Lactococcus lactis Delivery of Surface Layer Protein A Protects Mice from Colitis by Re-Setting Host Immune Repertoire.

Ananta Prasad Arukha,Subhashinie Kariyawasam,Meerambika Mishra,Christian Furlan Freguia,Neil A Fanger,Gary R Fanger,Jyoti K Jha,Bikash Sahay,Ellen M Zimmermann

doi:10.3390/biomedicines9091098

Ananta Prasad Arukha, Subhashinie Kariyawasam + Show 7 more

Open Access

https://doi.org/10.3390/biomedicines9091098

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Abstract

Inflammatory bowel disease (IBD) is characterized by gastrointestinal inflammation comprised of Crohn’s disease and ulcerative colitis. Centers for Disease Control and Prevention report that 1.3% of the population of the United States (approximately 3 million people) were affected by the disease in 2015, and the number keeps increasing over time. IBD has a multifactorial etiology, from genetic to environmental factors. Most of the IBD treatments revolve around disease management, by reducing the inflammatory signals. We previously identified the surface layer protein A (SlpA) of Lactobacillus acidophilus that possesses anti-inflammatory properties to mitigate murine colitis. Herein, we expressed SlpA in a clinically relevant, food-grade Lactococcus lactis to further investigate and characterize the protective mechanisms of the actions of SlpA. Oral administration of SlpA-expressing L. lactis (R110) mitigated the symptoms of murine colitis. Oral delivery of R110 resulted in a higher expression of IL-27 by myeloid cells, with a synchronous increase in IL-10 and cMAF in T cells. Consistent with murine studies, human dendritic cells exposed to R110 showed exquisite differential gene regulation, including IL-27 transcription, suggesting a shared mechanism between the two species, hence positioning R110 as potentially effective at treating colitis in humans.

Highlights

Inflammatory bowel disease (IBD) is a chronic intestinal ailment affecting 6.8 million individuals globally [1]
To construct an acceptable surface layer protein A (SlpA) delivery platform for human studies and improve the pharmacodynamic potential of SlpA, we developed an L. lactis probiotic expressing high levels of secreted SlpA from a genome integrated cassette
The R110 strain was generated by integrating the SlpA expression cassette into the L. lactis genome using double homologous recombination methods

Summary

Introduction

Inflammatory bowel disease (IBD) is a chronic intestinal ailment affecting 6.8 million individuals globally [1]. IBD is divided into two major groups: Crohn’s disease (CD) and ulcerative colitis (UC). In UC, the intestinal inflammation is typically superficial, involving only the mucosal layer, and confined to the colon. In CD, the inflammation is transmural, extending through the intestinal wall to the serosal layer, and can affect the entire gastrointestinal (GI) tract. While the significant area of pathology (and the most responsible for the patients’ symptoms) is the GI tract, inflammatory mediators can leak into the systemic circulation and affect other organs, such as the musculoskeletal system [3,4,5,6], and their disease progression is linked to the gut pathology.

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