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 RoRγt 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‐β 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.

Probiotic Lactobacilli Isolated from Kefir Promote Down-Regulation of Inflammatory Lamina Propria T Cells from Patients with Active IBD

“…Long term Treg cultures, like the ones performed in this work, have been shown to lose FOXP3 signaling upon repeated stimulation cycles (Hoffmann et al, 2009). In mice, in vitro incubation of CD4 + T cells with sonicated extracts of Lactobacillus rhamnosus GG diminished IL-17 secretion by these cells and increased FOXP3 and IL-10 secretion via TLR2 mechanism, clearly showing the plasticity induced by the probiotic (Jia et al, 2020). Our results could be showing the functional plasticity of human lamina propria effector T cells in response to the probiotic or its metabolites, which may induce FOXP3 induction.…”

Lactobacillus rhamnosus GG Orchestrates an Antitumor Immune Response

“…15 In addition, other studies that investigated the influence of Lactobacillus rhamnosus GG (LGG) on gut health and disease have reported that LGG and other lactobacilli promote an anti-inflammatory response in the intestine by regulating interleukin (IL)10 levels and promoting regulatory T-cell activity. [17][18][19] At first, these reports seemed contradictory because increasing immunotherapy response rates would imply proinflammatory responses and modulating regulatory T cells would suggest anti-inflammatory responses. However, LGG also was reported to modulate the immune landscape in a proinflammatory manner, including increased M1 macrophage polarization, increased antibody production, modulation of dendritic cell activity, and reducing viral burden during influenza infections.…”

“…We propose that these The data reported here contrast with some published reports on immune response to lactobacilli, but importantly are consistent with several published data investigating the immunomodulatory activity of LGG. [17][18][19][20][21][22][23]41 Previous reports on the anti-inflammatory influences of LGG showed that LGG expanded regulatory T-cell populations in the gut and in the bone marrow. 17 In that report, it was shown that LGG induced anti-inflammatory mechanisms via generation of the short-chain fatty acid butyrate.…”

Co-pathogens in Periodontitis and Inflammatory Bowel Disease

“…Mice who were orally administered P. gingivalis exhibited increased levels of amino acid metabolism, including biosynthesis of phenylalanine, glutamine, tyrosine, and tryptophan in the gut and serum, implying that oral administration of P. gingivalis induced alterations of the gut microbiota composition and metabolites ( 20 ). Jia et al ( 36 ) found that P. gingivalis upregulated the Th17-associated transcription factor, RoRγt, and increased the IL-17 and IL-6 levels. Conversely, P. gingivalis downregulates the expression of Treg transcription factor Foxp3, TGF-β, and IL-10 via the TLR4 pathway.…”

“…Conversely, P. gingivalis downregulates the expression of Treg transcription factor Foxp3, TGF-β, and IL-10 via the TLR4 pathway. These authors revealed the relationship between P. gingivalis and IBD through a dextran sodium sulfate (DSS)-induced IBD mouse model in which P. gingivalis activated CD4+ T cells and exacerbated colitis by upregulating the Th17/Treg ratio via the JAK-STAT signaling pathway ( 36 ). Tsuzuno et al ( 37 ) found a significant exacerbation of colitis in DSS-induced mice administered P. gingivalis .…”