Secretion of Recombinant Interleukin-22 by Engineered Lactobacillus reuteri Reduces Fatty Liver Disease in a Mouse Model of Diet-Induced Obesity

Abstract

The incidence of metabolic syndrome continues to rise globally. In mice, intravenous administration of interleukin-22 (IL-22) ameliorates various disease phenotypes associated with diet-induced metabolic syndrome. In patients, oral treatment is favored over intravenous treatment, but methodologies to deliver IL-22 via the oral route are nonexistent. The goal of this study was to assess to what extent engineered Lactobacillus reuteri secreting IL-22 could ameliorate nonalcoholic fatty liver disease. We used a mouse model of diet-induced obesity and assessed various markers of metabolic syndrome following treatment with L. reuteri and a recombinant derivative. Mice that received an 8-week treatment of wild-type probiotic gained less weight and had a smaller fat pad than the control group, but these phenotypes were not further enhanced by recombinant L. reuteri. However, L. reuteri secreting IL-22 significantly reduced liver weight and triglycerides at levels that exceeded those of the probiotic wild-type treatment group. Our findings are interesting in light of the observed phenotypes associated with reduced nonalcoholic liver disease, in humans the most prevalent chronic liver disease, following treatment of a next-generation probiotic that is administered orally. Once biological and environmental containment strategies are in place, therapeutic applications of recombinant Lactobacillus reuteri are on the horizon. IMPORTANCE In humans, nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease due to the increased prevalence of obesity. While treatment of NAFLD is often geared toward lifestyle changes, such as diet and exercise, the use of dietary supplements such as probiotics is underinvestigated. Here, we report that probiotic Lactobacillus reuteri reduces fatty liver in a mouse model of diet-induced obesity. This phenotype was further enhanced upon delivery of recombinant interleukin-22 by engineered Lactobacillus reuteri. These observations pave the road to a better understanding of probiotic mechanisms driving the reduction of diet-induced steatosis and to development of next-generation probiotics for use in the clinic. Ultimately, these studies may lead to rational selection of (engineered) probiotics to ameliorate fatty liver disease.

Usefulness of Probiotics in the Management of NAFLD: Evidence and Involved Mechanisms of Action from Preclinical and Human Models

“…In general, the majority of these studies have addressed the effects of specific probiotic strains in animals challenged by diets leading to NAFLD. In this line, the administration of several probiotic strains (mainly Lactobacillus and Bifidobacterium ) has been shown to be effective in reducing liver lipid accumulation under dietary conditions providing 40 to 65% of energy as fat [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. Moreover, this effect is also maintained when excessive hepatic lipid accumulation is mediated by dietary conditions providing high sugar intakes (10 to 30% of energy as fructose).…”

Native and Engineered Probiotics: Promising Agents against Related Systemic and Intestinal Diseases

“…paracasei F19 can provide the enzyme N -acyl-phosphatidylethanolamine-preferring phospholipase D, which indirectly produces a natural lipid, palmitoylethanolamide, playing a role in regulating inflammation [ 250 ]. Moreover, through modulating the intestinal microbiota and reducing bacterial translocation to the liver, IL-22-expressing Limosilactobacillus reuteri has been reported to alleviate ethanol-induced steatohepatitis [ 247 ] and reduce nonalcoholic fatty liver diseases [ 246 ]. These constructed probiotics exert a powerful anti-inflammatory capacity, especially shown in the hepatic and intestinal axis.…”

Gut–Liver Axis in Nonalcoholic Fatty Liver Disease: the Impact of the Metagenome, End Products, and the Epithelial and Vascular Barriers

“…Besides, some studies have revealed the potential use of engineered bacteria (e.g., Lactobacillus reuteri producing IL-22) to restore homeostasis to the gut-liver axis. 157,158 Other approach under study is to directly target the microbiota either with antibiotics, currently nonspecific and with potential side effects, or with bacteriophages, viruses that can defeat specific species of bacteria. Another approach that has gained attention lately is the supplementation with microbe-derived products (so-called postbiotics) to replace metabolic activities lost due to dysbiosis.…”