Engineered bacteria producing aryl‐hydrocarbon receptor agonists protect against ethanol‐induced liver disease in mice

Abstract

AbstractBackground and PurposeGut bacteria metabolize tryptophan into indoles. Intestinal levels of the tryptophan metabolite indole‐3‐acetic acid are reduced in patients with alcohol‐associated hepatitis. Supplementation of indole‐3‐acetic acid protects against ethanol‐induced liver disease in mice. The aim of this study was to evaluate the effect of engineered bacteria producing indoles as Aryl‐hydrocarbon receptor (Ahr) agonists.MethodsC57BL/6 mice were subjected to chronic‐plus‐binge ethanol feeding and orally given PBS, control Escherichia coli Nissle 1917 (EcN) or engineered EcN‐Ahr. The effects of EcN and EcN‐Ahr were also examined in mice lacking Ahr in interleukin 22 (Il22)‐producing cells.ResultsThrough the deletion of endogenous genes trpR and tnaA, coupled with overexpression of a feedback‐resistant tryptophan biosynthesis operon, EcN‐Ahr were engineered to overproduce tryptophan. Additional engineering allowed conversion of this tryptophan to indoles including indole‐3‐acetic acid and indole‐3‐lactic acid. EcN‐Ahr ameliorated ethanol‐induced liver disease in C57BL/6 mice. EcN‐Ahr upregulated intestinal gene expression of Cyp1a1, Nrf2, Il22, Reg3b, and Reg3g, and increased Il22‐expressing type 3 innate lymphoid cells. In addition, EcN‐Ahr reduced translocation of bacteria to the liver. The beneficial effect of EcN‐Ahr was abrogated in mice lacking Ahr expression in Il22‐producing immune cells.ConclusionsOur findings indicate that tryptophan metabolites locally produced by engineered gut bacteria mitigate liver disease via Ahr‐mediated activation in intestinal immune cells.