Systemic Antibiotic Therapy Reduces Circulating Inflammatory Dendritic Cells and Treg–Th17 Plasticity in Periodontitis

Abstract

Periodontitis (PD) is a common dysbiotic inflammatory disease that leads to local bone deterioration and tooth loss. PD patients experience low-grade bacteremias with oral microbes implicated in the risk of heart disease, cancer, and kidney failure. Although Th17 effectors are vital to fighting infection, functional imbalance of Th17 effectors and regulatory T cells (Tregs) promote inflammatory diseases. In this study, we investigated, in a small pilot randomized clinical trial, whether expansion of inflammatory blood myeloid dendritic cells (DCs) and conversion of Tregs to Th17 cells could be modulated with antibiotics (AB) as part of initial therapy in PD patients. PD patients were randomly assigned to either 7 d of peroral metronidazole/amoxicillin AB treatment or no AB, along with standard care debridement and chlorhexidine mouthwash. 16s ribosomal RNA analysis of keystone pathogen Porphyromonas gingivalis and its consortium members Fusobacterium nucleatum and Streptococcus gordonii confirmed the presence of all three species in the reservoirs (subgingival pockets and blood DCs) of PD patients before treatment. Of the three species, P. gingivalis was reduced in both reservoirs 4-6 wk after therapy. Further, the frequency of CD1C + CCR6 + myeloid DCs and IL-1R1 expression on IL-17A + FOXP3 + CD4 + T cells in PD patients were reduced to healthy control levels. The latter led to decreased IL-1b-stimulated Treg plasticity in PD patients and improvement in clinical measures of PD. Overall, we identified an important, albeit short-term, beneficial role of AB therapy in reducing inflammatory DCs and Treg-Th17 plasticity in humans with PD.

Transient Expression of IL-17A in Foxp3 Fate-Tracked Cells in Porphyromonas gingivalis-Mediated Oral Dysbiosis

“…The microbiome likely plays a role in Treg transdifferentiation, as various Clostridium species of human origin favor the induction of murine colonic Foxp3 + Treg cells co-expressing RORγt (55). At least one study has demonstrated that antibiotic treatment that reduces levels of periodontal pathogens reduces the number of IL-17 + Foxp3 + T cells from peripheral blood of periodontitis patients, again supporting a connection between inflammatory environment, microbiome, and Treg plasticity (87).…”

“…Populations of Foxp3 + RORγt + cells with Th17 potential have been reported in human peripheral blood (86). These double positive cells were found to have significantly lower expression of Foxp3 than classical suppressive Tregs, although other groups have reported that human pro-inflammatory IL-17A + Foxp3 + T cells have significantly higher expression of Foxp3 than classic Tregs (87). Suppressor Foxp3 int.…”

Infectious Triggers in Periodontitis and the Gut in Rheumatoid Arthritis (RA): A Complex Story About Association and Causality

“…However, although the autoantibody profile against citrullinated peptides remained unaffected, it was shown in another uncontrolled study that FMD plus antibiotics could be beneficial for RA in some highly selected patients (154). More mechanistically, no significant changes in the peripheral blood DC or T cell population were observed upon standard nonsurgical local therapy for PD (136), but myeloid DCs (mDCs) with a pro-inflammatory phenotype were reduced upon one week of antibiotic co-therapy (136). These changes in numbers of mDCs with an inflammatory phenotype to the levels of healthy control subjects was paralleled by lower Th17 to Treg ratios (136).…”

“…DCs can be subdivided into predominantly resident DCs and those with migratory potential. For the spreading of RA relevant antigens, the latter appear to be of greater interest (136). With regard to their migratory capacity, Pg.…”

Involvement of Cathepsins in Innate and Adaptive Immune Responses in Periodontitis

“…erefore, the plasticity and cross-talk in T-cell subsets are vital for the regulation of the cellular immune response during periodontitis and therapeutic strategies comprising Tregs inhibiting the immuno-inflammatory response and restoring alveolar bone homeostasis [55]. Indeed, the effect of antibiotic therapy in regulating Treg-17 plasticity in humans with periodontitis is demonstrated [56].…”