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.
Highlights
The incidence of metabolic syndrome continues to rise globally
We cloned a fusion of a Lactobacillus reuteri signal peptide and the coding sequence of murine interleukin-22 in the high-copy number plasmid pJP028 (Table S1), which was established in L. reuteri to yield L. reuteri expressing IL-22
By enzymelinked immunosorbent assay (ELISA), we demonstrated that L. reuteri expressing IL-22 produced up to 171 ng/ml of murine interleukin-22 (mIL-22) in LDM3 medium (Fig. 1b)
Summary
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. 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 dietinduced steatosis and to development of next-generation probiotics for use in the clinic. In a mouse model of colitis, oral administration of recombinant L. lactis reduced intestinal inflammation, and the results of phase I clinical trial demonstrated safety [10] This seminal work laid the foundation to develop lactic acid bacteria as in situ TPP delivery vectors. L. reuteri ATCC PTA 6475, the strain we used in this study, has probiotic features, including amelioration of obesity [15] (Fig. 1a)
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