In Silico Analysis of the Small Molecule Content of Outer Membrane Vesicles Produced by Bacteroides thetaiotaomicron Indicates an Extensive Metabolic Link between Microbe and Host

Abstract

The interactions between the gut microbiota and its host are of central importance to the health of the host. Outer membrane vesicles (OMVs) are produced ubiquitously by Gram-negative bacteria including the gut commensal Bacteroides thetaiotaomicron. These vesicles can interact with the host in various ways but until now their complement of small molecules has not been investigated in this context. Using an untargeted high-coverage metabolomic approach we have measured the small molecule content of these vesicles in contrasting in vitro conditions to establish what role these metabolites could perform when packed into these vesicles. B. thetaiotaomicron packs OMVs with a highly conserved core set of small molecules which are strikingly enriched with mouse-digestible metabolites and with metabolites previously shown to be associated with colonization of the murine GIT. By use of an expanded genome-scale metabolic model of B. thetaiotaomicron and a potential host (the mouse) we have established many possible metabolic pathways between the two organisms that were previously unknown, and have found several putative novel metabolic functions for mouse that are supported by gene annotations, but that do not currently appear in existing mouse metabolic networks. The lipidome of these OMVs bears no relation to the mouse lipidome, so the purpose of this particular composition of lipids remains unclear. We conclude from this analysis that through intimate symbiotic evolution OMVs produced by B. thetaiotaomicron are likely to have been adopted as a conduit for small molecules bound for the mammalian host in vivo.

Host- and Microbiota-Derived Extracellular Vesicles, Immune Function, and Disease Development

“…EVs are also an efficient system of detoxification, facilitating the evacuation of toxic compounds important for bacteria survival. Bacterial EVs also favour bacterial adaptation to a novel niche, with a study suggesting that EVs from commensal bacteria could also contribute to their colonization in the gastrointestinal tract [94]. Based on their membrane properties, bacteria are classified as Gram-negative (G−) or Gram-positive (G+).…”

The Uptake, Trafficking, and Biodistribution of Bacteroides thetaiotaomicron Generated Outer Membrane Vesicles

“…These non-replicative spherical vesicles bud from the bacterial outer membrane and range in size from 20 to 400 nm (Toyofuku et al, 2019). The protective outer lipid bilayer encapsulates and protects their cargo of bioactive proteins, nucleic acids, and metabolites (Bryant et al, 2017). OMVs are increasingly being recognized as a key mode of interkingdom communication between bacteria and host tissues, contributing to a diverse range of functions including nutrient uptake, gene transfer, biofilm formation, antimicrobial protection, and transfer of microbial toxins and virulence factors during infection (Kulp and Kuehn, 2010;Jan, 2017).…”

Fantastic voyage: the journey of intestinal microbiota-derived microvesicles through the body

“…The molecular mechanism of their biogenesis is still unclear, although several models of OMV formation have been proposed and have been recently reviewed [ 3 , 4 ]. OMVs range in size from 20 to 400 nm and can transport a variety of biomolecules such as enzymes, toxins, antigenic determinants, nucleic acids [ 5 ] and metabolites [ 6 , 7 ]. OMV contents are protected from enzymatic degradation by a lipid bilayer envelope that protects against the harsh extracellular environments of the GI tract [ 8 , 9 ].…”