Exploiting the microbiota-stromal cell axis for microbiota-targeted medicine

PROJECT SUMMARY The development of successful vaccines is a significant achievement in public health. However, vaccines exhibit varying efficacy across different individuals and populations. Vulnerable groups such as infants, the elderly, immunocompromised individuals, and those in low- and middle-income countries often experience suboptimal vaccine responses. Research suggests that the gut microbiota, the community of microorganisms in the digestive tract, plays a crucial role in shaping immune responses to vaccines. The composition of the gut microbiota varies significantly among individuals, and its diversity and stability tend to decrease in infancy and with age, correlating with reduced vaccine responsiveness. This has led to a growing interest in exploring cost- effective microbiota-targeted interventions to enhance vaccine effectiveness, especially in at-risk populations. However, the precise mechanisms by which the gut microbiota influences host immunity, particularly B cell responses, remain poorly understood, posing a significant barrier to unlocking the therapeutic potential of the microbiota. Recent research has highlighted the role of stromal cells as key mediators in initiating, sustaining, and concluding B-cell responses. My prior study found that distinctions in intestinal microbiota composition have been observed to affect immune responses by mediating stromal cells' function, underscoring the ability of stromal cells to detect microbiota differences and orchestrate immune responses accordingly. Building upon these insights, I hypothesize that stromal cells play a pivotal role in sensing microbiota differences and establishing the appropriate immune environment for B-cell development. To test this hypothesis and uncover the molecular mechanisms involved, this proposed project will leverage the microbiota-stromal cell axis to identify bacterial strains or molecules that enhance stromal cell function to promote B-cell responses and antibody production following vaccination. This research will employ a well-established gnotobiotic mouse model in which germ-free mice are colonized with human-derived microbiota that transmit the high or low responsiveness to oral cholera vaccines (OCV) of their donors. Through a combination of novel animal models, stromal cell-specific culture systems, microbiota analysis, single-cell RNA sequencing, and proteomics, we will 1) Identify the gut stromal cell populations that fail to produce essential immune factors for B-cell development and antibody production 2) Identify microbial components that are crucial for stromal cell development and activation. The successful completion of this research will a) provide a proof-of-concept that the gut microbiota can influence stromal cell activation, thereby affecting vaccine responses in both the gut and extraintestinal sites, b) Lay the groundwork for the development of novel immunostimulatory microbial components that can significantly enhance stromal cell function and vaccine responses, not only for OCV but also for other vaccines and c) Provide a blueprint for the future development of microbiota-targeted stromal cell therapies for various microbiota-related immune diseases, including inflammatory bowel disease (IBD) and cancer immunotherapy.