UCLA researchers in the Department of Integrative Biology and Physiology have identified a microbiome-driven signaling pathway that increases serotonin production and colorectal cancer (CRC) risk which may serve as a valuable therapeutic target for CRC.
BACKGROUND: The gut microbiome plays a central role in regulating host physiology through interactions with the immune, nervous, and gastrointestinal systems. Enterochromaffin cells (ECs), a subset of enteroendocrine cells, serve as key sensors of microbial signals and are responsible for producing approximately 90% of peripheral serotonin (5-HT). Prior studies have demonstrated that spore-forming gut bacteria can induce serotonin production in ECs, influencing gut motility, neuronal signaling, and host behavior. However, the role of microbiome-induced EC-derived serotonin in regulating immune function and disease risk has remained poorly understood.
Recent advances in cancer biology have highlighted the importance of immune tolerance mechanisms in enabling tumor progression, particularly in colorectal cancer (CRC). Regulatory T cells (Tregs) and tolerogenic dendritic cells contribute to immunosuppressive tumor microenvironments that allow cancer cells to evade immune surveillance. While microbiome composition has been linked to CRC risk, the molecular mechanisms by which microbial signals regulate immune tolerance and tumorigenesis are not fully elucidated. Understanding how these microbial signals link immune programming to cancer risk would allow the development of therapeutic strategies that target upstream regulators of immune suppression.
INNOVATION: Researchers at UCLA, led by Dr. Elaine Hsiao, have identified a novel microbiome-driven signaling pathway in certain bacteria which induce serotonin (5-HT) production by enterochromaffin cells in the colon. This EC-derived serotonin then signals to immune cells in the gut to promote a tolerogenic environment characterized by increased regulatory T cell activity. Importantly, this pathway links specific bacterial populations to immune suppression and disease risk. In preclinical models, serotonin-inducing bacteria were shown to increase colorectal tumor burden and dysregulate circulating and intratumoral serotonin levels, while disruption of serotonin-inducing bacteria and serotonin production or downstream signaling reduced tumorigenesis. These findings establish a direct mechanistic connection between the gut microbiome, serotonin signaling, immune tolerance, and colorectal cancer which can be leveraged to develop novel therapies for colorectal cancer.
POTENTIAL APPLICATIONS:
- Colorectal cancer therapeutics targeting immune tolerance mechanisms
- Microbiome-based therapeutic strategies for immunology and immuno-oncology
- Biomarker strategies to identify patients or track disease progression and responses.
ADVANTAGES:
- Targeting specific bacteria can serve as a preventative immunomodulating therapy
- Targeting bacterial pathways which are upstream of immune suppression rather than directly on tumor cells may allow for synergistic benefits with immuno-oncology therapeutics
DEVELOPMENT-TO-DATE: Researchers have established the link between serotonin-inducing bacteria and CRC burden in preclinical mouse models.
Keywords: Colorectal cancer, colon, microbiome, immunology, immune suppression, immune tolerance, serotonin, enterochromaffin cells, immuno-oncology, bacteria, enteroendocrine cells, microbial signals