Ischemia reperfusion injury (IRI) is a common, damaging and untreatable event in surgical procedures, trauma and stroke1. IRI often leads to multiple organ failure (MOF), the foremost cause of death in critically ill patients2. Neutrophils (or polymorphonuclear leukocytes (PMN’s)), the most common type of white blood cell in humans, are the primary responders following ischemia and reperfusion and represent important components in the prolonged inflammatory response and severity associated with IRI3. The short chain fatty acids (SCFA’s), propionate, butyrate and acetate are endogenous orthosteric agonists of the free fatty acid receptor 2 (FFA2) (a G protein-coupled receptor), and have shown to ameliorate inflammation in inflammatory bowel disease and asthma. FFA2 is abundantly expressed on immune cells, especially neutrophils and inducing neutropenia in animal models has shown to protect various organs from IRI4. Here we investigated the role of acetate and a novel FFA2 allosteric ligand in a mouse model of mesenteric IRI to address the potential anti-inflammatory effects of these ligands. Untreated mice had significant villi damage in the small intestine after IRI. Dosing with acetate or the allosteric agonist afforded significant protection to the villi during IRI, and acetate almost completely maintained villi morphology. Interestingly though neutrophil infiltration was excessive in the acetate dosed group. Our data suggests that agonists of FFA2 modulate neutrophil function to protect the intestinal villi in IRI and may prevent MOF by preventing reverse migration of neutrophils that lead to systemic inflammation and secondary organ damage.