title: FolC2-mediated folate metabolism contributes to suppression of inflammation by probiotic Lactobacillus reuteri.
abstract: Bacterial-derived compounds from the intestinal microbiome modulate host mucosal immunity. Identification and mechanistic studies of these compounds provide insights into host-microbial mutualism. Specific Lactobacillus reuteri strains suppress production of the proinflammatory cytokine, tumor necrosis factor (TNF), and are protective in a mouse model of colitis. Human-derived L. reuteri strain ATCC PTA 6475 suppresses intestinal inflammation and produces 5,10-methenyltetrahydrofolic acid polyglutamates. Insertional mutagenesis identified the bifunctional dihydrofolate synthase/folylpolyglutamate synthase type 2 (folC2) gene as essential for 5,10-methenyltetrahydrofolic acid polyglutamate biosynthesis, as well as for suppression of TNF production by activated human monocytes, and for the anti-inflammatory effect of L. reuteri 6475 in a trinitrobenzene sulfonic acid-induced mouse model of acute colitis. In contrast, folC encodes the enzyme responsible for folate polyglutamylation but does not impact TNF suppression by L. reuteri. Comparative transcriptomics between wild-type and mutant L. reuteri strains revealed additional genes involved in immunomodulation, including previously identified hdc genes involved in histidine to histamine conversion. The folC2 mutant yielded diminished hdc gene cluster expression and diminished histamine production, suggesting a link between folate and histadine/histamine metabolism. The identification of genes and gene networks regulating production of bacterial-derived immunoregulatory molecules may lead to improved anti-inflammatory strategies for digestive diseases.
authors.affiliation: Integrative Molecular and Biomedical Sciences (IMBS), Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030.
authors.forename: Carissa M
authors.initials: CM
authors.lastname: Thomas
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas.|Department of Pathology, Texas Children's Hospital, 1102 Bates Ave, Houston, Texas, 77030.
authors.forename: Delphine M A
authors.initials: DM
authors.lastname: Saulnier
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas.|Department of Pathology, Texas Children's Hospital, 1102 Bates Ave, Houston, Texas, 77030.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Spinler
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas.
authors.forename: Peera
authors.initials: P
authors.lastname: Hemarajata
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas.|Department of Pathology, Texas Children's Hospital, 1102 Bates Ave, Houston, Texas, 77030.
authors.forename: Chunxu
authors.initials: C
authors.lastname: Gao
authors.affiliation: Integrative Molecular and Biomedical Sciences (IMBS), Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Jones
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas.|Department of Pathology, Texas Children's Hospital, 1102 Bates Ave, Houston, Texas, 77030.
authors.forename: Ashley
authors.initials: A
authors.lastname: Grimm
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas.|Department of Pathology, Texas Children's Hospital, 1102 Bates Ave, Houston, Texas, 77030.
authors.forename: Miriam A
authors.initials: MA
authors.lastname: Balderas
authors.affiliation: Structural and Computational Biology and Molecular Biophysics Graduate Program, Baylor College of Medicine, Houston, Texas.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Burstein
authors.affiliation: Integrative Molecular and Biomedical Sciences (IMBS), Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030.|Department of Pathology, Texas Children's Hospital, 1102 Bates Ave, Houston, Texas, 77030.
authors.forename: Christina
authors.initials: C
authors.lastname: Morra
authors.affiliation: Department of Molecular Immunology, Beckman Research Institute of the City of Hope, 1500 E Duarte Rd., Duarte, California, 91010.
authors.forename: Daniel
authors.initials: D
authors.lastname: Roeth
authors.affiliation: Department of Molecular Immunology, Beckman Research Institute of the City of Hope, 1500 E Duarte Rd., Duarte, California, 91010.
authors.forename: Markus
authors.initials: M
authors.lastname: Kalkum
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas. jamesv@bcm.edu.|Department of Pathology, Texas Children's Hospital, 1102 Bates Ave, Houston, Texas, 77030. jamesv@bcm.edu.
authors.forename: James
authors.initials: J
authors.lastname: Versalovic
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000628:therapy; D052200:Limosilactobacillus reuteri / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009097:Multienzyme Complexes / Q000378:metabolism*; D016254:Mutagenesis, Insertional; D010453:Peptide Synthases / Q000378:metabolism*; D019936:Probiotics / Q000627:therapeutic use*; D013763:Tetrahydrofolates / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D009097:Multienzyme Complexes; D013763:Tetrahydrofolates; D014409:Tumor Necrosis Factor-alpha; D014302:Trinitrobenzenesulfonic Acid; D010453:Peptide Synthases; C020041:dihydrofolate synthetase; C023103:folylpolyglutamate synthetase
keywords: 
  folC2
  ; Colitis; Lactobacillus reuteri.; folate; histamine; immunomodulation