Girasoles 2.0: Understanding the Role of Microbiota, Inflammation, and Metabolomics in Heat-related Illness

With climate models projecting increasing frequency and severity of heat waves, heat-related illness (HRI) due to environmental exposure is a public health concern. HRI covers a spectrum of symptoms, ranging in severity from sweating to heat stroke or, perhaps, death. Despite recent advances, HRI pathophysiology is not well understood. Heat initiates HRI, but septicemia becomes a driving factor after adaptive mechanisms fail. Evidence suggests gut microbiota and inflammation drive escalating heat stress response into florid HRI. Gut microbes and the short chain fatty acids (SCFAs) they produce modulate immune function. Inflammatory biomarkers and measurable plasma lipopolysaccharide (LPS) levels, a bacterial cell wall constituent that, when measured in blood, provides evidence of bacterial translocation from gut, indicate gut permeability increases in HRI. Primary and secondary bile acids (PSBAs) may shape and be shaped by gut microbes. We will assess the role of gut microbiota and their interplay with inflammation and metabolism to further explore HRI pathophysiology. Our overarching hypothesis is gut microbial communities, systemic and gut inflammation, SCFAs, and PSBAs influence the likelihood and severity of HRI, which we will evaluate in a cross-sectional study of 100 agricultural workers who labor in extreme heat environments. Our project translates from 1) the infrastructure resulting from our experience since 2009 collaborating with the Farmworker Association of Florida in prior and current investigations of health issues among Hispanic agricultural workers exposed to high heat environments; and 2) exciting preliminary data demonstrating microbial community changes associated with high heat exposure and perturbations of metabolic pathways for SCFAs among heat-exposed agricultural workers in relation to HRI. To complement our expertise in HRI and inflammation, we are fostering new collaborations with Dr. Ortlund (Emory University; lipidomics) and Dr. Konstantinidis (Georgia Institute of Technology or “Georgia Tech”; microbiome). We will execute the following specific aims: 1) using whole genome sequencing, evaluate gut microbial species or strain genomes correlating with symptoms and perform targeted isolation of the most promising strains to validate their functional role using human cell lines under high vs. normal body temperatures; 2) evaluate plasma and stool inflammatory biomarkers in relation to symptoms; and 3) evaluate SCFA and PSBA concentrations in plasma and stool. We will perform integrative analyses to improve understanding of interrelationships between gut microbial communities, inflammation, and metabolism. For metabolites associated with microbial species or strains, we will perform functional gene annotation and flux balance metabolic modeling of corresponding genomes to further corroborate the associations, creating hypothesis about which metabolite is produced by which microbial species and testing them experimentally. Our results will allow discernment of novel biomarkers of HRI vulnerability, spurring new preventive approaches or treatments in the setting of extreme heat environments.