Pathogenic role of dental caries-causing bacteria in IgA nephropathy

The kidneys act as a filtering system in the human body that help in the removal of excess fluids and unwanted wastes from the bloodstream. Inflammation of “glomeruli” or the tiny filtering units within the kidneys, also known as “glomerulonephritis,” results in the alteration to the functioning of kidneys. IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis with deposition of the antibody—immunoglobulin A (IgA) in the glomerular region. The underlying disease progression is complex and multifactorial, and 30–40% of patients develop terminal kidney failure. Given the intractable nature of the disease, there is a need to understand specific pathological mechanisms contributing to IgAN, and develop targeted treatments.

Tonsillitis (inflammation or immune response of the tonsils) and bacteria related to dental caries and periodontal disease have been implicated in IgAN pathogenesis. This is likely due to the entry of the pathogen into circulation during invasive dental procedures. Streptococcus mutans is one such bacterial caries-causing pathogen, known to cause bacterial sepsis (extreme response of immune system to an infection leading to death) and infective endocarditis (inflammation of the inner lining of the heart). Moreover, S. mutans expressing a surface collagen-binding protein (Cnm) has been found more frequently in patients with IgAN than in healthy individuals. The precise role in IgAN development is, however, unclear.

A research team led by Dr. Shuhei Naka, including co-first author, Professor Michiyo Matsumoto-Nakano from Department of Pediatric Dentistry, Okayama University, Professor Kazuhiko Nakano from the Department of Pediatric Dentistry, Osaka University, Dr. Taro Misaki from the Seirei Hamamatsu General Hospital, and Assistant Professor Daiki Matsuoka from the Department of Pediatric Dentistry, Okayama University, Japan, were involved in this study.  

The team of researchers sought to uncover the potential virulent role of Cnm from S. mutans in the progression of IgAN disease. “Until now, oral pathogens and kidney disease have been studied independently. We have been able to obtain useful research results over 10 years by establishing a collaboration between clinicians and researchers in oral pathogens and kidney diseases,” says Dr. Naka as a personal motivation behind the study. The team has previously shown that injection of a Cnm-expressing S. mutans strain in rats induces the formation of IgA-like renal lesions following intensive caries and simulation of invasive dental procedures. The potential link between the oral pathogen and renal lesions prompted the researchers to assess the role of the Cnm protein itself.

Explaining the rationale behind their current work published in Communications Biology, on 14 September, 2024, Dr. Naka, the corresponding author of the article, says, “Collagen-binding protein, one of the proteins present on the surface of dental caries, may be associated with the development of IgA nephropathy. Future development of research through medical-dental collaborations may lead to the development of a fundamental treatment for IgA nephropathy.”

They injected a Cnm-positive strain of S. mutans isolated from the oral cavity of a patient with severe IgAN, a Cnm-deficient strain, a complementation strain (with a similar genetic makeup as Cnm positive), and recombinant Cnm protein ([rCnm], a genetically modified variant), intravenously in rats. Next, they went on to assess the clinical features of IgAN, namely proteinuria (presence of protein in urine), hematuria (presence of blood in urine), and renal function in the animals.

Notably, while there was no change in proteinuria and renal function across the experimental animals, hematuria was significantly higher in the Cnm-positive, Cnm complementation groups, and rCnm groups, compared to the negative controls. This finding suggests that Cnm protein or Cnm-expressing S. mutans may induce hematuria in the early stages of IgAN.

Next, the researchers evaluated stained tissue sections of kidneys isolated from the treated animals. Mesangial cell and matrix proliferation (types of cells in the kidney tissue which are altered in IgAN present in the supporting medium known as mesangial matrix) were significantly higher in the Cnm-positive and rCnm groups compared to Cnm-negative groups. Furthermore, tissue sections obtained from Cnm-positive rats showed higher deposition of IgA, complement C3, and IgG (a prominent feature of IgAN) in the mesangial region of the glomerulus. The researchers also noted the presence of Cnm protein in the mesangial region —another hallmark feature of IgAN—in animals injected with rCnm. Given that both Cnm-expressing S. mutans and rCnm induce IgA-like nephropathy, the Cnm protein by itself may have a pathogenic role in the development of IgAN.

The researchers also highlight that the amount of Cnm protein present in one milligram of dental plaque is equivalent to the amount injected in the rat model. Therefore, invasive dental procedures which allow the entry of Cnm-expressing S. mutans can trigger IgAN-like nephropathy. Furthermore, Cnm deposition may independently, or in combination with IgA and/or IgG, contribute to the development of an IgAN.

Talking to us about the long-term implications of these findings, Dr. Naka says “Our findings suggest that the kidneys’ condition may be improved by reducing carious bacteria through a preventive dental approach in patients with IgAN. We intend to further advance this project and obtain results that can be delivered to clinical settings.”

About Okayama University, Japan

As one of the leading universities in Japan, Okayama University aims to create and establish a new paradigm for the sustainable development of the world. Okayama University offers a wide range of academic fields, which become the basis of the integrated graduate schools. This not only allows us to conduct the most advanced and up-to-date research, but also provides an enriching educational experience.

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About Associate Professor Shuhei Naka from Okayama University, Japan

Dr. Shuhei Naka is an Associate Professor at the Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences. He completed his doctoral studies in dentistry from Osaka University. His research interests include non-alcoholic steatohepatitis, understanding the pathogenic roles of cariogenic bacteria in nephropathies, tonsilitis, and community and developmental dentistry. He is an eminent member of several scientific and dental research  societies. He has published over 50 research articles with more than 1,200 citations and 3,400 publication views.