Gut Microbes Take Their Vitamins

Abstract

The dense microbial ecosystem within the gut is connected through a complex web of metabolic interactions. In this issue of Cell Host & Microbe, Degnan et al. (2014) establish the importance of different vitamin B12transporters that help a Bacteroides species acquire vitamins from the environment tomaintain a competitive edge.

The intestinal microbiota has rapidly become one of the most intensely studied microbial ecosystems on the planet, yet much of its biology remains unexplored (Gordon, 2012; Proctor, 2011). Insights into the genomic underpinnings of adaptation andthe molecular mechanismsemployed by model microbial communities living within gnotobiotic mice have begun to illuminatewhat life is likefor microbes within the gut (Qin et al., 2010; Sonnenburg et al., 2010). However, much of this research has focused on the primary economy of gut residents, the conversion of carbohydrates into fermentation productslike short-chain fatty acids(Fischbach and Sonnenburg, 2011; Koropatkin et al., 2012). Some studies have furthered our understanding of these main metabolic thoroughfares by investigating the consumption of these “end-products” by other microbial scavengers(Rey et al., 2013). The metabolic flow of the primary sources of carbon and energy, and the dynamics they dictate within the microbial ecosystem, serve as important fundamental principles. However, it is clear that many poorly understood facets of microbiota metabolism occurring on adjacent pathways are equally important.Even with bountiful carbohydrates, whether a microbe can successfully acquire essential cofactors can mean the difference between life and death.

In this issue, Degnan et al. delve into the dizzying set of transporters encoded within the microbiome for the acquisition of vitamin B12 analogs known as corrinoids (Degnan et al., 2014). Over 20 corrinoids have been defined to date and, although not entirely functionally equivalentto one another,many substitute as cofactors to the same enzymes(Yi et al., 2012). By surveying over 300 sequenced microbiota-derived bacterial genomes, the authors show that at least 83% of sequenced strains surveyed possess enzymes that are dependent on vitamin B12. De novo biosynthesis of corrinoids takes a staggering numberof enzymatic steps (~30), so it is not surprising that only a small set of gut microbes produce these molecules, while the remainder scavenge them from other microbes or the host’s diet. These findings highlight a “corrinoid economy” within the gut,in which these compounds represent a form of currency that is highly valued and exchanged between microbes.

In performing the genomic analysis, the authors recognized that manystrainspossessmultiple genes encoding corrinoid transporters, some up to four copies.Yet it was unclear why such apparent redundancy within a single genomewas necessary. Thisstudy focused on Bacteroides thetaiotaomicron, a genetically tractableand common member of the human microbiota that encodes three B12-acquisition systems. Knockoutsof all pairwise combinations of the outer-membrane,corrinoid-transporter genes (named BtuB1, BtuB2, and BtuB3) enableda single transporter to be studied in isolation. Using these mutants inculture competition assays with a precious panel of chemically synthesized corrinoids that differ in one variable structural motif known as the lower ligand, the authorsdemonstrate that each corrinoid transporter is differentially competent in B12 transport andspecializes in a specific subset of structurally distinct corrinoids. Extending these competitions to a gnotobiotic mouse gut, the authors corroborate the in vitro data:a fitness advantage in vivo depends upon whether each mutant strain (harboring just one of the transporters) is more proficient at transporting the corrinoid present in the environment compared to a competing mutant strain (with another single transporter). These data reveal that the seemingly redundant corrinoid transporterseach confer a fitness advantage given the appropriate environmental conditions.

Dozens of apparent BtuB “families” are encoded within the microbiota. Widespread and disorganized distribution of the transporter familiesacross phylogenetic groups suggeststhat many modes of evolution are likely playing a role in their proliferation including duplication-and-divergence and horizontalgene transfer. Thepervasiveness of corrinoid acquisition systems supports the idea that the importance and specialization of these transporters demonstrated for a Bacteroides species is likely to be widely applicable. The authors note that by focusing on an outer-membrane transporter of Gram-negative bacteria,they have probably underestimatedthemicrobiota-wide distribution of corrinoid acquisition systems.

This study provides a beautiful example of how microbes appreciate the chemistry of their environment in exquisite detail. To be a survivor within the competitive gut ecosystem, each microbe must be able to discriminate, harvest, and use specific small molecules, and in some casessubstitute compounds that are chemically closely related. With several species encoding multiple corrinoid transporters, the tenacity with which these microbes have studied and mastered nuanced organic chemistry could serve as a valuable lesson for many undergraduates (and perhaps a few PIs).

The authors have unearthed numerous additional gaps in knowledge about the basic biology of microbial biosynthesis, acquisition and use of corrinoids. How many cellular processes are dependent upon B12-like compounds? Whyare there so many structural variants of these molecules? Are these compounds serving as yet unappreciated roles in providing specificity for microbe-microbe communication?How is gene expression regulated by the quantity and type of corrinoid that a cell imports, and what is the role and specificity of associated corrinoid riboswitches?

Since each of us possesses a unique gut microbiota, important next steps include determining how this individuality (and the complement of B12 analogs that are produced) can dictate whethera newly arriving strain with its assortment of transport systems is able to entrench and persist in the ecosystem. This information is key to understanding the rules that govern the evolution of a microbiota over time and also contributes to our understanding of how to deliberately reprogram a microbiota with new species and functionality.Harnessing the therapeutic potential of the gut microbiota will require understanding the mechanisms governing community dynamics. With dozens of corrinoid transporter families encoded within the human microbiome, it is clear that this study is just a first step in understanding a complex and critical facet of the complex web of microbial interactions thatis taking place inside each of us continually.

Figure 1.

Corrinoid transporters determine Bacteroides fitness in an environment-dependent manner

Expressing the correct member of the three BtuB outer-membrane transporters, which has specificity matching the corrinoid present in the gut, provides B. thetaiotaomicron with a competitive advantage over mutants expressing a transporter not well matched to the environment.