown. In our lab, we utilize the gut organ culture system to systemically map the intestinal immune responses to neonatal microbiota at birth and to unravel their long-term immunological impact. Discovery of intestinal pathways that maintain host-microbiota mutualism at birth, and are disrupted by antibiotics or other neonatal medical interventions, might reveal novel therapeutic targets that improve long-term health by restoring healthy, early-life host-microbiota communications.
Autoimmune diseases such as multiple sclerosis or systemic lupus erythematosus are characterized by powerful, yet inadequate immune responses to vital cells and organs. In heathy organisms, special regulatory mechanisms control the strength and duration of inflammatory responses to avoid autoimmune pathology. We investigate how changes to gut microbiome composition in human patients alters beneficial host-microbiota cross-talks, and disrupts the healthy balance between inflammation and immunological tolerance. Our goal is to identify specific microbial species, or microbial-derived metabolites, that possess immunomodulatory properties and that potentially could be harnessed as novel anti-inflammatory therapeutics.
In addition to their cytotoxic effects on host tissues, chemotherapeutics disrupt the composition of the gut microbiome. While a dysbiotic microbiome is often associated with gut inflammation, the potential effects of chemotherapy-induced microbial dysbiosis on host-microbiota communications and intestinal homeostasis is unclear. We utilize the gut organ culture system, as well as in vivo and in vitro models, to study whether chemotherapy-disrupted microbiota from mice and humans affects immunological homeostasis in the gut. We aim to identify microbial species that control gut inflammation during chemotherapy and their molecular mechanisms of action. Potentially, these insights may be harnessed for developing microbiome-based therapeutics that ameliorate chemotherapy side effects, alleviate pain in cancer patients and boost anti-cancer therapy.
Technological advances drive research and facilitate scientific discoveries. We contribute to host-microbiota interactions research by constantly making improvements to the 3D gut organ culture technology, including developing advanced methods for precise control over the cellular components of the enteric neuro-immune-microbiome axis. This leads us closer to acquiring real-time and high-resolution readouts in response to various luminal perturbations, including human and mouse microbiome, drugs and metabolites.