Heat stress enhances gut microbial arginine catabolism to amplify MyD88-dependent inflammatory responses

As global temperatures continue to rise, heat stress (HS) has emerged as a major health threat of growing concern. HS triggers systemic inflammation and multi-organ damage, but so far its molecular mechanisms remain unclear. In this study, we explored the potential mechanism by which the gut microbial alterations amplify HS-associated inflammatory responses. We found that the gut microbiota was disrupted in HS mice as characterized by increased LPS levels and enhanced arginine catabolism. Transplant of fecal microbiota from HS mice aggravated inflammatory responses in recipient mice after HS. Exogenous arginine pretreatment notably suppressed inflammation in the liver and cortex of HS mice. Mechanistically, arginine reduced MyD88 protein levels by activating its ubiquitination and weakened the MyD88-TLR4 interaction, thereby inhibiting the nuclear translocation of p65 and the expression of pro-inflammatory genes. Clinically, lower arginine levels were detected in the serum of HS patients and positively related with liver injury and inflammatory indicators. An arginine-enriched oral inulin hydrogel was developed to prevent inflammatory responses exacerbated by the gut microbial alterations through maintaining the gut microbiota homeostasis to reduce LPS and providing a sustained supply of arginine. This study reveals a mechanism by which the gut microbial alterations exacerbates HS-associated inflammatory responses via disrupting the balance between LPS and arginine, thereby providing a novel target for the prevention of HS. Video Abstract