Vancomycin modestly attenuates symptom severity during onset of and recovery from exertional heat stroke in mice

Increased intestinal permeability during exertion and subsequent leakage of bacteria into circulation is hypothesized to accelerate exertional heat stroke (EHS) onset and/or exacerbate EHS severity. To provide proof of concept for this theory, we targeted intestinal microbiota via antibiotic prophylaxis and determined whether vancomycin would delay EHS onset and/or mitigate EHS severity and mortality rates using a mouse model of EHS. Mice were 1) designated as EHS or Exercise Control (ExC) and 2) given 7 days of vancomycin (VEHS, VExC) or untreated water (EHS, ExC) before EHS/Exercise. Following EHS/ExC, mice were euthanized immediately (0 h) or returned to their home cage (25°C) and euthanized after 3 h or 24 h. VEHS mice exhibited reduced abundance and altered composition of fecal bacteria (with notable decreases in genera within orders Clostridiales and Bacteroidales); increased water consumption, lower core temperature (T_C) before and during heating (T_CMax), lower circulating markers of organ damage and inflammation at 24 h; and reduced hepatic activation of stress pathways at 0 and 3 h compared with EHS mice. Vancomycin-induced alterations to the intestinal microbiota likely influenced EHS outcomes, but it is unconfirmed whether this is due to attenuated bacterial leakage into circulation or other (in)direct effects on physiology and behavior (e.g., decreased T_C, increased water consumption). To our knowledge, this is the first study quantitating antibiotic effects in conscious/unanesthetized, exertional HS animals.NEW & NOTEWORTHY Vancomycin prophylaxis lowered core temperature before and during EHS, mitigated EHS-associated rise of hepatic biomarkers and cytokines/chemokines in circulation (particularly at 24 h), and corresponded to inhibited phosphorylation of hepatic c-Jun NH₂-terminal kinase on Threonine 183/Tyrosine 185 at 0 and 3 h in conscious, unanesthetized mice. However, vancomycin also induced cecal enlargement suggesting its off-target effects could limit its utility against EHS.