Bacteroides: the good, the bad, and the nitty-gritty

Abstract

Bacteroides species are significant clinical pathogens and are found in most anaerobic infections, with an associated mortality of more than 19%. The bacteria maintain a complex and generally beneficial relationship with the host when retained in the gut, but when they escape this environment they can cause significant pathology, including bacteremia and abscess formation in multiple body sites. Genomic and proteomic analyses have vastly added to our understanding of the manner in which Bacteroides species adapt to, and thrive in, the human gut. A few examples are (i) complex systems to sense and adapt to nutrient availability, (ii) multiple pump systems to expel toxic substances, and (iii) the ability to influence the host immune system so that it controls other (competing) pathogens. B. fragilis, which accounts for only 0.5% of the human colonic flora, is the most commonly isolated anaerobic pathogen due, in part, to its potent virulence factors. Species of the genus Bacteroides have the most antibiotic resistance mechanisms and the highest resistance rates of all anaerobic pathogens. Clinically, Bacteroides species have exhibited increasing resistance to many antibiotics, including cefoxitin, clindamycin, metronidazole, carbapenems, and fluoroquinolones (e.g., gatifloxacin, levofloxacin, and moxifloxacin).

FIG. 1.

Proportions of Bacteroides species seen clinically.

FIG. 2.

Gene arrangement in the B. fragilis bme5 efflux pump operon and analysis of the B. fragilis bme5 gene sequences. The bme operon codes for the three components of the RND efflux pumps: bmeA codes for the linker protein which connects the pump to the outer membrane barrel, bmeB codes for the efflux pump, and bmeC codes for the outer membrane barrel through which the substance is exported. Most of the B. fragilis bme pump operons are in the order (bmeA-bmeB-bmeC) but some (e.g., bmeABC5, shown here) are different. Another distinctive feature of bmeABC5 is that it has two promoter regions (indicated by the gold stars). Genomic analysis revealed a putative regulator sequence upstream of bmeABC5 (bmeR5). We demonstrated that the BmeR5 protein binds to the first intergenic region (IT1) but not to the second or third intergenic region (IT2 or IT3). A closer analysis of IT1 revealed that it had two inverted repeats (IR) (GGGAAT******ATTCCC) separated by six nucleotides. We analyzed a clinical metronidazole-resistant isolate of B. fragilis and found a G→ T mutation in the IT1 region. Gel shift assays demonstrated that BmeR5 was no longer able to bind to this region.

FIG. 3.

Cartoon depiction of the salient features of a theoretical composite of Bacteroides fragilis and Bacteroides thetaiotaomicron that underscores the extent of its interaction with its environment. (A) Tetracycline has a stimulatory effect on expression of the RteA-RteB two-component regulatory system and induces expression and transfer of tetracycline resistance. The RteA-RteB two-component system controls the expression of a third regulatory gene, rteC, which, in turn controls excision and transfer of CTnDot, a conjugative transposon carrying the tetracycline resistance gene (tetQ). CTnDot can then transfer tetQ to other bacteria. (B and C) ECF-type σ-factor and its membrane-tethered cognate anti-σ-factor. These factors are frequently associated with operons for starch utilization and may be involved in the adaptive ability of B. thetaiotomicron to express different enzymes according to specific nutrient availability. (D) ETBF can excrete an endotoxin implicated in GI illness and possibly IBD. (E) B. fragilis may resist antimicrobial action in a number of ways. Two of these mechanisms are periplasmic β-lactamase enzymes that digest β-lactamases (and, depending on the enzyme, carbapenems). Another mechanism is the RND-type efflux pumps, which can expel the antibiotic and may contribute to multiple antimicrobial resistance. (F) A hybrid two-component signal system interprets the nutrient environment and may also be involved in sensing the neighboring polysaccharide landscape and modulating “mimicry” so that the surface polysaccharide structure of the bacterium can be altered to match the surrounding landscape. This may allow the bacterium to avoid eliciting a host immune response. (G) The capsule of B. fragilis can induce abscesses in the host. Somewhat ironically, the zwitterionic nature of the capsule allows it to “dock” on a groove on the APC and be presented to the CD4⁺ T cell, which then produces a number of cytokines, including IL-10, which can inhibit abscess formation in the host. (H) Expression of the bmeB RND pumps in B. fragilis can be induced by a variety of agents, including bile, antimicrobial agents, cleansers, and autoinducers important in quorum sensing among bacteria.