Pep27 Mutant Immunization Inhibits Caspase-14 Expression to Alleviate Inflammatory Bowel Disease via Treg Upregulation

• Published in: Microorganisms (Basel) 2022-09, Vol.10 (9), p.1871
• Main Authors: Iqbal, Hamid, Kim, Gyu-Lee, Kim, Ji-Hoon, Ghosh, Prachetash, Shah, Masaud, Lee, Wonsik, Rhee, Dong-Kwon
• Format: Article
• Language: English
• Subjects: Antibodies; Caspase; caspase-14; Cloning; Colon; Cytokines; Dextran; Dextran sulfate; Dextrans; Drinking water; Dysbacteriosis; Feces; Gastroenteritis; gut microbiome; immune tolerance; Immunization; Immunological tolerance; Immunology; Immunoregulation; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory diseases; Interleukin 10; Intestinal microflora; Intestine; Lymphocytes; Lymphocytes T; Microbiomes; Microbiota; Microorganisms; Mutants; Neutralization; Neutrophils; Oxidative stress; Pathogenesis; pep27; Permeability; Physiological aspects; Prevention; Proteins; regulatory T cells; rRNA 16S; Sodium; Streptococcus infections; Sulfates; T cells; Therapeutic targets; Transcriptomes; Transforming growth factor-b1; Up-regulation; Wnt protein
• ISSN: 2076-2607; 2076-2607
• DOI: 10.3390/microorganisms10091871

Inflammatory bowel disease (IBD) is a highly prevalent gut inflammatory disorder. Complicated clinical outcomes prolong the use of conventional therapy and often lead to compromised immunity followed by adverse events and high relapse rates. Thus, a profound medical intervention is required. Previously, intranasal immunization of pneumococcal pep27 mutant (Δpep27) exhibited long-lasting protection against immune-related disorders. System biology analysis has predicted an inverse correlation between Δpep27 immunization and gastroenteritis. Recently, we established that Δpep27-elicited Tregs repressed Wnt5a expression and enhanced barrier integrity, suggesting the restoration of immunological tolerance. Therefore, we evaluated whether Δpep27 can alleviate IBD. Δpep27 dose-dependent response was analyzed in dextran sulfate sodium-induced mice using transcriptome analysis. Pro- and anti-inflammatory signatures were cross-correlated by quantitative PCR and western blot analyses. To address the hierarchy regulating the activity of caspase-14, an undefined marker in IBD, and regulatory T cells (Tregs), antibody-based neutralization studies were conducted. Fecal microbiome profiles were analyzed by 16S rRNA pyrosequencing. Δpep27 significantly attenuated dextran sulfate sodium-induced oxidative stress parameters, proinflammatory cytokines, caspase-14 expression level, and upregulated tight junction, anti-inflammatory genes IL-10 and TGF-β1 via upregulation of Tregs to restore healthy gut microbiota. Neutralization studies unveiled that ∆pep27 had a remedial effect via Treg upregulation. Caspase-14, being an important mediator in the pathogenesis of IBD, can be an alternate therapeutic target in IBD. ∆pep27-increased Tregs repressed caspase-14 expression and reversed gut microbial dysbiosis, aiding to re-establish immunological tolerance.