Girasoles 2.0: Mechanisms Relating the Gut Microbiome to Heat-Related Illness

With climate models projecting increasing frequency and severity of heat waves, heat-related illness (HRI) due to environmental exposure is of increasing public health concern. Agricultural workers are particularly vulnerable to HRI. HRI covers a spectrum of symptoms, ranging in severity from sweating to heat stroke or, perhaps, death. Despite recent scientific advances, the processes underlying HRI are not well understood, and health inequities persist among agricultural workers. Heat is the initiating factor in HRI, but septicemia becomes a driving factor after adaptive mechanisms fail. Evidence suggests that gut microbiota and inflammation play a role in escalating the response to heat stress into florid HRI. Gut microbiota, and the short chain fatty acids (SCFAs) they produce, help regulate levels and activity of antioxidant enzymes and modulate immune function. Gut permeability increases in HRI as demonstrated by biomarkers of inflammation and non-negligible plasma levels of lipopolysaccharide (LPS, also known as endotoxin), a constituent of bacterial cell walls that, when present in circulation, provides evidence of bacterial translocation from the gut. Recent evidence indicates that gut bile salts and interleukin (IL)-22, an inflammatory biomarker, may also play roles in shaping gut microbial community structure. We will assess the role of gut microbiota and their interplay with inflammation and metabolism to further explore HRI pathophysiology. The overarching hypothesis of this VICTeR proposal is gut microbial communities, systemic and gut inflammation, SCFAs, and bile salts influence the likelihood and severity of HRI. We propose a cross-sectional design to evaluate 100 agricultural workers. Our project translates from 1) our experience since 2009 collaborating with the Farmworker Association of Florida in prior and current investigations of occupational health issues among Hispanic agricultural workers and the resulting infrastructure; and 2) exciting preliminary data demonstrating elevations of inflammatory biomarkers in serum and stool 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. Eric Ortlund (Emory University; lipidomics) and Dr. Kostas Konstantinidis (Georgia Institute of Technology or “Georgia Tech”; microbiome). We will collect blood and stool samples from participants and resolve gut microbes to the strain level using whole genome sequencing (WGS). We will carry out the following specific aims: 1) evaluate gut species or stain genomes recovered in the WGS data that correlate 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 bile salt concentrations in plasma and stool. Our findings will allow us to identify microbial and bile salt biomarkers of HRI vulnerability and spur new preventive approaches or HRI treatments in the setting of extreme heat work environments.