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.
Highlights
Lactobacillus reuteri are natural residents of mammalian and avian gastrointestinal (GI) tracts as well as the human urogenital tract and breast milk
To visualize differences between the genomes, we generated the nucleotide alignments of the genomes shown in Figure 2 by blastn using the complete clade II genome (JCM 1112) as the reference and the program BLAST Ring Generator (BRIG) (Alikhan, et al 2011)
In a previous study comparing RNA expression levels from wild-type and a pocR insertion mutant in American Type Culture Collection (ATCC) 6475, we showed that PocR regulates transcription of operons involved in both reuterin and vitamin B12 synthesis in the clade II strains Japan Collection of Microorganisms (JCM) 1112 and ATCC 6475 (Santos, et al 2011)
Summary
Lactobacillus reuteri are natural residents of mammalian and avian gastrointestinal (GI) tracts as well as the human urogenital tract and breast milk. L. reuteri exhibits strain-specific beneficial properties relevant to human health, making it a model organism for studying host:symbiont interactions as well as microbe:host co-evolution. Comparative genomic studies of Lactobacillus species performed as part of the Human Microbiome Project highlighted significant heterogeneity within and between species and significant interspecies diversity among strains of L. reuteri (Nelson, et al 2010). Previous phylogenetic studies of L. reuteri used amplified-fragment length polymorphism (AFLP) and multi-locus sequence analysis (MLSA) to study more than 100 strains, and these identified host origin as one basis for intraspecies diversity (Oh, et al 2010), with lineage-specific genomic differences reflecting the niche characteristics in the GI tract of respective hosts (Frese, et al 2011). The nature of evolutionary processes and their influence on specific host-microbe interactions and health status deserve exploration
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