Intestinal TLR9 deficiency exacerbates hepatic IR injury via altered intestinal inflammation and short-chain fatty acid synthesis.

Abstract

Mice deficient in intestinal epithelial TLR9 develop small intestinal Paneth cell hyperplasia and higher Paneth cell IL-17A levels. Since small intestinal Paneth cells and IL-17A play critical roles in hepatic ischemia reperfusion (IR) injury, we tested whether mice lacking intestinal TLR9 have increased hepatic IR injury. Mice lacking intestinal TLR9 had profoundly increased liver injury after hepatic IR compared to WT mice with exacerbated hepatocyte necrosis, apoptosis, neutrophil infiltration, and inflammatory cytokine generation. Moreover, we observed increased small intestinal inflammation and apoptosis after hepatic IR in intestinal TLR9 deficient mice. As a potential explanation for increased hepatic IR injury, fecal short-chain fatty acids butyrate and propionate levels were lower in intestinal TLR9 deficient mice. Suggesting a potential therapy for hepatic IR, exogenous administration of butyrate or propionate protected against hepatic IR injury in intestinal TLR9 deficient mice. Mechanistically, butyrate induced small intestinal IL-10 expression and downregulated the claudin-2 expression. Finally, IL-10 neutralization abolished the protective effects of butyrate against hepatic IR injury. Our studies show intestinal TLR9 deficiency results in exacerbated hepatic IR injury with increased small intestinal apoptosis and inflammation. Furthermore, short-chain fatty acids butyrate and propionate protect against hepatic IR injury and intestinal apoptosis/inflammation in intestinal TLR9 deficient mice.