Sodium Butyrate Exacerbates Inflammation and Osteoblastic Dysfunction in Various Oral Cell Types Infected with Porphyromonas gingivalis
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Background: Sodium butyrate, a short-chain fatty acid produced by anaerobic bacteria within periodontal pockets, is traditionally regarded as an anti-inflammatory metabolite in the gut. However, its biological functions in the periodontal environment, particularly during Porphyromonas gingivalis infection, remain unclear. This study aimed to elucidate effects of sodium butyrate on inflammatory and bone-regulating responses in various oral cell types. Methods: Immortalized human oral keratinocytes (IHOKs), Terasaki Human Peripheral blood leukemia (THP)-1 macrophages, and osteoblasts (MC3T3-E1) were treated with various sodium-butyrate concentrations, with or without P. gingivalis infection. Cytotoxicity was assessed using MTT assays (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). Inflammatory cytokines (interleukin [IL]-8, IL-22, and IL-1β) were measured using enzyme-linked immunosorbent assay; osteogenic markers (runt-related transcription factor 2 [RUNX2], osteoprotegerin [OPG], and receptor activator of nuclear factor-κB ligand [RANKL]) were assessed using quantitative polymerase chain reaction. Results: Sodium butyrate significantly increased IL-8 (p＜0.05) and IL-22 (p＜0.05) production in IHOKs, with IL-8 further elevated by P. gingivalis (p＜0.05). In THP-1 macrophages, sodium butyrate markedly enhanced IL-1β expression (p＜0.01), especially under P. gingivalis infection (p＜0.05). In MC3T3-E1 cells, sodium butyrate reduced RUNX2 (p＜0.05) and OPG (p＜0.001) mRNA levels and upregulated RANKL (p＜0.05) expression, leading to a substantial elevation in the RANKL/OPG ratio (p＜0.05). These detrimental effects were further aggravated by P. gingivalis (p＜0.05). Conclusion: Sodium butyrate aggravated inflammatory cytokine production in keratinocytes and macrophages while disrupting osteoblast-mediated bone homeostasis by elevating the RANKL/OPG ratio. These findings indicate that butyrate, which accumulates in dysbiotic periodontal pockets, acts as a pathogenic metabolic factor driving immune dysregulation and an imbalance in bone remodeling within periodontal tissues.
Abstract
Background: Sodium butyrate, a short-chain fatty acid produced by anaerobic bacteria within periodontal pockets, is traditionally regarded as an anti-inflammatory metabolite in the gut. However, its biological functions in the periodontal environment, particularly during Porphyromonas gingivalis infection, remain unclear. This study aimed to elucidate effects of sodium butyrate on inflammatory and bone-regulating responses in various oral cell types. Methods: Immortalized human oral keratinocytes (IHOKs), Terasaki Human Peripheral blood leukemia (THP)-1 macrophages, and osteoblasts (MC3T3-E1) were treated with various sodium-butyrate concentrations, with or without P. gingivalis infection. Cytotoxicity was assessed using MTT assays (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). Inflammatory cytokines (interleukin [IL]-8, IL-22, and IL-1β) were measured using enzyme-linked immunosorbent assay; osteogenic markers (runt-related transcription factor 2 [RUNX2], osteoprotegerin [OPG], and receptor activator of nuclear factor-κB ligand [RANKL]) were assessed using quantitative polymerase chain reaction. Results: Sodium butyrate significantly increased IL-8 (p＜0.05) and IL-22 (p＜0.05) production in IHOKs, with IL-8 further elevated by P. gingivalis (p＜0.05). In THP-1 macrophages, sodium butyrate markedly enhanced IL-1β expression (p＜0.01), especially under P. gingivalis infection (p＜0.05). In MC3T3-E1 cells, sodium butyrate reduced RUNX2 (p＜0.05) and OPG (p＜0.001) mRNA levels and upregulated RANKL (p＜0.05) expression, leading to a substantial elevation in the RANKL/OPG ratio (p＜0.05). These detrimental effects were further aggravated by P. gingivalis (p＜0.05). Conclusion: Sodium butyrate aggravated inflammatory cytokine production in keratinocytes and macrophages while disrupting osteoblast-mediated bone homeostasis by elevating the RANKL/OPG ratio. These findings indicate that butyrate, which accumulates in dysbiotic periodontal pockets, acts as a pathogenic metabolic factor driving immune dysregulation and an imbalance in bone remodeling within periodontal tissues.