Antiseptic mouthwash, the nitrate-nitrite-nitric oxide pathway, and hospital mortality: a hypothesis generating review

Abstract

Meta-analyses and several large cohort studies have demonstrated that antiseptic mouthwashes are associated with mortality in hospitalized patients. A clear pathogenic mechanism is lacking, leading to controversy and a reluctance to abandon or limit the use of antiseptic mouthwashes. Here, we generate the hypothesis that a disturbance in nitric oxide homeostasis by antiseptic mouthwashes may be responsible for the observed increase in mortality risk. Nitric oxide is essential in multiple physiological processes, and a reduction in nitric oxide bioavailability is associated with the occurrence or worsening of pathologies, such as atherosclerosis, diabetes, and sepsis. Oral facultative anaerobic bacteria are essential for the enterosalivary nitrate-nitrite-nitric oxide pathway due to their capacity to reduce nitrate to nitrite. Nitrate originates from dietary sources or from the active uptake by salivary glands of circulating nitrate, which is then excreted in the saliva. Because antiseptic mouthwashes eradicate the oral bacterial flora, this nitric oxide-generating pathway is abolished, which may result in nitric oxide-deficient conditions potentially leading to life-threatening complications such as ischaemic heart events or sepsis.

Keywords: Antiseptic mouthwash; Chlorhexidine; Enterosalivary pathway; Mortality; Nitrate–nitrite–NO pathway; Nitric oxide; Oral care.

Fig. 1

Pathways of nitric oxide generation. In the classic NO synthase-dependent pathway, NO is mainly generated in the endothelium from L-arginine, oxygen, and several cofactors (nicotinamide adenine dinucleotide phosphate, calmodulin, Ca²⁺, tetrahydrobiopterin). NO is then rapidly oxidized to nitrite and nitrate by oxygenated haemoglobin. Circulating nitrate is either eliminated renally or taken up into the salivary glands and excreted in the saliva. In the alternative, non-enzymatic, enterosalivary pathway, nitrate excreted in the saliva, together with dietary-derived nitrate, is partially reduced to nitrite by oral bacteria. This nitrite is ingested into the stomach, where a non-enzymatic reduction to NO occurs. In the intestinal tract, nitrite is systemically absorbed. In the circulation and tissues, nitrite can be further reduced to NO by enzymatic and non-enzymatic pathways. Green boxes indicate physiological effects of NO that are potentially compromised by antiseptic mouthwashes, impeding the enterosalivary pathway. (Figure partially inspired by ref. #40)