Lipidomic analysis of Porphyromonas gingivalis reveals novel glycerol bisphosphoceramide, phosphatidyl-, and phosphoglycerol dipeptide lipid families

Kleiboeker, Brian A.; Frankfater, Cheryl; Davey, Mary E.; Hsu, Fong-Fu

doi:10.1016/j.jlr.2023.100470

Cited by 5 publications

(4 citation statements)

References 36 publications

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“…3C ), further indicating that these eight uncharacterized metabolites likely represent novel sphingolipids. Interestingly, these molecular features are not found in Bacteroides cultures, suggesting that these uncharacterized sphingolipids are unique to P. copri and therefore merit further analysis ( 15 , 17 ).…”

Section: Resultsmentioning

confidence: 99%

“…A second family, the Rikenellaceae, including the less populous Alistipes species, have been found to produce lipids similar in structure to sphingolipids, sulfonolipids ( 16 ). Porphyromonas gingivalis, a member of another family known to produce sphingolipids, the Porphyromonadaceae, has recently been found to produce a set of novel sphingolipids ( 17 ). A fourth family, Prevotellaceae, is known to produce sphingolipids and is the most widely prevalent and abundant of the Bacteroidaceae due to its dominance in the gut microbiomes of the population of non-industrialized or non-Westernized countries ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

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Prevotella copri variants among a single host diverge in sphingolipid production

Xiao,

Le,

Lee

et al. 2024

mBio

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Sphingolipids serve as vital structural and signaling components of the cell membranes in both eukaryotes and prokaryotes. Within the gut microbiome, Bacteroides species have been identified as major producers of sphingolipids, and Bacteroides -produced sphingolipids have been shown to be modulators of host immune and metabolic functions. While Bacteroides species are a prominent feature of the gut microbiomes of populations living in industrialized countries, Prevotella copri , a member of the same phyla, albeit a different family, is the dominant feature across the remainder of the global population, although their sphingolipid-producing capabilities have not been as thoroughly investigated. To fill this gap, we examined the genomes of over 60 diverse isolates of P. copri and identified several key enzymes involved in sphingolipid synthesis in P. copri . Combining bioorthogonal labeling and liquid chromatography-mass spectrometry (LC-MS) based lipidomics, we functionally characterized the first step in P. copri de novo sphingolipid synthesis in addition to profiling the sphingolipidomes of P. copri strains, identifying key enzymes that may play roles in producing a diverse set of P. copri sphingolipids. Given the limited genetic engineering tools amenable for use in P. copri , our approach takes advantage of comparative genomics and phenotypic profiling to explore sphingolipid production in these understudied, yet highly prevalent, organisms. IMPORTANCE Sphingolipids are important signaling molecules for maintaining metabolic and immune homeostasis in the host. These lipids are also produced by gut commensals, most notably by Bacteroides species. Despite the global prevalence of Prevotella copri in gut microbiomes of individuals, little is known about the types of sphingolipids they produce and whether they are similar in composition and structure to those produced by Bacteroides . Given the varied associations of P. copri with diverse sphingolipid-related health outcomes, such as rheumatoid arthritis and glucose intolerance, it is important to first characterize the specific sphingolipids produced by individual strains of P. copri and to identify the genes involved in their pathways of production. This characterization of P. copri -derived sphingolipids provides further insight into how bacterial sphingolipid production can serve as a mechanism for microbial modulation of host phenotypes.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prevotella copri variants among a single host diverge in sphingolipid production

Xiao,

Le,

Lee

et al. 2024

mBio

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“…We investigated the role of c-di-AMP signaling in the regulation of the LPS profile by assessing the capabilities of P. gingivalis WT and mutant strains in regulating ‘relative abundances’ of major lipid A variants, as well as relevant core oligosaccharide region, and total LPS polysaccharide. Given P. gingivalis capability to produce different lipid classes ( Nichols et al., 2004 , 2006 ; Moye et al., 2016 ; Kleiboeker et al., 2023 ), we sought to confirm the specific regulatory role of c-di-AMP signaling on the LPS profile and regulation of other lipid classes. Hence, we analyzed distinct lipid classes in the WT, as well as the Δ pde pg and Δ cdaR mutants, cultivated at low and high hemin concentrations.…”

Section: Resultsmentioning

confidence: 99%

The multifaceted role of c-di-AMP signaling in the regulation of Porphyromonas gingivalis lipopolysaccharide structure and function

Ghods,

Muszyński,

Yang

et al. 2024

Front. Cell. Infect. Microbiol.

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BackgroundThis study unveils the intricate functional association between cyclic di-3’,5’-adenylic acid (c-di-AMP) signaling, cellular bioenergetics, and the regulation of lipopolysaccharide (LPS) profile in Porphyromonas gingivalis, a Gram-negative obligate anaerobe considered as a keystone pathogen involved in the pathogenesis of chronic periodontitis. Previous research has identified variations in P. gingivalis LPS profile as a major virulence factor, yet the underlying mechanism of its modulation has remained elusive.MethodsWe employed a comprehensive methodological approach, combining two mutants exhibiting varying levels of c-di-AMP compared to the wild type, alongside an optimized analytical methodology that combines conventional mass spectrometry techniques with a novel approach known as FLATn.ResultsWe demonstrate that c-di-AMP acts as a metabolic nexus, connecting bioenergetic status to nuanced shifts in fatty acid and glycosyl profiles within P. gingivalis LPS. Notably, the predicted regulator gene cdaR, serving as a potent regulator of c-di-AMP synthesis, was found essential for producing N-acetylgalactosamine and an unidentified glycolipid class associated with the LPS profile.ConclusionThe multifaceted roles of c-di-AMP in bacterial physiology are underscored, emphasizing its significance in orchestrating adaptive responses to stimuli. Furthermore, our findings illuminate the significance of LPS variations and c-di-AMP signaling in determining the biological activities and immunostimulatory potential of P. gingivalis LPS, promoting a pathoadaptive strategy. The study expands the understanding of c-di-AMP pathways in Gram-negative species, laying a foundation for future investigations into the mechanisms governing variations in LPS structure at the molecular level and their implications for host-pathogen interactions.

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“…We investigated the role of c-di-AMP signaling in the regulation of the LPS profile by assessing the capabilities of P. gingivalis WT and mutant strains in regulating 'relative abundances' of major lipid A variants, as well as relevant core oligosaccharide region, and total LPS polysaccharide. Given P. gingivalis capability to produce different lipid classes (Nichols et al, 2004(Nichols et al, , 2006Moye et al, 2016;Kleiboeker et al, 2023), we sought to confirm the specific regulatory role of c-di-AMP signaling on the LPS profile and regulation of other lipid classes. Hence, we analyzed distinct lipid classes in the WT, as well as the Dpde pg and DcdaR mutants, cultivated at low and high hemin concentrations.…”

Section: Dysregulation Of C-di-amp Signaling Significantly Compromise...mentioning

confidence: 99%

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Lipidomic analysis of Porphyromonas gingivalis reveals novel glycerol bisphosphoceramide, phosphatidyl-, and phosphoglycerol dipeptide lipid families

Cited by 5 publications

References 36 publications

Prevotella copri variants among a single host diverge in sphingolipid production

Prevotella copri variants among a single host diverge in sphingolipid production

The multifaceted role of c-di-AMP signaling in the regulation of Porphyromonas gingivalis lipopolysaccharide structure and function

Table_4.docx

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