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Porphyromonas gingivalis and Lactobacillus rhamnosus GG regulate the Th17/Treg balance in colitis via TLR4 and TLR2.

ABSTRACT: Objectives: CD4⁺ T cells are the key to many immune-inflammatory diseases mediated by microbial disorders, especially inflammatory bowel disease (IBD). The purpose of this study was to explore how pathogenic and probiotic bacteria directly affect the T helper (Th)17 and T regulatory (Treg) cell balance among CD4⁺ T cells to regulate inflammation.

Methods: Porphyromonas gingivalis (Pg; ATCC 33277) and Lactobacillus rhamnosus GG (LGG; CICC 6141) were selected as representative pathogenic and probiotic bacteria, respectively. Bacterial extracts were obtained via ultrasonication and ultracentrifugation. Flow cytometry, RT-qPCR, ELISAs, immunofluorescence and a Quantibody cytokine array were used. The dextran sodium sulphate (DSS)-induced colitis model was selected for verification.

Results: The Pg ultrasonicate induced the apoptosis of CD4⁺ T cells and upregulated the expression of the Th17-associated transcription factor RoR?t and the production of the proinflammatory cytokines IL-17 and IL-6, but downregulated the expression of the essential Treg transcription factor Foxp3 and the production of the anti-inflammatory factors TGF-? and IL-10 via the TLR4 pathway. However, LGG extract maintained Th17/Treg homeostasis by decreasing the IL-17⁺ Th17 proportion and increasing the CD25⁺ Foxp3⁺ Treg proportion via the TLR2 pathway. In vivo, Pg-stimulated CD4⁺ T cells aggravated DSS-induced colitis by increasing the Th17/Treg ratio in the colon and lamina propria lymphocytes (LPLs), and Pg + LGG-stimulated CD4⁺ T cells relieved colitis by decreasing the Th17/Treg ratio via the JAK-STAT signalling pathway.

Conclusions: Our findings suggest that pathogenic Pg and probiotic LGG can directly regulate the Th17/Treg balance via different TLRs.

SUBMITTER: Jia L

PROVIDER: S-EPMC7685903 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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<i>Porphyromonas gingivalis</i> and <i>Lactobacillus rhamnosus</i> GG regulate the Th17/Treg balance in colitis via TLR4 and TLR2.

Jia Lu L Wu Ruiqing R Han Nannan N Fu Jingfei J Luo Zhenhua Z Guo Lijia L Su Yingying Y Du Juan J Liu Yi Y

Clinical & translational immunology 20201124 11

<h4>Objectives</h4>CD4<sup>+</sup> T cells are the key to many immune-inflammatory diseases mediated by microbial disorders, especially inflammatory bowel disease (IBD). The purpose of this study was to explore how pathogenic and probiotic bacteria directly affect the T helper (Th)17 and T regulatory (Treg) cell balance among CD4<sup>+</sup> T cells to regulate inflammation.<h4>Methods</h4><i>Porphyromonas gingivalis</i> (Pg; ATCC 33277) and <i>Lactobacillus rhamnosus</i> GG (LGG; CICC 6141) wer ...[more]

PMID: 33282294

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Project description:ObjectivePeriodontitis is a microbe-induced chronic inflammatory disease. Previous exposure of the host to bacteria or their virulence factors leads to refractory responses to further stimuli, which is called tolerance. Porphyromonas gingivalis (P. gingivalis) is one of the most important pathogenic microorganisms associated with periodontitis, and is a potent inducer of pro- and anti-inflammatory cytokines. The aim of this study was to explore the roles and possible mechanisms of tolerance induced by P. gingivalis.MethodsTHP-1-derived macrophages were pretreated with 1x108 colony-forming units/ml P. gingivalis ATCC 33277 or 21 clinical isolates from moderate to severe chronic periodontitis patients (24 h), washed (2 h) and treated with P. gingivalis ATCC 33277 or the same clinical isolates again (24 h). Levels of pro-inflammatory cytokines TNF-α and IL-1β and anti-inflammatory cytokine IL-10 in supernatants were detected by ELISA. Moreover, to identify the possible mechanisms for the changes in cytokine secretion, Toll-like receptor 2 (TLR2) and TLR4 protein expressions were explored in these cells by flow cytometry.ResultsAfter repeated challenge with P. gingivalis ATCC 33277 or clinical isolates, production of TNF-α and IL-1β in macrophages was decreased significantly compared with that following a single stimulation (p<0.05), while only comparable levels of IL-10 were detected in P. gingivalis ATCC 33277 or clinical isolate-tolerized cells (p>0.05). In addition, there was interstrain variability in the ability to induce IL-1β and IL-10 production after repeated P. gingivalis stimulation. However, no significant changes in TLR2 or TLR4 were detected in macrophages that were repeatedly treated with P. gingivalis ATCC 33277 or clinical isolates compared with those stimulated with P. gingivalis only once (p>0.05).ConclusionsRepeated P. gingivalis stimulation triggered tolerance, which might contribute to limiting periodontal inflammation. However, tolerance induced by P. gingivalis might develop independently of TLR2 and TLR4 and be related to molecules in signaling pathways downstream of TLR2 and TLR4.

Project description:BackgroundSalmonella typhimurium (S.T), as an important foodborne bacterial pathogen, can cause diarrhea and gastroenteritis in humans and animals. Numerous studies have confirmed that exopolysaccharides (EPSs) have various biological functions, but the mechanism through which EPSs improve the immunity of animals against the invasion of pathogenic bacteria is unclear. Here, we explored the protective effect of EPSs of Lactobacillus rhamnosus GG (LGG) on the S.T-infected intestine.MethodsMice received adequate food and drinking water for one week before the start of the experiment. After 7 d of prefeeding, 2×108 CFU/mL S.T solution and an equivalent volume of saline (control group) were given orally for 1 d. On the fourth day, the mice were treated with 0.5 mg/mL EPSs, 1.0 mg/mL EPSs, 2.0 mg/mL EPSs, or 2.0 mg/mL penicillin for 7 d. Finally, the body and relative organ weight, histological staining, and the levels of antioxidant enzyme activity and inflammatory cytokines were determined.ResultsThe S.T-infected mice exhibited symptoms of decreased appetite, somnolence, diarrhea and flagging spirit. Treatment with EPSs and penicillin improved the weight loss of the mice, and the high dose of EPSs showed the best therapeutic effect. EPSs significantly ameliorated S.T-induced ileal injury in mice. High-dose EPSs were more effective than penicillin for alleviating ileal oxidative damage induced by S.T. The mRNA levels of inflammatory cytokines in the ileum of mice showed that the regulatory effects of EPSs on inflammatory cytokines were better than those of penicillin. EPSs could inhibit the expression and activation of key proteins of the TLR4/NF-κB/MAPK pathway and thereby suppress the level of S.T-induced ileal inflammation.ConclusionsEPSs attenuate S.T-induced immune responses by inhibiting the expression of key proteins in the TLR4/NF-κB/MAPK signaling pathway. Moreover, EPSs could promote bacterial aggregation into clusters, which may be a potential strategy for reducing the bacterial invasion of intestinal epithelial cells.

Dataset Information

Porphyromonas gingivalis and Lactobacillus rhamnosus GG regulate the Th17/Treg balance in colitis via TLR4 and TLR2.

Publications

<i>Porphyromonas gingivalis</i> and <i>Lactobacillus rhamnosus</i> GG regulate the Th17/Treg balance in colitis via TLR4 and TLR2.

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