title: Small molecule immunomodulins from cultures of the human microbiome member Lactobacillus plantarum.
abstract: Lactobacillus plantarum strains are noted for their presence in the human gastrointestinal tract and are distinguished for their immunomodulatory actions and therapeutic applications. Despite the uncertainty in the underlining molecular mechanisms, recent evidence suggests that L. plantarum secretes immunomodulatory agents that alter immunological signaling cascades. Elaboration of these metabolic products from L. plantarum strain WCFS1 was demonstrated previously to correlate with the mid-log-stationary transition, perhaps consistent with secondary metabolite expression. Here, we present the metabolomic shifts revealed by principal component analysis that correspond to the mid-log-stationary transition of L. plantarum, and identify pyroglutamic (pyro) dipeptides within this transition as correlative with the immunomodulatory actions. Four of these (pyro-phenylalanine, pyro-leucine, pyro-isoleucine, pyro-tryptophan) were characterized and the two dominant members, pyro-phenylalanine and pyro-tryptophan, were directly interrogated for immunomodulatory activity through in vivo administration using C57BL/6 mice. Administration of these compounds resulted in decreased production of pro-inflammatory cytokine interferon (IFN)-gamma, which is of noted importance in gastrointestinal immune homeostasis.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Department of Chemistry and Chemical Biology, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada.
authors.forename: Rostyslav
authors.initials: R
authors.lastname: Zvanych
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Department of Chemistry and Chemical Biology, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada.
authors.forename: Nikola
authors.initials: N
authors.lastname: Lukenda
authors.affiliation: Department of Pathology and Molecular Medicine, Farncombe Family Digestive Health Research Institute, Health Sciences Centre, McMaster University, Hamilton, ON, Canada.
authors.forename: Janice J
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Department of Chemistry and Chemical Biology, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Gastrointestinal Diseases Research Unit and Division of Infectious Diseases, Department of Medicine, Queen's University, Kingston, ON, Canada.
authors.forename: Elaine O
authors.initials: EO
authors.lastname: Petrof
authors.affiliation: Department of Pathology and Molecular Medicine, Farncombe Family Digestive Health Research Institute, Health Sciences Centre, McMaster University, Hamilton, ON, Canada.
authors.forename: Waliul I
authors.initials: WI
authors.lastname: Khan
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Department of Chemistry and Chemical Biology, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Magarvey
mesh_terms: D000818:Animals; D004151:Dipeptides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D048191:Lactiplantibacillus plantarum / Q000378:metabolism*; D008297:Male; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota; D010649:Phenylalanine / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D025341:Principal Component Analysis; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry; D014364:Tryptophan / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology
chemical_list: D004151:Dipeptides; D007155:Immunologic Factors; D018836:Inflammation Mediators; D010649:Phenylalanine; D007371:Interferon-gamma; D014364:Tryptophan; D011761:Pyrrolidonecarboxylic Acid