Bacteria engineered to produce IL-22 in intestine induce expression of REG3G to reduce ethanol-induced liver disease in mice

Abstract

ObjectiveAntimicrobial C-type lectin regenerating islet-derived 3 gamma (REG3G) is suppressed in the small intestine during chronic ethanol feeding. Our aim was to determine the mechanism that underlies REG3G suppression during experimental alcoholic liver disease.DesignInterleukin 22 (IL-22) regulates expression of REG3G. Therefore, we investigated the role of IL-22 in mice subjected to chronic-binge ethanol feeding (NIAAA model).ResultsIn a mouse model of alcoholic liver disease, we found that type 3 innate lymphoid cells produce lower levels of IL-22. Reduced IL-22 production was the result of ethanol-induced dysbiosis and lower intestinal levels of indole-3-acetic acid (IAA), a microbiota-derived ligand of the aryl hydrocarbon receptor (AHR), which regulates expression of IL-22. Importantly, faecal levels of IAA were also found to be lower in patients with alcoholic hepatitis compared with healthy controls. Supplementation to restore intestinal levels of IAA protected mice from ethanol-induced steatohepatitis by inducing intestinal expression of IL-22 and REG3G, which prevented translocation of bacteria to liver. We engineered Lactobacillus reuteri to produce IL-22 (L. reuteri/IL-22) and fed them to mice along with the ethanol diet; these mice had reduced liver damage, inflammation and bacterial translocation to the liver compared with mice fed an isogenic control strain and upregulated expression of REG3G in intestine. However, L. reuteri/IL-22 did not reduce ethanol-induced liver disease in Reg3g–/– mice.ConclusionEthanol-associated dysbiosis reduces levels of IAA and activation of the AHR to decrease expression of IL-22 in the intestine, leading to reduced expression of REG3G; this results in bacterial translocation to the liver and steatohepatitis. Bacteria engineered to produce IL-22 induce expression of REG3G to reduce ethanol-induced steatohepatitis.

Indoles: metabolites produced by intestinal bacteria capable of controlling liver disease manifestation

“…Importantly, indole‐3‐acetic acid treatment protected against alcoholic steatohepatitis via the induction of Reg3 g and prevention of bacterial translocation to the liver, probably via AhR‐dependent mechanisms. Moreover, alcoholic hepatitis patients had lower intestinal levels of indole‐3‐acetic acid, indicating the involvement of tryptophan catabolism during human alcohol‐induced liver disease . Taken together, these data suggest that alcohol consumption changes microbial composition, thereby affecting the bacterial metabolome which alters host immunity and allows bacterial translocation.…”

“…We recently demonstrated that dysbiosis during alcoholic liver disease is associated with altered tryptophan metabolism by bacteria, both in human as well as in an experimental rodent model . Using chronic‐binge ethanol feeding to mice as a well‐established model of alcoholic steatohepatitis , we found that intestinal levels of indole‐3‐acetic acid, a ligand for the AhR , are lower upon ethanol feeding compared to controls.…”

Genetically Engineered Escherichia coli Nissle 1917 Secreting GLP‐1 Analog Exhibits Potential Antiobesity Effect in High‐Fat Diet‐Induced Obesity Mice

“…The use of engineered bacteria to deliver therapeutic molecules has been reported in various studies . Notably, probiotics, including EcN, bifidobacteria, and lactobacilli, have already been engineered to produce GLP‐1 or GLP‐1 analogs to treat diabetes or inflammation‐induced memory impairment .…”

“…In recent years, ongoing research has focused on genetic manipulation of EcN as a carrier of therapeutics for the treatment of obesity, diabetes, intestinal disease, and other diseases . In addition, this approach could also be used in a novel oral administration form to deliver bioactive molecules to the intestine without degradation; oral administration remains the most preferred route of drug delivery for the management of chronic diseases, owing to patient compliance.…”

Changes in the composition of the human intestinal microbiome in alcohol use disorder: a systematic review

“…REG3 are C-type lectins involved in the immunological response against pathogens. Prevention of alcohol-induced down-regulation of REG3G in a mouse model has been shown to reduce bacterial translocation to the liver (56). The mechanism by which ethanol causes down-regulation of REG3 involves an alcohol-induced reduction of interleukin 22 (IL-22) (57).…”