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B. thetaiotaomicron LPS and P. gingivalis LPS contain penta-acylated, monophosphorylated lipid A structures, as well as nonphosphorylated lipid A structures. (A) Negative-ion mode MALDI-TOF MS analysis of lipid A derived from B. thetaiotaomicron LPS. (B) Negative-ion mode MALDI-TOF MS analysis of lipid A derived from P. gingivalis 1626KO LPS. (C) Positive-ion mode MALDI-TOF MS analysis of lipid A derived from B. thetaiotaomicron LPS. (D) Positive-ion mode MALDI-TOF MS analysis of lipid A derived from P. gingivalis 1626KO LPS.
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The human symbiont Bacteroides thetaiotaomicron promotes intestinal function and health, whereas the phylogenetically related pathogen Porphyromonas gingivalis is associated with the chronic oral inflammatory disease periodontitis. Although both B. thetaiotaomicron and P. gingivalis synthesize lipopolysaccharides (LPS) consisting of penta-acylated,...
Citations
... 12 Interestingly, a mutant of Bacteroides thetaiotaomicron that cannot remove the C-4' phosphate from its lipid A was displaced from the microbiota during inflammation caused by infection. 13 Thus, it appears that fine structural features of lipid A of Bacteroides contribute not only to immune-modulatory activity but also to maintenance of a healthy microbiota. ...
The inflammation-inducing properties of lipopolysaccharides (LPS) of gram-negative bacteria reside in its lipid A moiety. Bacillus fragilis, which is a commensal gram-negative bacterium, biosynthesizes lipid A that is structurally distinct...
... As a result, there are notable differences in endotoxin activity and toxicity of Bacteroides LPS and Escherichia coli LPS (Johne et al., 1987). The plasma LPS by the end of study could be mainly contributed by bacteria such as Bacteroides, which is more abundant than Escherichia coli (Coats et al., 2011). The Escherichia coli LPS injected subcutaneously could also trigger a different immune response compared with the symbiotic counterpart (Coats et al., 2011). ...
... The plasma LPS by the end of study could be mainly contributed by bacteria such as Bacteroides, which is more abundant than Escherichia coli (Coats et al., 2011). The Escherichia coli LPS injected subcutaneously could also trigger a different immune response compared with the symbiotic counterpart (Coats et al., 2011). ...
... Some bacteria have evolved biosynthetic pathways resulting in extensive modifications of classical lipid A (2) allowing evasion of an inflammatory host response by becoming more tolerogenic. Such modifications include the reduction of acyl chain numbers (9), elongation of the acyl chain lengths (10,11), developing branched acyl chains (12,13), removal of one phosphate group (14,15), and blockage of the phosphates with positively charged groups (10,(16)(17)(18)(19)(20)(21). These modifications can significantly regulate proinflammatory immune responses (6), leading to a more tolerogenic life-long colonization as exemplified by organisms inhabiting the human gut. ...
Lipopolysaccharides (LPS) and lipooligosaccharides (LOS) are ubiquitous structures found on the outer membrane of gram-negative bacteria. Bacteroides fragilis , is a gram-negative anaerobe commonly inhabiting the human colon. The LOS of this organism is known to trigger a type I interferon response in dendritic cells. However, detailed structural analysis of this LOS has been largely elusive. Using top-down mass spectrometry, we have unraveled the comprehensive fine structure of B. fragilis LOS. Our analysis reveals that this LOS has a poly-galactose-rhamnose-KDO-lipid A architecture, which can be modified by hexuronic acid and ethanolamine via phosphodiester linkages. The lipid moiety typically includes three to five acyl chains of varying length on a glucosamine disaccharide. This investigation lays the groundwork for deeper immunological exploration of B. fragilis LOS and underscores the efficacy of top-down mass spectrometry in characterizing intact LOS/LPS structures and their modifications.
... For instance, endotoxicity is reduced by removal of one phosphate group. Interestingly, it has been shown that lipid A with a reducing terminal phosphate (at the 1 position) was more highly inflammatory than lipid A with a non-reducing terminal phosphate (at the 4' position) (Coats et al., 2011). ...
The primary focus of my PhD work was to develop new tandem mass spectrometry based structural elucidation strategies with the systemic interpretation of fragmentation mass spectra of synthetic and natural lipid A molecules. Since any immunological effect induced by a bacterial lipid A molecule depends on its primary structure, such improved structure elucidation techniques would aid in the search for the treatment of sepsis.
... Lipopolysaccharides (LPS) present on the surface membrane of periodontal pathogen P. gingivalis can cause periodontal tissue destruction, a risk factor for systemic diseases [120]. LPS of P. gingivalis (Pg-LPS) is widely recognized by host defense systems via Toll-like receptor 4 (TLR4) or Toll-like receptor 2 (TLR2) to activate immune response [121,122]. Kajiwara et al. reported that LPS from P. gingivalis caused diabetic renal inflammation, which includes glomerulosclerosis and tubulitis. Overexpression of E-selectin was observed in renal intertubular capillaries, parenchyma, and glomeruli, which led to macrophage infiltration and kidney damaged by Pg-LPS-induced inflammation in diabetes [86]. ...
... However, the research investigating the relationship between periodontal bacteria and selectins in periodontitis-associated diseases is limited, and the findings remain inconclusive. Induce platelet activation and aggregation [115,116] E-selectin CVD Facilitate monocytes adhering to endothelial cells [117,118] LPS is recognized Via TLR4 and TLR2 to mediate the function of endothelium [121,122] Facilitate monocytes and T cells recruiting and adhering to endothelium [126] Promote neovascularization through PI3K-and p38 MAPK-signaling pathways, as well as a NOSrelated pathway [105] Atherosclerosis Activate NOD1, NOD2, and TLR2 expression to regulate the function of endothelium [108,124,125] Diabetes Induce diabetic renal inflammation by infiltrating Mac-1-positive macrophages [86] A. actinomycetemcomitans P-,E-selectin /PSGL-1 ...
Periodontal diseases are predisposing factors to the development of many systemic disorders, which is often initiated via leukocyte infiltration and vascular inflammation. These diseases could significantly affect human health and quality of life. Hence, it is vital to explore effective therapies to prevent disease progression. Periodontitis, which is characterized by gingival bleeding, disruption of the gingival capillary’s integrity, and irreversible destruction of the periodontal supporting bone, appears to be caused by overexpression of selectins in periodontal tissues. Selectins (P-, L-, and E-selectins) are vital members of adhesion molecules regulating inflammatory and immune responses. They are mainly located in platelets, leukocytes, and endothelial cells. Furthermore, selectins are involved in the immunopathogenesis of vascular inflammatory diseases, such as cardiovascular disease, diabetes, cancers, and so on, by mediating leukocyte recruitment, platelet activation, and alteration of endothelial barrier permeability. Therefore, selectins could be new immunotherapeutic targets for periodontal disorders and their associated systemic diseases since they play a crucial role in immune regulation and endothelium dysfunction. However, the research on selectins and their association with periodontal and systemic diseases remains limited. This review aims to discuss the critical roles of selectins in periodontitis and associated systemic disorders and highlights the potential of selectins as therapeutic targets.
... However some strains of D.desulfuricans isolated from the same host have a different lipid A structure with different proinflammatory properties.High levels of lipid A heterogeneity are also present in the genera of the Bacteroidetes phylum, consisting of Bacteroides, Alistipes, Parabacteroides and Prevotella[54].Bacteroides LPS expresses a different lipid A structure compared to the prototypical Proteobacterial lipid A , since different Bacteroides species only possess penta -and tetra acylated species, containing branched fatty acids (15-17 carbon atoms in length), and the sugar backbone is substituted with only one phosphate group[55][56][57]. This lipid A modification contributes to reduced activation of the TLR4/MD-2 LPS receptor[58][59][60][61][62][63][64][65][66]. ...
Lipopolysaccharide (LPS) is for most but not all Gram-negative bacteria an essential component of the outer leaflet of the outer membrane. LPS contributes to the integrity of the outer membrane, which acts as an effective permeability barrier to antimicrobial agents and protects against complement-mediated lysis. In commensal and pathogenic bacteria LPS interacts with pattern recognition receptors (e.g LBP, CD14, TLRs) of the innate immune system and thereby plays an important role in determining the immune response of the host. LPS molecules consist of a membrane-anchoring lipid A moiety and the surface-exposed core oligosaccharide and O-antigen polysaccharide. While the basic lipid A structure is conserved among different bacterial species, there is still a huge variation in its details, such as the number, position and chain length of the fatty acids and the decoration of the glucosamine disaccharide with phosphate, phosphoethanolamine or amino sugars. New evidence has emerged over the last few decades on how this lipid A heterogeneity confers distinct benefits to some bacteria because it allows them to modulate host responses in response to changing host environmental factors. Here we give an overview of what is known about the functional consequences of this lipid A structural heterogeneity. In addition, we also summarize new approaches for lipid A extraction, purification and analysis which have enabled analysis of its heterogeneity.
... Bacteroides LPS expresses a different lipid A structure compared to the prototypical Proteobacterial lipid A, since different Bacteroides species only possess penta-and tetra acylated species, containing branched fatty acids (15-17 carbon atoms in length), and the sugar backbone is substituted with only one phosphate group (Weintraub et al. 1989, Berezow et al. 2009, Vatanen et al. 2016). This lipid A modification contributes to reduced activation of the TLR4/MD-2 LPS receptor (Rietschel et al. 1998, Phillips et al. 2004, Que-Gewirth et al. 2004, Kanistanon et al. 2008, Munford 2008, Cullen and Trent 2010, Coats et al. 2011, Cullen et al. 2011. Broad conservation of the LpxF enzyme across commensal Bacteroidetes is responsible for removing a single lipid A phosphate residue which provides resistance to antimicrobial peptides and increases bacterial resilience in the intestine . ...
... The vaccine is now use for HPV-16 and 18 associated cervical cancers 131 . P. gingivalis has heterogeneous TLR4 activity found to be caused by the ability to shift its LPS structure, specifically the lipid-A moiety, to that of TLR4 antagonist or agonist 132,133 . P. gingivalis can alter its lipid-A structure during changes to environmental conditions such as levels of hemin or temperature, both important features of inflammation activation 134,135 . ...
Mucosal tissues act as a barrier throughout the oral, nasopharyngeal, lung, and intestinal systems, offering first-line protection against potential pathogens. Conventionally, vaccines are applied parenterally to induce serotype-dependent humoral response but fail to drive adequate mucosal immune protection for viral infections such as influenza, HIV, and coronaviruses. Oral mucosa, however, provides a vast immune repertoire against specific microbial pathogens and yet is shaped by an ever-present microbiome community that has co-evolved with the host over thousands of years. Adjuvants targeting mucosal T-cells abundant in oral tissues can promote soluble-IgA (sIgA)-specific protection to confer increased vaccine efficacy. Th17 cells, for example, are at the center of cell-mediated immunity and evidence demonstrates that protection against heterologous pathogen serotypes is achieved with components from the oral microbiome. At the point of entry where pathogens are first encountered, typically the oral or nasal cavity, the mucosal surfaces are layered with bacterial cohabitants that continually shape the host immune profile. Constituents of the oral microbiome including their lipids, outer membrane vesicles, and specific proteins, have been found to modulate the Th17 response in the oral mucosa, playing important roles in vaccine and adjuvant designs. Currently, there are no approved adjuvants for the induction of Th17 protection, and it is critical that this research is included in the preparedness for the current and future pandemics. Here, we discuss the potential of oral commensals, and molecules derived thereof, to induce Th17 activity and provide safer and more predictable options in adjuvant engineering to prevent emerging infectious diseases.
... A few reports suggested that some specific microorganisms (e.g. Porphyromonas and Bacteroides) disturb or inhibit protective signaling normally induced by toll-like receptors (TLR), accompanied by lower levels of IL-8 (Coats et al., 2011;SenGupta et al., 2016). A possible explanation is that lipid A, as a toxic component of LPS, can be expressed in a variety of forms by these pathogens, allowing for evasion of the host's innate immune system and chronic infection (Coats et al., 2011;Paciello et al., 2013;SenGupta et al., 2016). ...
... Porphyromonas and Bacteroides) disturb or inhibit protective signaling normally induced by toll-like receptors (TLR), accompanied by lower levels of IL-8 (Coats et al., 2011;SenGupta et al., 2016). A possible explanation is that lipid A, as a toxic component of LPS, can be expressed in a variety of forms by these pathogens, allowing for evasion of the host's innate immune system and chronic infection (Coats et al., 2011;Paciello et al., 2013;SenGupta et al., 2016). Intriguingly, some potential links between these genera and IL-8 are further supported by our current findings, despite the potential mechanism needing to be further evaluated. ...
Heat stress (HS) can be detrimental to the gut health of swine. Many negative outcomes induced by HS are increasingly recognized as including modulation of intestinal microbiota. In turn, the intestinal microbiota is a unique ecosystem playing a critical role in mediating the host stress response. Therefore, we aimed to characterize gut microbiota of pigs’ exposure to short-term HS, to explore a possible link between the intestinal microbiota and HS-related changes, including serum cytokines, oxidation status, and intestinal epithelial barrier function. Our findings showed that HS led to intestinal morphological and integrity changes (villus height, serum diamine oxidase [DAO], serum D-lactate and the relative expressions of tight junction proteins), reduction of serum cytokines (interleukin [IL]-8, IL-12, interferon-gamma [IFN-γ]), and antioxidant activity (higher glutathione [GSH] and malondialdehyde [MDA] content, and lower superoxide dismutase [SOD]). Also, 16S rRNA sequencing analysis revealed that although there was no difference in microbial α-diversity, some HS-associated composition differences were revealed in the ileum and cecum, which partly led to an imbalance in the production of short-chain fatty acids including propionate acid and valerate acid. Relevance networks revealed that HS-derived changes in bacterial genera and microbial metabolites, such as Chlamydia, Lactobacillus, Succinivibrio, Bifidobacterium, Lachnoclostridium, and propionic acid, were correlated with oxidative stress, intestinal barrier dysfunction, and inflammation in pigs. Collectively, our observations suggest that intestinal damage induced by HS is probably partly related to the gut microbiota dysbiosis, though the underlying mechanism remains to be fully elucidated.
... An unmodified version of this lipid A structure is typically expressed by E. coli and induces a robust inflammatory response as is when in septic shock [32]. Modifications to this basic lipid A structure are observed in alterations to acyl chains or terminal phosphate groups [33]. H. pylori [34], Legionella pneumophila [35], Yersinia pestis [36], and Francisella novicida [37] express under-acylated lipid A moieties, in comparison to the canonical LPS expressed by E. coli, and are poorly recognized by TLR4. ...
Porphyromonas gingivalis (Pg) is a primary oral pathogen in the widespread biofilm-induced “chronic” multi-systems inflammatory disease(s) including Alzheimer’s disease (AD). It is possibly the only second identified unique example of a biological extremophile in the human body. Having a better understanding of the key microbiological and genetic mechanisms of its pathogenesis and disease induction are central to its future diagnosis, treatment, and possible prevention. The published literature around the role of Pg in AD highlights the bacteria’s direct role within the brain to cause disease. The available evidence, although somewhat adopted, does not fully support this as the major process. There are alternative pathogenic/virulence features associated with Pg that have been overlooked and may better explain the pathogenic processes found in the “infection hypothesis” of AD. A better explanation is offered here for the discrepancy in the relatively low amounts of “Pg bacteria” residing in the brain compared to the rather florid amounts and broad distribution of one or more of its major bacterial protein toxins. Related to this, the “Gingipains Hypothesis”, AD-related iron dyshomeostasis, and the early reduced salivary lactoferrin, along with the resurrection of the Cholinergic Hypothesis may now be integrated into one working model. The current paper suggests the highly evolved and developed Type IX secretory cargo system of Pg producing outer membrane vesicles may better explain the observed diseases. Thus it is hoped this paper can provide a unifying model for the sporadic form of AD and guide the direction of research, treatment, and possible prevention.
