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

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.

Role of gut microbiota in infectious and inflammatory diseases

“…UC is the most common form of IBD, which affects more than 5 million individuals worldwide ( Alatab et al, 2020 ; Yang et al, 2021 ). Its inflammation is limited to the mucous layer, causing superficial damage restricted to the wall of the rectum and colon ( Kobayashi et al, 2020 ; Arukha et al, 2021 ). CD is characterized by irregular transmural inflammation that extends through the intestinal wall into the serous layer, and it affects mainly the terminal ileum, but it can affect any part of the gastrointestinal tract ( Arukha et al, 2021 ; Jergens et al, 2021 ).…”

Emerging Noninfectious Indications for Live Biotherapeutic Products in Gastroenterology

“…Emerging possible LBPs for UC include genetically engineered probiotics and bacteriophages. R-3750 is a surface layer protein A-expressing thymidine-dependent L. lactis strain currently in phase 1 trials for mild-to-moderate UC (34,35). Preclinical data from mouse models show that a lytic bacteriophage consortium targeting IBD-associated Klebsiella pneumoniae may be beneficial for reducing inflammation.…”

Intestinal Engineered Probiotics as Living Therapeutics: Chassis Selection, Colonization Enhancement, Gene Circuit Design, and Biocontainment

“…The probiotic properties of traditional probiotics, such as EcN, Bifidobacterium species, − and Lactobacillus species, ,,− have been extensively described. Traditional probiotics can protect the intestinal mucosa, − modulate gut microbiota, and produce beneficial metabolites .…”