Host-microbial symbiosis in the vertebrate gastrointestinal tract and the Lactobacillus reuteri paradigm

Abstract

Vertebrates engage in symbiotic associations with vast and complex microbial communities that colonize their gastrointestinal tracts. Recent advances have provided mechanistic insight into the important contributions of the gut microbiome to vertebrate biology, but questions remain about the evolutionary processes that have shaped symbiotic interactions in the gut and the consequences that arise for both the microbes and the host. Here we discuss the biological principles that underlie microbial symbiosis in the vertebrate gut and the potential of the development of mutualism. We then review phylogenetic and experimental studies on the vertebrate symbiont Lactobacillus reuteri that have provided novel insight into the ecological and evolutionary strategy of a gut microbe and its relationship with the host. We argue that a mechanistic understanding of the microbial symbiosis in the vertebrate gut and its evolution will be important to determine how this relationship can go awry, and it may reveal possibilities by which the gut microbiome can be manipulated to support health.

Fig. 1.

Associations of L. reuteri strain 100-23 with the forestomach epithelium of an ex-Lactobacillus-free mouse 7 d after inoculation. The micrographs were produced by transmission electron microscopy as described by Walter et al. (99). (A) Biofilm formed on the stratified squamous epithelium present in the forestomach. (B) L. reuteri cells that adhere directly to stratified cells.

Fig. 2.

Phylogenetic and genomic analysis of L. reuteri isolates originating from different vertebrate hosts. (A) Genealogy of 116 L. reuteri strains as inferred from MLSA sequences using the ClonalFrame software as described by Oh et al. (68). The branches in the tree are color coded by host origin, and cohesive subpopulations are labeled. The human cluster II is enlarged, and the four sequence types (STs, strains with seven identical housekeeping genes) represented in this cluster are indicated. Strains that produce reuterin and posses the pduC gene (large subunit of glycerol/diol dehydratase) are marked by closed black circles; strains that do not produce reuterin or possess the pduC gene are marked with open black circles. Strains that produce urease and posses the ureC (urease alfa subunit) are marked with closed red circles; strains that do not produce urease or the ureC gene are labeled with open red circles. (B) Human isolates of the L. reuteri cluster II form one clonal complex (CC). Allelic profiles were analyzed by eBurst, and CCs were defined as sets of related strains sharing identical alleles at five of the seven MLSA loci with at least one other member of the group. The figure shows the clonal grouping among the human L. reuteri strains of cluster II, which is comprised of four STs. The black circle in the middle indicates the putative founder (ST47). (C) Visualization of SNPs in the genomes of the human L. reuteri strains JCM 1112^T (DSM 20016^T), ATCC PTA 4659, ATCC PTA 5289, and ATCC 6475. SNPs with red markings are found solely in ATCC PTA 4659, SNPs with blue markings are found solely in ATCC PTA 5289, and SNPs with black markings are found in ATCC 4659, 5289, and 6475. Nonsynonymous SNPs are represented with thick markings and synonymous SNPs with thin markings.

Fig. 3.

Effects of L. reuteri on immune cells that contribute to tolerance in the gut. L. reuteri has been shown to suppress the production of proinflammatory cytokines such as TNF-α and IL-12 in macrophages, monocytes, and dendritic cells. The modulation of dendritic cells by L. reuteri has been shown to be mediated through DC-SIGN and promote development of regulatory T cells producing high amounts of IL-10 and TGF-β. This suppression of immune responses is likely to underlie the ability of L. reuteri to reduce intestinal inflammation in several murine colitis models. Please see text for details and references.