Host Gut-Resistome and Gut-Immune Axes are the key to Non-cholera Vibrioinfection severity in aging and heat stress

Abstract Global incidences of periodic heat waves and exposures are on the rise and that also have impacted non-cholera Vibrioabundance in coastal waters. We hypothesized that aging and a parallel heat stress (HS) may potentiate the risk of non-cholera Vibrioinfections in the host and exacerbate the pathology. To study the underlying pathological changes in possible co-exposure of HS and subsequent non-cholera Vibriochallenge, an aging mouse model was used. Mice were exposed to HS at 40°C for three hours/day for 15 days. This was followed by a Vibrio vulnificuschallenge 24 hours post HS exposure. Results showed that HS exposure decreased the diversity of the host gut microbiome and altered the relative abundance of many important taxa as assessed by Whole Meta-Genome Sequencing (WMS). Gut leaching was evident via the alteration of tight junction proteins and concomitant endotoxemia was evident. Decrease in abundance of Akkermansia muciniphila, a species well known for protection of gut barrier integrity was observed. Serum CRP levels, a clinical indicator of septicemia was elevated in the HS mice following Vibrio vulnificusinfection, over and above the Vibrio-only or HS-only group. Significant amplification of gut leaching, gastrointestinal and systemic inflammation (IL-1β, IL-6, TNF-α), T-cell senescence and altering IgA levels were also noted in the HS+ Vibriogroup. WMS also showed an altered host resistome signature and abundance of genes harboring the antimicrobial resistance to tetracycline group of antibiotics, a common antibiotic used for treatment of non-cholera Vibrioinfections. In summary, HS augmented susceptibility to non-cholera vibriosis via host variability in resistome patterns and altered gut-immune mediators. This study was supported by NIH/NIEHS Grant 1P01ES028942-01#Project 4 Toxicology awarded to Dr. S. Chatterjee.