The structurally similar, penta-acylated lipopolysaccharides of Porphyromonas gingivalis and Bacteroides elicit strikingly different innate immune responses

Abstract

Lipid A structural modifications can substantially impact the host's inflammatory response to bacterial LPS. Bacteroides fragilis, an opportunistic pathogen associated with life-threatening sepsis and intra-abdominal abscess formation, and Bacteroides thetaiotaomicron, a symbiont pivotal for proper host intestinal tissue development, both produce an immunostimulatory LPS comprised of penta-acylated lipid A. Under defined conditions, Porphyromonas gingivalis, an oral pathogen associated with periodontitis, also produces an LPS bearing a penta-acylated lipid A. However, this LPS preparation is 100-1000 times less potent than Bacteroides LPS in stimulating endothelial cells. We analyzed Bacteroides and P. gingivalis lipid A structures using MALDI-TOF MS and gas chromatography to determine the structural basis for this phenomenon. Even though both Bacteroides and P. gingivalis lipid A molecules are penta-acylated and mono-phosphorylated, subtle differences in mass and fatty acid content could account for the observed difference in LPS potency. This fatty acid heterogeneity is also responsible for the peak "clusters" observed in the mass spectra and obfuscates the correlation between LPS structure and immunostimulatory ability. Further, we show the difference in potency between Bacteroides and P. gingivalis LPS is TLR4-dependent. Altogether, the data suggest subtle changes in lipid A structure may profoundly impact the host's innate immune response.

Defining the gut microbiota in individuals with periodontal diseases: an exploratory study

“…Taken all together, our results support the idea that a relatively large variety of oral species can gain access to the intestinal microbiota, regardless of the periodontal status. Whether these microorganisms colonize or not this body site, they may cause disturbances in this environment by releasing metabolites and cell components, which induce an inflammatory state [76]. They may also interact and enhance the pathogenic effects of other species that colonize the gut [77].…”

The Lipid A Phosphate Position Determines Differential Host Toll-Like Receptor 4 Responses to Phylogenetically Related Symbiotic and Pathogenic Bacteria

“…P. gingivalis ATCC 33277 was obtained from our stock collection. The isogenic mutant strain P. gingivalis 1626KO exhibits a lipid A phenotype that is characteristic of P. gingivalis grown in hemin (1 g/ml), which represents low-hemin-concentration growth conditions as described previously (1,3,5). The isogenic mutant strain of P. gingivalis designated P. gingivalis 1587KO displays penta-acylated, 4Ј-phosphorylated lipid A and lacks nonphosphorylated lipid A, as described previously (5).…”

“…Both B. thetaiotaomicron and P. gingivalis produce LPS that contains penta-acylated, monophosphorylated lipid A (3,14,30). Paradoxically, we observed that despite the high degree of lipid A structural similarity, the LPS of B. thetaiotaomicron is significantly more potent than that of P. gingivalis in stimulating TLR4-dependent innate immune responses (3).…”

The Sweet Tooth of Bacteria: Common Themes in Bacterial Glycoconjugates

“…For instance, it has been shown that intestinal alkaline phosphatase reduces the proinflammatory potential of LPS of gut bacteria by removing the phosphate groups (159). In addition, many gut bacteria, such as Bacteroides species, seem to have a less immunogenic lipid A structure by having fewer acyl chains (160,161). The hypoacylation of lipid A is also a strategy used by pathogens such as P. aeruginosa and N. meningitidis to decrease their immunogenicity (162,163).…”