An insider's perspective: Bacteroides as a window into the microbiome

Abstract

Over the last decade, our appreciation for the contribution of resident gut microorganisms-the gut microbiota-to human health has surged. However, progress is limited by the sheer diversity and complexity of these microbial communities. Compounding the challenge, the majority of our commensal microorganisms are not close relatives of Escherichia coli or other model organisms and have eluded culturing and manipulation in the laboratory. In this Review, we discuss how over a century of study of the readily cultured, genetically tractable human gut Bacteroides has revealed important insights into the biochemistry, genomics and ecology that make a gut bacterium a gut bacterium. While genome and metagenome sequences are being produced at breakneck speed, the Bacteroides provide a significant 'jump-start' on uncovering the guiding principles that govern microbiota-host and inter-bacterial associations in the gut that will probably extend to many other members of this ecosystem.

Figure 1. Global distributions and abundances of human gut microorganisms at the phylum and genus levels

Of the gut microbial taxa represented among healthy adult human populations, the Gram-positive Firmicutes and the Gram-negative Bacteroidetes appear to be universal. While different microbiota can appear similar at the phylum level (for example, Sweden versus Russia), they often differ significantly at lower taxonomic levels. In this figure, each pie chart represents an average per cohort, with outer pies depicting phylum-level taxa and Archaea, and inner pies depicting genus-level taxa within Bacteroidetes. Inter-personal variation within each country is also significant. Data adapted from ref. .

Figure 2. Consumption and production of polysaccharides in Bacteroides

a, The starch utilization system. Starch-binding lipoproteins in the outer membrane (SusDEF) bind to and immobilize large extracellular starch polymers, which are then broken into smaller oligosaccharides by the α-amylase SusG. The TonB-dependent transporter SusC carries these oligosaccharides into the periplasm, where the α-amylase SusA and the α-glucosidase SusB break them down further into disaccharides (maltose) or monosaccharides (glucose) for import into the cytoplasm through a sugar-transporting permease. The presence of maltose in the periplasm triggers the regulator SusR to promote the expression of additional Sus components. Bacteroides typically encode 80 or more PULs within their genomes. OM, outer membrane; IM, inner membrane; n, variable polysaccharide size. The starch utilization system is indicated by (1) in the inset. b, Capsule biosynthesis and host protection. Capsular polysaccharide biosynthesis in Bacteroides, such as B. fragilis, is regulated by invertible promoter regions (inverted triangles), trans-locus inhibitors (UpxZ, where x is a, b, c, and so on, depending on the locus), and cis-acting transcriptional anti-terminators (UpxY). Polysaccharide A can promote immunological tolerance to pathobionts such as Helicobacter hepaticus, thus protecting the host from pathogen-induced colitis. The cell capsule is indicated by (2) in the inset.

Figure 3. Commensal colonization of colonic crypts

a, Colonization exclusion. Stable colonization of germfree mice with B. fragilis prevents the subsequent colonization by isogenic B. fragilis sister cells, suggesting that the initial population of B. fragilis has occupied all niches available to it and are not subject to forces of random displacement. b, Co-colonization. Stable colonization of germfree mice with B. fragilis does not prevent invasion by another species of Bacteroides, suggesting limited niche overlap between the two species. c, Niche displacement. Stable colonization of germfree mice with a B. fragilis mutant lacking genes for a specialized PUL named commensal colonization factor (CCF) can be disrupted by subsequent colonization by wildtype B. fragilis cells. B. fragilis ccf mutants are defective in their ability to colonize deep within the colonic crypts, which are thought to serve as a microbial reservoir that seeds the gut lumen and promotes long-term colonization of the gut. Figure based on data from ref. .

Figure 4. Mechanisms of inter-bacterial cooperation and antagonism among Bacteroides

a, Outer membrane vesicles. OMVs are generated and released by Bacteroides both in vitro and in vivo. They can act as carriers of public goods, including Sus-like components, small molecule (SM) cofactors, anti-inflammatory capsule components, such as PSA, antimicrobial (AM) proteins, such as BSAP-1, and other enzymes (Enz). Outer membrane vesicles are indicated by (1) in the inset. b, Bacteroidetes type VI secretion systems. The bacterial T6SS is a contractile molecular lancet that rapidly delivers toxic effector proteins into neighbouring cells in a manner dependent on cell-to-cell contact. The outer tube, which consists of TssB/TssC multimers in a high-energy state, contracts to a low-energy state that forces the rigid inner tube, composed of Hcp multimers, out of the donor cell and into a nearby recipient cell. The needle tip can carry bound effector proteins that mediate cell damage and death in susceptible recipient cells lacking cognate immunity proteins. The Bacteroidetes T6SS lacks a subset of components found in Proteobacterial T6SSs, and carries novel components of unknown function or structure (not depicted). IM, inner membrane; OM, outer membrane. The T6SS is indicated by (2) in the inset.