Imagine a bacterium that normally lives peacefully in your oral cavity suddenly becoming a potentially deadly threat in the liver. This is not science fiction. Streptococcus intermedius, a normally harmless commensal microorganism, can damage human cells through toxins it produces itself.
A study published in the Indonesian Journal of Cancer Chemoprevention revealed a surprising finding: two widely known immunosuppressive drugs, cyclosporine A (CsA) and tacrolimus (FK506), were able to completely block the inflammatory activation pathway triggered by the bacterial toxin. The study was led by Prof. drg. Heni Susilowati, M.Kes., Ph.D., PBO, from the Department of Oral Biology, Faculty of Dentistry, Universitas Gadjah Mada, together with researchers from The University of Tokushima Graduate School, Japan.
From the Mouth to the Liver: An Unexpected Journey of a Toxin
S. intermedius is not an unfamiliar bacterium. It normally inhabits the human oral cavity, gastrointestinal tract, and urogenital tract. However, some strains produce a protein called intermedilysin (ILY), a cytolytic toxin that specifically targets human cells and is a major contributor to the bacterium’s virulence.
What makes ILY dangerous is its ability to trigger a surge of calcium inside cells. This increase in intracellular calcium activates the enzyme calcineurin, which then promotes the translocation of the transcription factor NFAT1 (Nuclear Factor of Activated T Cells 1) into the cell nucleus. Once NFAT1 enters the nucleus, it activates genes that regulate immune and inflammatory responses. In the context of bacterial infection, excessive activation of this pathway can instead worsen tissue damage.
In this study, the researchers used human cholangiocarcinoma cells (HuCCT1), a relevant model because S. intermedius is frequently found in cases of liver abscesses and biliary disease. The cells were exposed to various concentrations of ILY, and morphological changes were observed.
The results were striking. Cells exposed to 40 ng/mL of ILY became smaller, lost their cytoplasmic processes, and developed nuclear condensation—hallmarks of cell death. Furthermore, NFAT1 was observed to enter the nucleus in a dose-dependent manner: the higher the ILY concentration, the greater the number of cells showing positive NFAT1 translocation.
Two Old Drugs, One New Finding
This is where the study becomes particularly interesting.
Prof. Heni’s team then tested whether CsA and FK506, two calcineurin inhibitors that have been used for decades in organ transplantation and autoimmune disease management, could stop ILY-induced NFAT1 activation. HuCCT1 cells were pretreated with CsA or FK506 for 30 minutes before exposure to ILY and were subsequently examined using immunofluorescence microscopy.
The results were clear: both drugs completely blocked nuclear translocation of NFAT1. CsA was effective at a concentration of 100 nM, while FK506 worked at 5 ng/mL. Interestingly, FK506 was approximately 16 times more potent than CsA in preventing ILY-induced NFAT1 activation.
“Given the ability of CsA and FK506 to prevent NFAT1 activation in ILY-infected HuCCT1 cells, we suggest that these calcineurin inhibitors may potentially function as potent regulators of inflammatory responses in infections caused by ILY-producing S. intermedius.”
The difference in potency can be explained by their distinct mechanisms of action. FK506 binds to the FKBP protein, forming a stable FK506-FKBP complex, which then inhibits calcineurin. This mechanism also affects activation pathways that are not sensitive to CsA, giving it a broader inhibitory effect.
Why Does This Matter to Dentistry?
This study is not merely a complicated piece of molecular biology conducted in a laboratory. It has real clinical implications, particularly for dentistry.
S. intermedius is a common resident of the oral cavity. Odontogenic infections, or infections originating from the teeth and their supporting tissues, can provide a pathway for this bacterium to enter the systemic circulation. From there, it can reach the liver, brain, and even the central nervous system. Cases of brain and liver abscesses caused by this bacterium have been reported in the medical literature.
The finding that the inflammatory pathway triggered by this oral bacterial toxin can be pharmacologically controlled opens up new possibilities. This study provides a molecular basis for understanding how S. intermedius infections can trigger biliary disease and how the resulting inflammatory response might be moderated.
Of course, the journey from laboratory findings to clinical application is still a long one. Nevertheless, few studies have successfully connected an oral commensal bacterium, the calcium-calcineurin signaling pathway, and the potential for anti-inflammatory therapy within a single, well-defined series of experiments. Prof. Heni and her team have done precisely that, and the results deserve further attention.
Source DOI: http://dx.doi.org/10.14499/indonesianjcanchemoprev1iss2pp67-73
Authors: Anny Anggraini; drg. Achmad Zam Zam Aghasy, M.Kes.
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