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Single-Cell Transcriptomic Analysis of Salivary Gland Endothelial Cells. 唾液腺内皮细胞的单细胞转录组分析
Pub Date : 2024-03-01 DOI: 10.1177/00220345231219987
A L Altrieth, J Kenney, D A Nelson, E G Suarez, V Gellatly, S Gabunia, M Larsen

Vascular endothelial cells have important tissue-specific functions in fibrosis and regeneration. In the salivary gland, endothelial cells are required for proper development, but their roles within adult glands are largely unknown. To identify ligand-receptor interactions between endothelial cells and other cell types that may be important during fibrosis and regeneration, we used a reversible ductal ligation injury. To induce injury, a clip was applied to the primary ducts for 14 d, and to induce a regenerative response, the clip was subsequently removed for 5 d. To identify endothelial cell-produced factors, we used single-cell RNA sequencing of stromal-enriched cells from adult female submandibular and sublingual salivary glands. Transcriptional profiles of homeostatic salivary gland endothelial cells were compared to endothelial cells of other organs. Salivary gland endothelial cells expressed many unique genes and displayed the highest overlap in gene expression with other fenestrated endothelial cells from the colon, small intestine, and kidney. Comparison of the 14-d ligated, mock-ligated, and 5-d deligated stromal-enriched transcripts and lineage tracing revealed that endothelial cells retain their identity following ligation and recovery from injury. CellChat and NATMI were used to predict changes in ligand-receptor interactions from endothelial cells to other cells in response to ligation and deligation. CellChat and NATMI predicted that after ligation, interactions with fibroblasts, epithelial cells, and glial cells were increased, and following deligation, interactions with pericyte, glia, fibroblasts, and immune cells were increased. Some of the highest-ranked interactions predicted in ligated compared to mock endothelial cells were between glial cells via Col4a2-Cd93 and Jag2-Notch1, as well as epithelial cells via Pecam1-Cd38, while in deligated compared to ligated endothelial cells, the top interactions were between fibroblasts via Ntf3-Ntrk2, glial cells via Hspg2-Itgb1, and pericytes via Jam2-F11r. Understanding salivary gland endothelial cell signaling will inform future endothelial cell-based regenerative therapies.

血管内皮细胞在纤维化和再生过程中具有重要的组织特异性功能。在唾液腺中,内皮细胞是正常发育所必需的,但它们在成人唾液腺中的作用却大多不为人知。为了确定内皮细胞与其他细胞类型之间的配体-受体相互作用在纤维化和再生过程中的重要作用,我们使用了可逆性导管结扎损伤。为了诱导损伤,在原发性导管上放置夹子 14 天,为了诱导再生反应,随后移除夹子 5 天。为了确定内皮细胞产生的因子,我们对成年女性颌下腺和舌下腺的基质富集细胞进行了单细胞 RNA 测序。我们将唾液腺内皮细胞的转录谱与其他器官内皮细胞的转录谱进行了比较。唾液腺内皮细胞表达了许多独特的基因,并与结肠、小肠和肾脏的其他栅栏状内皮细胞在基因表达上有最大的重叠。对 14 天结扎、模拟结扎和 5 天脱落的基质富集转录本进行比较和系谱追踪发现,内皮细胞在结扎和损伤恢复后仍能保持其特性。CellChat 和 NATMI 被用来预测结扎和脱落后内皮细胞与其他细胞之间配体-受体相互作用的变化。根据 CellChat 和 NATMI 预测,在结扎后,与成纤维细胞、上皮细胞和神经胶质细胞的相互作用增加,而在去除结扎后,与包膜细胞、神经胶质细胞、成纤维细胞和免疫细胞的相互作用增加。与模拟内皮细胞相比,在已连接内皮细胞中预测的最高级相互作用是神经胶质细胞之间通过 Col4a2-Cd93 和 Jag2-Notch1 以及上皮细胞之间通过 Pecam1-Cd38 进行的相互作用,而与已连接内皮细胞相比,在已脱连接内皮细胞中预测的最高级相互作用是成纤维细胞之间通过 Ntf3-Ntrk2 进行的相互作用、神经胶质细胞之间通过 Hspg2-Itgb1 进行的相互作用以及周细胞之间通过 Jam2-F11r 进行的相互作用。了解涎腺内皮细胞信号转导将为未来基于内皮细胞的再生疗法提供信息。
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引用次数: 0
Electrolyzed Saline Targets Biofilm Periodontal Pathogens In Vitro. 电解生理盐水体外靶向生物膜牙周病原体
Pub Date : 2024-03-01 Epub Date: 2024-01-07 DOI: 10.1177/00220345231216660
N Zayed, H Munjaković, M K Aktan, K Simoens, K Bernaerts, N Boon, A Braem, F Pamuk, M Saghi, W Van Holm, A Fidler, R Gašperšič, W Teughels

Preventing the development and recurrence of periodontal diseases often includes antimicrobial mouthrinses to control the growth of the periodontal pathogens. Most antimicrobials are nonselective, targeting the symbiotic oral species as well as the dysbiosis-inducing ones. This affects the overall microbial composition and metabolic activity and consequently the host-microbe interactions, which can be detrimental (associated with inflammation) or beneficial (health-associated). Consequently, guiding the antimicrobial effect for modulating the microbial composition to a health-associated one should be considered. For such an approach, this study investigated electrolyzed saline as a novel rinse. Electrolyzed saline was prepared from sterile saline using a portable electrolysis device. Multispecies oral homeostatic and dysbiotic biofilms were grown on hydroxyapatite discs and rinsed daily with electrolyzed saline (EOS). Corresponding positive (NaOCl) and negative (phosphate-buffered saline) controls were included. After 3 rinses, biofilms were analyzed with viability quantitative polymerase chain reaction and scanning electron microscopy. Supernatants of rinsed biofilms were used for metabolic activity analysis (high-performance liquid chromatography) through measuring organic acid content. In addition, human oral keratinocytes (HOKs) were exposed to EOS to test biocompatibility (cytotoxicity and inflammation induction) and also to rinsed biofilms to assess their immunogenicity after rinsing. Rinsing the dysbiotic biofilms with EOS could reduce the counts of the pathobionts (>3 log10 Geq/mm2 reduction) and avert biofilm dysbiosis (≤1% pathobiont abundance), leading to the dominance of commensal species (≥99%), which altered both biofilm metabolism and interleukin 8 (IL-8) induction in HOKs. EOS had no harmful effects on homeostatic biofilms. The scanning electron micrographs confirmed the same. In addition, tested concentrations of EOS did not have any cytotoxic effects and did not induce IL-8 production in HOKs. EOS showed promising results for diverting dysbiosis in in vitro rinsed biofilms and controlling key periopathogens, with no toxic effects on commensal species or human cells. This novel rinsing should be considered for clinical applications.

预防牙周疾病的发生和复发通常包括使用抗菌漱口水来控制牙周病原体的生长。大多数抗菌剂都是非选择性的,既针对口腔共生菌种,也针对引起菌群失调的菌种。这会影响整体微生物组成和代谢活动,进而影响宿主与微生物之间的相互作用,这种相互作用可能是有害的(与炎症有关),也可能是有益的(与健康有关)。因此,应考虑引导抗菌效果,将微生物组成调整为有益健康。为此,本研究将电解生理盐水作为一种新型冲洗剂进行了研究。电解生理盐水是使用便携式电解装置从无菌生理盐水中制备出来的。在羟基磷灰石圆片上培养多菌种口腔同源生物膜和菌群失调生物膜,每天用电解生理盐水(EOS)冲洗。同时还包括相应的阳性(NaOCl)和阴性(磷酸盐缓冲盐水)对照组。冲洗 3 次后,用活力定量聚合酶链反应和扫描电子显微镜分析生物膜。冲洗后的生物膜上清液用于代谢活性分析(高效液相色谱法),测量有机酸含量。此外,还将人类口腔角质细胞(HOKs)暴露于 EOS,以测试其生物相容性(细胞毒性和炎症诱导),并将其暴露于冲洗后的生物膜,以评估其冲洗后的免疫原性。用 EOS 冲洗菌群失调的生物膜可减少病原菌的数量(减少量大于 3 log10 Geq/mm2),并避免生物膜菌群失调(病原菌丰度≤1%),从而使共生菌占优势(≥99%),这改变了 HOK 的生物膜代谢和白细胞介素 8(IL-8)诱导。EOS 对同源生物膜没有有害影响。扫描电子显微照也证实了这一点。此外,测试浓度的 EOS 没有任何细胞毒性作用,也不会诱导 HOK 产生 IL-8。EOS 在转移体外冲洗生物膜中的菌群失调和控制主要围病原体方面显示出良好的效果,而且对共生物种或人类细胞无毒性影响。应考虑将这种新型冲洗方法应用于临床。
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引用次数: 0
P. gingivalis-Induced TLR2 Interactome Analysis Reveals Association with PARP9. 牙龈脓疱病诱导的 TLR2 相互作用组分析显示与 PARP9 有关。
Pub Date : 2024-03-01 Epub Date: 2024-02-12 DOI: 10.1177/00220345231222181
K Pandi, S Angabo, H Makkawi, H Benyamini, S Elgavish, G Nussbaum

Porphyromonas gingivalis is a Gram-negative anaerobic bacterium strongly associated with periodontal disease. Toll-like receptor 2 (TLR2) is indispensable for the host response to P. gingivalis, but P. gingivalis escapes from immune clearance via TLR2-dependent activation of phosphoinositide-3-kinase (PI3K). To probe the TLR2-dependent escape pathway of P. gingivalis, we analyzed the TLR2 interactome induced following P. gingivalis infection or activation by a synthetic lipopeptide TLR2/1 agonist on human macrophages overexpressing TLR2. Interacting proteins were stabilized by cross-linking and then immunoprecipitated and analyzed by mass spectrometry. In total, 792 proteins were recovered and network analysis enabled mapping of the TLR2 interactome at baseline and in response to infection. The P. gingivalis infection-induced TLR2 interactome included the poly (ADP-ribose) polymerase family member mono-ADP-ribosyltransferase protein 9 (PARP9) and additional members of the PARP9 complex (DTX3L and NMI). PARP9 and its complex members are highly upregulated in macrophages exposed to P. gingivalis or to the synthetic TLR2/1 ligand Pam3Cys-Ser-(Lys)4 (PAM). Consistent with its known role in virally induced interferon production, PARP9 knockdown blocked type I interferon (IFN-I) production in response to P. gingivalis and reduced inflammatory cytokine production. We found that P. gingivalis drives signal transducer and activation of transcription (STAT) 1 (S727) phosphorylation through TLR2-PARP9, explaining PARP9's role in the induction of IFN-I downstream of TLR2. Furthermore, PARP9 knockdown reduced PI3K activation by P. gingivalis, leading to improved macrophage bactericidal activity. In summary, PARP9 is a novel TLR2 interacting partner that enables IFN-I induction and P. gingivalis immune escape in macrophages downstream of TLR2 sensing.

牙龈卟啉单胞菌是一种与牙周病密切相关的革兰氏阴性厌氧菌。Toll样受体2(TLR2)是宿主对牙龈卟啉单胞菌做出反应所不可或缺的,但牙龈卟啉单胞菌通过TLR2依赖性激活磷酸肌醇-3-激酶(PI3K)逃避免疫清除。为了探究牙龈脓毒性噬菌体依赖 TLR2 的逃逸途径,我们分析了牙龈脓毒性噬菌体感染或在过表达 TLR2 的人巨噬细胞上被合成脂肽 TLR2/1 激动剂激活后诱导的 TLR2 相互作用组。通过交联稳定相互作用蛋白,然后进行免疫沉淀和质谱分析。共回收了 792 个蛋白质,并通过网络分析绘制出了基线和感染时 TLR2 相互作用组的图谱。牙龈球菌感染诱导的 TLR2 相互作用组包括聚(ADP-核糖)聚合酶家族成员单-ADP-核糖基转移酶蛋白 9(PARP9)和 PARP9 复合物的其他成员(DTX3L 和 NMI)。PARP9 及其复合体成员在暴露于牙龈脓疱病菌或合成 TLR2/1 配体 Pam3Cys-Ser-(Lys)4 (PAM) 的巨噬细胞中高度上调。与已知的 PARP9 在病毒诱导的干扰素产生中的作用相一致,PARP9 基因敲除会阻止 I 型干扰素(IFN-I)在牙龈脓疱病中的产生,并减少炎性细胞因子的产生。我们发现牙龈脓疱疮通过 TLR2-PARP9 驱动信号转导和激活转录(STAT)1 (S727) 磷酸化,这解释了 PARP9 在 TLR2 下游诱导 IFN-I 中的作用。此外,PARP9 的敲除减少了牙龈脓毒性杆菌对 PI3K 的激活,从而提高了巨噬细胞的杀菌活性。总之,PARP9 是一种新型的 TLR2 相互作用伙伴,它能在 TLR2 传感下游诱导 IFN-I 并使牙龈脓疱噬菌体免疫逃逸。
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引用次数: 0
Gli1+ Periodontal Mesenchymal Stem Cells in Periodontitis. 牙周炎中的 Gli1+ 牙周间充质干细胞
Pub Date : 2024-03-01 Epub Date: 2024-01-29 DOI: 10.1177/00220345231220915
Y Deng, Q Li, K K H Svoboda, L A Opperman, L B Ruest, X Liu

Periodontal mesenchymal stem cells (MSCs) play a crucial role in maintaining periodontium homeostasis and in tissue repair. However, little is known about how periodontal MSCs in vivo respond under periodontal disease conditions, posing a challenge for periodontium tissue regeneration. In this study, Gli1 was used as a periodontal MSC marker and combined with a Gli1-cre ERT2 mouse model for lineage tracing to investigate periodontal MSC fate in an induced periodontitis model. Our findings show significant changes in the number and contribution of Gli1+ MSCs within the inflamed periodontium. The number of Gli1+ MSCs that contributed to periodontal ligament homeostasis decreased in the periodontitis-induced teeth. While the proliferation of Gli1+ MSCs had no significant difference between the periodontitis and the control groups, more Gli1+ MSCs underwent apoptosis in diseased teeth. In addition, the number of Gli1+ MSCs for osteogenic differentiation decreased during the progression of periodontitis. Following tooth extraction, the contribution of Gli1+ MSCs to the tooth socket repair was significantly reduced in the periodontitis-induced teeth. Collectively, these findings indicate that the function of Gli1+ MSCs in periodontitis was compromised, including reduced contribution to periodontium homeostasis and impaired injury response.

牙周间充质干细胞(MSCs)在维持牙周稳态和组织修复方面发挥着至关重要的作用。然而,人们对牙周间充质干细胞在牙周疾病条件下的体内反应知之甚少,这给牙周组织再生带来了挑战。在这项研究中,Gli1被用作牙周间充质干细胞的标记物,并结合Gli1-cre ERT2小鼠模型进行系谱追踪,以研究诱导性牙周炎模型中牙周间充质干细胞的命运。我们的研究结果表明,在发炎的牙周中,Gli1+间充质干细胞的数量和贡献率发生了重大变化。在牙周炎诱导的牙齿中,促进牙周韧带平衡的 Gli1+ 间充质干细胞数量减少。虽然 Gli1+ 间充质干细胞的增殖在牙周炎组和对照组之间没有显著差异,但在病变牙中有更多的 Gli1+ 间充质干细胞发生凋亡。此外,随着牙周炎的发展,用于成骨分化的 Gli1+ 间充质干细胞数量减少。拔牙后,Gli1+间充质干细胞对牙周炎引起的牙槽骨修复的贡献明显减少。总之,这些研究结果表明,Gli1+间充质干细胞在牙周炎中的功能受到损害,包括对牙周稳态的贡献减少和损伤反应受损。
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引用次数: 0
Casp11 Deficiency Alters Subgingival Microbiota and Attenuates Periodontitis. Casp11 缺乏会改变龈下微生物群并减轻牙周炎。
Pub Date : 2024-03-01 Epub Date: 2024-01-10 DOI: 10.1177/00220345231221712
S L Fu, Y Y Qian, A N Dai, H Y Li, X H Jin, W T He, S Kang, P H Ding

Periodontitis (PD) is the primary cause of tooth loss in adults. Porphyromonas gingivalis (P.g), a keystone pathogen, has been identified as a crucial contributor to this process. Pyroptosis activation in PD is acknowledged, with accumulating evidence underscoring the crucial role of Caspase-11 (described as Caspase-4/5 in humans)-mediated noncanonical pyroptosis. However, the mechanism behind its impact on PD remains unclear. In this study, we delved into the interplay between the Caspase-11-mediated noncanonical pyroptosis, subgingival microbiota alteration, and macrophage polarization. Clinical samples from PD patients revealed heightened expression of Caspase-4, gasdermin-D, and their active fragments, pointing to the activation of the noncanonical pyroptosis. Single-cell sequencing analysis linked Caspase-4 with gingival macrophages, emphasizing their involvement in PD. In vitro cell experiments confirmed that P.g-induced pyroptosis was activated in macrophages, with Casp11 deficiency attenuating these effects. In an experimental PD mouse model, Casp11 deficiency led to an alteration in subgingival microbiota composition and reduced alveolar bone resorption. Casp11-/- mice cohousing with wild-type mice confirmed the alteration of the subgingival microbiota and aggravated the alveolar bone resorption. Notably, Casp11 deficiency led to decreased M1-polarized macrophages, corresponding with reduced alveolar bone resorption, uncovering a connection between subgingival microbiota alteration, macrophage M1 polarization, and alveolar bone resorption. Taken together, we showed that Caspase-11 fulfilled a crucial role in the noncanonical pyroptosis in PD, potentially influencing the subgingival microbiota and linking to M1 polarization, which was associated with alveolar bone resorption. These findings underscored the pivotal role of the Caspase-11-mediated noncanonical pyroptosis in PD pathogenesis and may provide critical insights into potential therapeutic avenues for mitigating PD.

牙周炎(PD)是成年人牙齿脱落的主要原因。牙龈卟啉单胞菌(P.g)是一种关键的病原体,已被确定为这一过程的关键因素。人们已认识到牙周病中的裂解酶活化,不断积累的证据强调了 Caspase-11(在人类中被描述为 Caspase-4/5)介导的非典型裂解酶的关键作用。然而,其对帕金森病的影响机制仍不清楚。在本研究中,我们深入研究了 Caspase-11 介导的非典型性热脓毒症、龈下微生物群改变和巨噬细胞极化之间的相互作用。PD患者的临床样本显示,Caspase-4、gasdermin-D及其活性片段的表达增高,这表明非典型脓毒症被激活。单细胞测序分析将Caspase-4与牙龈巨噬细胞联系在一起,强调了它们在白血病中的参与。体外细胞实验证实,P.g诱导的热噬在巨噬细胞中被激活,而Casp11的缺乏会减弱这些效应。在实验性骨髓增生性疾病小鼠模型中,缺乏 Casp11 会导致龈下微生物群组成的改变,并减少牙槽骨的吸收。Casp11-/-小鼠与野生型小鼠同群饲养证实了龈下微生物群的改变,并加剧了牙槽骨的吸收。值得注意的是,Casp11缺陷导致M1极化巨噬细胞减少,与牙槽骨吸收减少相对应,揭示了龈下微生物群改变、巨噬细胞M1极化和牙槽骨吸收之间的联系。总之,我们的研究表明,Caspase-11在肺结核非典型性热蛋白沉积中起着关键作用,可能影响龈下微生物群,并与M1极化有关,而M1极化与牙槽骨吸收有关。这些发现强调了Caspase-11介导的非典型热脓毒症在脓疱病发病机制中的关键作用,并可能为缓解脓疱病的潜在治疗途径提供重要见解。
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引用次数: 0
Cannabidiol as an Alternative Analgesic for Acute Dental Pain. 大麻二酚作为急性牙痛的替代镇痛药。
Pub Date : 2024-03-01 Epub Date: 2023-11-01 DOI: 10.1177/00220345231200814
V Chrepa, S Villasenor, A Mauney, G Kotsakis, L Macpherson

Odontogenic pain can be debilitating, and nonopioid analgesic options are limited. This randomized placebo-controlled clinical trial aimed to assess the effectiveness and safety of cannabidiol (CBD) as an analgesic for patients with emergency acute dental pain. Sixty-one patients with moderate to severe toothache were randomized into 3 groups: CBD10 (CBD 10 mg/kg), CBD20 (CBD 20 mg/kg), and placebo. We administered a single dose of respective oral solution and monitored the subjects for 3 h. The primary outcome measure was the numerical pain differences using a visual analog scale (VAS) from baseline within and among the groups. Secondary outcome measures included ordinal pain intensity differences, the onset of significant pain relief, maximum pain relief, changes in bite force within and among the groups, psychoactive effects, mood changes, and other adverse events. Both CBD groups resulted in significant VAS pain reduction compared to their baseline and the placebo group, with a maximum median VAS pain reduction of 73% from baseline pain at the 180-min time point (P < 0.05). CBD20 experienced a faster onset of significant pain relief than CBD10 (15 versus 30 min after drug administration), and both groups reached maximum pain relief at 180-min. Number needed to treat was 3.1 for CBD10 and 2.4 for CBD20. Intragroup comparisons showed a significant increase in bite forces in both CBD groups (P < 0.05) but not in the placebo group (P > 0.05). CBD20 resulted in a significant difference in mean percent bite force change in the 90- and 180-min time points compared to the placebo group (P < 0.05). Compared to placebo, sedation, diarrhea, and abdominal pain were significantly associated with the CBD groups (P < 0.05). There were no other significant psychoactive or mood change effects. This randomized trial provides the first clinical evidence that oral CBD can be an effective and safe analgesic for dental pain.

牙源性疼痛可能会使人衰弱,非鸦片类镇痛的选择有限。这项随机安慰剂对照临床试验旨在评估大麻二酚(CBD)作为紧急急性牙痛患者止痛药的有效性和安全性。61名中度至重度牙痛患者被随机分为3组:CBD10(CBD 10 mg/kg)、CBD20(CBD 20 mg/kg)和安慰剂。我们分别给予单剂量口服溶液,并对受试者进行3小时的监测。主要的结果测量是使用视觉模拟量表(VAS)从基线开始测量各组内部和组之间的疼痛数值差异。次要结果测量包括顺序疼痛强度差异、显著疼痛缓解的开始、最大疼痛缓解、组内和组间咬合力的变化、精神活性影响、情绪变化和其他不良事件。与基线和安慰剂组相比,两个CBD组的VAS疼痛显著减轻,在180分钟的时间点,VAS疼痛的最大中位数从基线疼痛减轻了73%(P<0.05)。CBD20的显著疼痛缓解速度比CBD10更快(给药后15分钟和30分钟),两组在180分钟时都达到了最大疼痛缓解。CBD10和CBD20需要治疗的数量分别为3.1和2.4。组内比较显示,两个CBD组的咬合力显著增加(P<0.05),但安慰剂组没有(P>0.05)。与安慰剂组相比,CBD20导致90和180分钟时间点的平均咬合力变化百分比显著差异(P<0.05),腹痛与CBD组显著相关(P<0.05)。没有其他显著的精神活动或情绪变化影响。这项随机试验首次提供了临床证据,证明口服CBD是一种有效、安全的牙痛镇痛药。
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引用次数: 0
Cannabidiol for Toothache: Ups, Downs, and Regulatory Considerations. 治疗牙痛的大麻二酚:起伏与监管考虑。
Pub Date : 2024-03-01 Epub Date: 2024-02-12 DOI: 10.1177/00220345231223691
K N Theken, E V Hersh
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引用次数: 0
Impact of Periodontitis on the Leakage of Oral Bacteria to the Gut. 牙周炎对口腔细菌渗入肠道的影响
Pub Date : 2024-03-01 Epub Date: 2024-01-09 DOI: 10.1177/00220345231221709
E Buetas, M Jordán-López, A López-Roldán, A Mira, M Carda-Diéguez

Colorectal cancer (CRC) and periodontitis have recently been related due to the higher incidence of CRC in periodontal patients and the involvement of periodontal pathogens in carcinogenesis, suggesting that leakage from the oral cavity to the gut occurs. However, the magnitude of this pass-through in healthy individuals is controversial, and the effect that periodontitis could play in it is understudied. To evaluate the rate of bacterial leakage from the oral cavity to the gut, we analyzed the microbial composition of saliva, subgingival plaque, and fecal samples in healthy individuals without gastrointestinal disorders, including 20 periodontitis patients and 20 oral healthy controls, using PacBio full-length 16S rRNA gene sequencing. As expected, we observed a higher abundance of periodontal pathogens in the subgingival plaque and saliva of periodontal patients. In contrast, no significant differences were found between the fecal samples of both groups, implying that gut samples from periodontal patients were not enriched in periodontal pathogens. Fusobacterium nucleatum, a biomarker of CRC, was not found in the fecal samples of any participant. Our study does show a small leakage of some oral bacteria (mainly streptococci) to the gut, regardless of periodontal health status. Future studies should test whether other host factors and/or the preexistence of a gut disorder must be present in addition to periodontitis to promote the colonization of the gut by oral pathogens. The absence of periodontal pathogens in feces supports the idea that these bacteria could be used as biomarkers of intestinal disorders, including CRC.

最近,大肠癌(CRC)和牙周炎被联系起来,因为牙周病患者的大肠癌发病率较高,而且牙周病原体也参与了致癌过程。然而,健康人的这种渗透程度还存在争议,牙周炎在其中可能发挥的作用也未得到充分研究。为了评估细菌从口腔渗漏到肠道的速度,我们使用 PacBio 全长 16S rRNA 基因测序分析了没有胃肠道疾病的健康人(包括 20 名牙周炎患者和 20 名口腔健康对照组)唾液、龈下牙菌斑和粪便样本中的微生物组成。不出所料,我们在牙周炎患者的龈下牙菌斑和唾液中观察到了更多的牙周病原体。相比之下,两组患者的粪便样本没有发现明显差异,这意味着牙周病患者的肠道样本中并没有富集牙周病原体。在所有参与者的粪便样本中都没有发现作为 CRC 生物标志物的核酸镰刀菌。我们的研究确实表明,无论牙周健康状况如何,一些口腔细菌(主要是链球菌)会少量渗入肠道。未来的研究应该检验,除了牙周炎之外,是否还必须存在其他宿主因素和/或预先存在肠道疾病,才能促进口腔病原体在肠道的定植。粪便中没有牙周病原体支持了这样一种观点,即这些细菌可用作肠道疾病(包括 CRC)的生物标志物。
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引用次数: 0
Lacticaseibacillus rhamnosus GG Improves Periodontal Bone Repair via Gut-Blood Axis in Hyperlipidemia. 鼠李糖乳杆菌 GG 通过肠道-血液轴改善高脂血症患者的牙周骨修复
Pub Date : 2024-03-01 Epub Date: 2024-01-10 DOI: 10.1177/00220345231217402
Y Huang, R Ge, J Qian, J Lu, D Qiao, R Chen, H Jiang, D Cui, T Zhang, N Wang, S He, M Wang, F Yan

Periodontal bone regeneration remains a clinical challenge, and hyperlipidemia can aggravate alveolar bone resorption. Probiotics have recently been reported to improve bone mass. We aimed to determine the role of Lacticaseibacillus rhamnosus GG (LGG) in periodontal bone regeneration improvement within the context of periodontitis with hyperlipidemia. A Sprague Dawley rat model for periodontitis, hyperlipidemia, and periodontal fenestration defect was constructed (n = 36) and administered LGG gavage for 6 wk (the rats were subsequently sacrificed). Fecal microbiota from donor rats 3 wk after LGG gavage was transplanted into recipient rats to evaluate the role of LGG-modulated gut microbiota in periodontal bone regeneration. Regenerated bone mass was detected using micro-computerized tomography and hematoxylin and eosin stain. Gut microbiota was analyzed using 16S ribosomal RNA sequencing. Serum metabolites were detected by liquid chromatography-mass spectrometry (6 wk after LGG gavage). The pro-osteogenic effects of screened serum metabolite were verified in vitro on bone marrow mesenchymal stem cells (BMMSCs). We found that the bone mineral density, bone volume (BV), trabecular bone volume fraction (BV/TV), and trabecular thickness of the regenerated periodontal bone increased after LGG gavage (P < 0.05) but had little effect on oral flora. After LGG gavage, Staphylococcus, Corynebacterium, and Collinsella in the gut of donors were significantly changed, and these differences were maintained in recipients, who also showed increased trabecular thickness of the regenerated periodontal bone (P < 0.05). These key genera were correlated with BV/TV and BV (P < 0.05). In addition, LGG gavage significantly regulated bone-related blood metabolites, of which selenomethionine promoted BMMSC osteogenesis. Notably, selenomethionine was associated with key gut genera (P < 0.05). Collectively, LGG improved periodontal bone regeneration in the context of periodontitis with hyperlipidemia by modulating gut microbiota and increasing pro-osteogenic metabolites in the blood. These results reveal new insights into the use of probiotics to promote periodontal bone regeneration via the gut-blood-bone axis.

牙周骨再生仍是一项临床挑战,而高脂血症会加剧牙槽骨吸收。最近有报道称益生菌可改善骨量。我们旨在确定鼠李糖乳杆菌 GG(LGG)在牙周炎合并高脂血症的情况下对改善牙周骨再生的作用。构建了一个具有牙周炎、高脂血症和牙周瘘管缺损的 Sprague Dawley 大鼠模型(n = 36),给大鼠灌胃 LGG 6 周(随后大鼠被处死)。将供体大鼠灌胃 LGG 3 周后的粪便微生物群移植到受体大鼠体内,以评估 LGG 调节的肠道微生物群在牙周骨再生中的作用。使用微型计算机断层扫描和苏木精及伊红染色检测再生骨量。使用 16S 核糖体 RNA 测序分析肠道微生物群。采用液相色谱-质谱法检测血清代谢物(灌胃 LGG 6 周后)。筛选出的血清代谢物对骨髓间充质干细胞(BMMSCs)的促成骨作用在体外得到了验证。我们发现,灌胃 LGG 后,再生牙周骨的骨矿密度、骨量(BV)、骨小梁体积分数(BV/TV)和骨小梁厚度均有所增加(P < 0.05),但对口腔菌群的影响很小。灌胃 LGG 后,供体肠道中的葡萄球菌、棒状杆菌和柯林斯菌发生了显著变化,这些差异在受体中保持不变,受体再生牙周骨小梁厚度也有所增加(P < 0.05)。这些关键菌属与 BV/TV 和 BV 相关(P < 0.05)。此外,灌胃 LGG 能显著调节骨相关血液代谢物,其中硒蛋氨酸能促进 BMMSC 骨生成。值得注意的是,硒蛋氨酸与主要肠道菌属有关(P < 0.05)。总之,在牙周炎合并高脂血症的情况下,LGG通过调节肠道微生物群和增加血液中的促骨生成代谢物改善了牙周骨再生。这些结果揭示了使用益生菌通过肠道-血液-骨骼轴促进牙周骨骼再生的新见解。
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引用次数: 0
Sjögren's Disease and Oral Health: A Genetic Instrumental Variable Analysis. 斯约格伦病与口腔健康:遗传工具变量分析》。
Pub Date : 2024-03-01 Epub Date: 2024-01-29 DOI: 10.1177/00220345231218903
S L Reckelkamm, Z Alayash, B Holtfreter, M Nolde, S E Baumeister

Epidemiological studies have consistently shown that Sjögren's disease (SjD) increases the risk of dental caries. Despite similar evidence indicating an elevated risk of periodontitis, SjD remains a disputed risk factor for this disease. The risk of bias in observational research is a major impediment to confirming this link. Within an instrumental variable framework, genetic variants associated with a risk factor can be used to proxy its effect on an outcome while avoiding common sources of observational study bias. In this study, we leveraged an instrumental variable approach to investigate whether SjD affects the risk of caries and periodontitis. A total of 57 genetic variants strongly associated with SjD were identified from a genome-wide association study of 2,247 European descent cases and 332,115 controls. We tested for associations of these genetic instruments with caries (measured as the number of decayed, missing, and filled surfaces in 26,792 individuals) and periodontitis (17,353 clinical periodontitis cases and 28,210 European controls). Several sensitivity analyses were used to further validate the primary inverse variance weighted (IVW) estimate. IVW analysis revealed an adverse effect of SjD on caries (β = 0.039, P = 6.3e-16) and periodontitis (odds ratio = 1.033, P = 2.3e-05). Sensitivity analyses, conducted to assess the robustness to potential violations of instrumental variable assumptions, further support these findings. Our results showed that SjD has a detrimental effect on caries and also suggest that SjD promotes periodontitis.

流行病学研究一致表明,斯约格伦病(SjD)会增加龋齿的风险。尽管有类似的证据表明牙周炎的风险升高,但 SjD 仍然是一个有争议的风险因素。观察性研究中的偏倚风险是证实这种联系的主要障碍。在工具变量框架内,与风险因素相关的遗传变异可用于替代风险因素对结果的影响,同时避免观察性研究中常见的偏倚来源。在本研究中,我们利用工具变量方法研究了 SjD 是否会影响龋齿和牙周炎的风险。在对 2,247 例欧洲血统病例和 332,115 例对照进行的全基因组关联研究中,共发现了 57 个与 SjD 密切相关的遗传变异。我们检测了这些基因工具与龋齿(以 26,792 人的蛀蚀、缺失和填充表面的数量来衡量)和牙周炎(17,353 例临床牙周炎病例和 28,210 例欧洲对照)之间的关联。为了进一步验证主要的逆方差加权(IVW)估计值,我们进行了多项敏感性分析。IVW 分析显示,SjD 对龋齿(β = 0.039,P = 6.3e-16)和牙周炎(几率比 = 1.033,P = 2.3e-05)有不利影响。为评估可能违反工具变量假设的稳健性而进行的敏感性分析进一步支持了这些发现。我们的研究结果表明,SjD 对龋病有不利影响,同时也表明 SjD 会促进牙周炎。
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引用次数: 0
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Journal of dental research
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