Lemon Exosome-like Nanoparticles-Manipulated Probiotics Protect Mice from C. diff Infection
Chao Lei,
Jingyao Mu,
Yun Teng,
Liqing He,
Fangyi Xu,
Xiangcheng Zhang,
Kumaran Sundaram,
Anil Kumar,
Mukesh K. Sriwastva,
Matthew B. Lawrenz,
Lifeng Zhang,
Jun Yan,
Wenke Feng,
Craig J. McClain,
Xiang Zhang,
Huang-Ge Zhang
Affiliations
Chao Lei
Department of Chemistry, University of Louisville, CTRB 309 505 Hancock Street, Louisville, KY 40202, USA
Jingyao Mu
Department of Chemistry, University of Louisville, CTRB 309 505 Hancock Street, Louisville, KY 40202, USA
Yun Teng
Department of Chemistry, University of Louisville, CTRB 309 505 Hancock Street, Louisville, KY 40202, USA
Liqing He
Kidney Disease Program and Clinical Proteomics Center, University of Louisville, Louisville, KY, USA
Fangyi Xu
Department of Chemistry, University of Louisville, CTRB 309 505 Hancock Street, Louisville, KY 40202, USA
Xiangcheng Zhang
Department of ICU, the Affiliated Huaian NO.1 People's Hospital of Nanjing Medical University, Huaian, Jiangsu 223300, China
Kumaran Sundaram
Department of Chemistry, University of Louisville, CTRB 309 505 Hancock Street, Louisville, KY 40202, USA
Anil Kumar
Department of Chemistry, University of Louisville, CTRB 309 505 Hancock Street, Louisville, KY 40202, USA
Mukesh K. Sriwastva
Department of Chemistry, University of Louisville, CTRB 309 505 Hancock Street, Louisville, KY 40202, USA
Matthew B. Lawrenz
Department of Microbiology & Immunology, University of Louisville, Louisville, KY 40202, USA; Center for Predictive Medicine, University of Louisville, Louisville, KY 40202, USA
Lifeng Zhang
Department of Chemistry, University of Louisville, CTRB 309 505 Hancock Street, Louisville, KY 40202, USA
Jun Yan
Department of Chemistry, University of Louisville, CTRB 309 505 Hancock Street, Louisville, KY 40202, USA
Wenke Feng
Department of Medicine, University of Louisville, Louisville, KY 40202, USA
Craig J. McClain
Department of Medicine, University of Louisville, Louisville, KY 40202, USA
Xiang Zhang
Kidney Disease Program and Clinical Proteomics Center, University of Louisville, Louisville, KY, USA
Huang-Ge Zhang
Robley Rex Veterans Affairs Medical Center, Louisville, KY 40206, USA; Department of Chemistry, University of Louisville, CTRB 309 505 Hancock Street, Louisville, KY 40202, USA; Department of Microbiology & Immunology, University of Louisville, Louisville, KY 40202, USA; Corresponding author
Summary: Clostridioides difficile (C. diff) is the leading cause of antibiotic-associated colitis. Here, we report that lemon exosome-like nanoparticles (LELNs) manipulated probiotics to inhibit C. diff infection (CDI). LELN-manipulated Lactobacillus rhamnosus GG (LGG) and Streptococcus thermophilus ST-21 (STH) (LELN-LS) decrease CDI mortality via an LELN-mediated increase in bile resistance and gut survivability. LELN-LS treatment increases the AhR ligands indole-3-lactic acid (I3LA) and indole-3-carboxaldehyde (I3Ald), leading to induction of IL-22, and increases lactic acid leading to a decrease of C. diff fecal shedding by inhibiting C. diff growth and indole biosynthesis. A synergistic effect between STH and LGG was identified. The STH metabolites inhibit gluconeogenesis of LGG and allow fructose-1,6-bisphosphate (FBP) to accumulate in LGG; accumulated FBP then activates lactate dehydrogenase of LGG (LGG-LDH) and enhances production of lactic acid and the AhR ligand. Our findings provide a new strategy for CDI prevention and treatment with a new type of prebiotics.
