Amino Acid D-Alanine Can Help Prevent And Treat COVID-19 Severity

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A new breakthrough study by researchers from the National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN)-Japan and the Osaka University Graduate School of Medicine – Japan has found that supplementation with the amino acid D-Alanine can help prevent and also treat COVID-19 severity.

The study besides finding the critical role that D-Amino acids play in viral infections also found that D-Alanine could also be used as a biomarker for COVID-19 disease severity.

The study findings were published in the peer reviewed journal: Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease (Science Direct By Elsevier)
https://www.sciencedirect.com/science/article/pii/S0925443922002551

This study revealed the two-way functions of d-alanine as a biomarker and as a therapeutic agent for severe viral infection. The blood levels of d-amino acids decreased in mice after developing severe viral infection, and these levels were lower than the normal range of d-amino acids in severe human cases of COVID-19.

Supplementation with d-alanine improved the prognosis of IAV infection and COVID-19 mouse models, while blood levels of d-amino acids were also associated with the treatment effects.

d-Alanine and other d-amino acids are biomarkers that reflect the severity of influenza A virus (IAV) infection and COVID-19, and supplementation with d-alanine reduces the consequences of severe viral infections.

Low d-amino acid levels in blood have rarely been reported. The amounts of d-amino acids are extremely low in human blood by a few percent than that of l-amino acids [8], [25], and the blood levels of d-amino acids further decreased in patients and mice with severe viral infections.

The blood d-alanine level fluctuates with circadian rhythm [26], whereas the blood d-alanine level seen in severe viral infections is much lower than the normal range. In this study, the blood samples were consistently harvested in the morning, and thus, the variations in the levels of d-alanine are derived from the pathological conditions rather than the circadian clock.

The reported mean blood levels of d-alanine in daytime and nighttime were approximately 8 and 1.5 μM in mice, and 0.7 and 1.5 μM in human, respectively [27], [28]. The median blood levels of d-alanine were 15.7 and 0.95 μM for IAV uninfected and infected mice, and 0.93 and 0.40 μM for normal control and COVID-19 patients, respectively.

The low blood level of d-alanine in viral infections likely corresponds to, or is even lower than, its lowest level in the circadian rhythm.

Despite supplementation, it was difficult to maintain the blood d-alanine level during fulminant infection, suggesting the increased consumption. d-alanine may be used for host defense [13] or for the improvement of the systemic condition as indicated by the maintenance of body weight or blood levels of other d-amino acids.

The mechanism of d-alanine in the reduction of viral titers and alleviation of the lung lesions in IAV-infected mice remains elusive. Other d-amino acids, including d-serine, could also have the protective effects in viral infections, and the combinational usage of d-amino acids may be beneficial.

On the other hand, complication of diabetes may worsen the prognosis of COVID-19 [24], potentially through the aberrant metabolism of d-alanine [10], [29]. Further studies will elucidate the mechanisms and effective treatment.

d-Amino acids are natural nutrients present in daily foods or produced from the gut microbiota [13]. In the presence of severe viral infection, the intake of d-amino acids from foods is likely insufficient or deregulated microbiota may not produce sufficient d-amino acids.

d-Alanine is suitable for the supportive care of viral infections, although its protective effect was limited. This may partially be attributable to the difficulty in maintaining its blood level. The dose of d-alanine should be adjusted to avoid its decline in blood level, whereas excessive amounts of d-amino acids could be biphasic [30].

Monitoring the blood d-alanine level helps adjust the dosing of d-alanine and thus may maximize the supplemental effect of d-alanine. Besides d-alanine, the blood levels of other d-amino acids also reflected severity of viral infections even after supplementation with d-alanine.

To monitor the safety, treatment efficacy and activity of infections, the blood d-amino acid levels should be measured upon supplementation of d-alanine.

There are limitations to this study. This study mainly bases preclinical investigations and the effects of d-alanine were tested only in mouse models. The clinical cohort was small and the presence of comorbidity may form a limitation in the interpretation of the results. An ancestral strain of SARS-CoV-2 was used for the COVID-19 model, and the evaluation on new variants of SARS-CoV-2 could be interesting.

The results of this study will provide key information for clinics and public health. Monitoring d-alanine enables the stratification of COVID-19 patients at high risk, rendering the triage of patients and optimization of medical resources. Provision of d-alanine, a basically safe nutrient, as a therapeutic option will facilitate the patient care.

For the next pandemic of viral infections, d-alanine could be a therapeutic candidate for the prompt clinical application. Preclinical and clinical studies will be promoted by using d-alanine as a sensitive biomarker. We believe that the dual function of d-alanine, as a biomarker and a therapeutic option for severe viral infections, will be utilized efficiently in the clinical settings and for the public health.

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