title: From prediction to function using evolutionary genomics: human-specific ecotypes of Lactobacillus reuteri have diverse probiotic functions.
abstract: The vertebrate gut symbiont Lactobacillus reuteri has diversified into separate clades reflecting host origin. Strains show evidence of host adaptation, but how host-microbe coevolution influences microbial-derived effects on hosts is poorly understood. Emphasizing human-derived strains of L. reuteri, we combined comparative genomic analyses with functional assays to examine variations in host interaction among genetically distinct ecotypes. Within clade II or VI, the genomes of human-derived L. reuteri strains are highly conserved in gene content and at the nucleotide level. Nevertheless, they share only 70-90% of total gene content, indicating differences in functional capacity. Human-associated lineages are distinguished by genes related to bacteriophages, vitamin biosynthesis, antimicrobial production, and immunomodulation. Differential production of reuterin, histamine, and folate by 23 clade II and VI strains was demonstrated. These strains also differed with respect to their ability to modulate human cytokine production (tumor necrosis factor, monocyte chemoattractant protein-1, interleukin [IL]-1β, IL-5, IL-7, IL-12, and IL-13) by myeloid cells. Microarray analysis of representative clade II and clade VI strains revealed global regulation of genes within the reuterin, vitamin B12, folate, and arginine catabolism gene clusters by the AraC family transcriptional regulator, PocR. Thus, human-derived L. reuteri clade II and VI strains are genetically distinct and their differences affect their functional repertoires and probiotic features. These findings highlight the biological impact of microbe:host coevolution and illustrate the functional significance of subspecies differences in the human microbiome. Consideration of host origin and functional differences at the subspecies level may have major impacts on probiotic strain selection and considerations of microbial ecology in mammalian species.
authors.affiliation: Texas Children's Microbiome Center, Department of Pathology, Texas Children's Hospital, Houston, TXDepartment of Pathology & Immunology, Baylor College of Medicine, Houston, TX spinler@bcm.edu.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Spinler
authors.affiliation: Texas Children's Microbiome Center, Department of Pathology, Texas Children's Hospital, Houston, TXDepartment of Pathology & Immunology, Baylor College of Medicine, Houston, TX.
authors.forename: Amrita
authors.initials: A
authors.lastname: Sontakke
authors.affiliation: Texas Children's Microbiome Center, Department of Pathology, Texas Children's Hospital, Houston, TXDepartment of Pathology & Immunology, Baylor College of Medicine, Houston, TX.
authors.forename: Emily B
authors.initials: EB
authors.lastname: Hollister
authors.affiliation: Texas Children's Microbiome Center, Department of Pathology, Texas Children's Hospital, Houston, TXDepartment of Pathology & Immunology, Baylor College of Medicine, Houston, TX.
authors.forename: Susan F
authors.initials: SF
authors.lastname: Venable
authors.affiliation: Department of Food Science and Technology, University of Nebraska, Lincoln.
authors.forename: Phaik Lyn
authors.initials: PL
authors.lastname: Oh
authors.affiliation: Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX.
authors.forename: Miriam A
authors.initials: MA
authors.lastname: Balderas
authors.affiliation: Texas Children's Microbiome Center, Department of Pathology, Texas Children's Hospital, Houston, TXDepartment of Pathology & Immunology, Baylor College of Medicine, Houston, TXPresent address: Department of Gastrointestinal Microbiology, German Institute of Human Nutrition, Nuthetal, Germany.
authors.forename: Delphine M A
authors.initials: DM
authors.lastname: Saulnier
authors.affiliation: Texas Children's Microbiome Center, Department of Pathology, Texas Children's Hospital, Houston, TXDepartment of Pathology & Immunology, Baylor College of Medicine, Houston, TX.
authors.forename: Toni-Ann
authors.initials: TA
authors.lastname: Mistretta
authors.affiliation: Texas Children's Microbiome Center, Department of Pathology, Texas Children's Hospital, Houston, TXDepartment of Pathology & Immunology, Baylor College of Medicine, Houston, TX.
authors.forename: Sridevi
authors.initials: S
authors.lastname: Devaraj
authors.affiliation: Department of Food Science and Technology, University of Nebraska, LincolnPresent address: Departments of Agricultural, Food, & Nutritional Science and Biological Sciences, University of Alberta, Edmonton, AB, Canada.
authors.forename: Jens
authors.initials: J
authors.lastname: Walter
authors.affiliation: Texas Children's Microbiome Center, Department of Pathology, Texas Children's Hospital, Houston, TXDepartment of Pathology & Immunology, Baylor College of Medicine, Houston, TXDepartment of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX.
authors.forename: James
authors.initials: J
authors.lastname: Versalovic
authors.affiliation: Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TXHuman Genome Sequencing Center, Baylor College of Medicine, Houston, TXPresent address: Genomic Medicine, J. Craig Venter Institute, La Jolla, CA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Highlander
mesh_terms: D000818:Animals; D002460:Cell Line; D019143:Evolution, Molecular; D023281:Genomics; D006801:Humans; D052200:Limosilactobacillus reuteri / Q000235:genetics / Q000502:physiology*; D046228:Microarray Analysis; D010802:Phylogeny; D019936:Probiotics
keywords: PocR transcriptional regulation; anti-inflammatory; histamine; host-based evolution; immunostimulatory; reuterin