Metabolite supplements as a route to enhance clearance of infections

Humans consume various nutrients, such as sugars, lipids, vitamins and proteins, to maintain the proper function of the body. Suboptimal diets, either in the form of malnutrition or overnutrition, affect the host immune system and are associated with various diseases. The importance of host nutrition and metabolism is increasingly acknowledged to be linked with host immunity and the progression of infectious diseases.1, 2 For example, bacterial and viral pathogens can manipulate host metabolism to favour their replication and spread. Indeed, the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has been reported to stimulate the host tricarboxylic acid cycle (TCA cycle), glycolysis and lipid metabolic pathways, turning the infected cell into a virus-producing factory favouring viral replication and propagation. On the other hand, patients infected with SARS-COV-2 may also have altered amino acid pathways, which in turn affect immune cell functions and modulate inflammatory responses.3 In the case of bacterial pathogens, such as Mycobacterium tuberculosis, the causative agent of tuberculosis, host immunity and nutritional metabolic states have also been linked to pathogenicity and treatment outcomes. For example, altered levels of host immune system players such as Zn2+ and vitamin A,4 as well as deficiency in host central catabolic pathways with imbalanced Nicotinamide adenine dinucleotide (NAD(H)) homeostasis,5 have been shown to affect host protection against this pathogen and progression of the disease. Considering this intricate interaction between nutritional metabolism, host immunity and infections, supplementation with certain nutrients as an adjuvant therapy has been studied to optimise host immune defence and to achieve better therapeutic outcomes.2 One such metabolite is α-ketoglutarate (αKG), which is a metabolite in the TCA cycle. Previous studies have reported the beneficial roles of αKG in processes such as cardioprotection6 and ageing,7 suggesting its importance and potential in promoting health. More recently, Shrimali et al.8 reported that αKG inhibits thrombosis and inflammatory responses in SARS-COV-2-infected mice by inhibiting prolyl hydroxylase-2 (PHD2), which in turn suppresses the functions of the serine–threonine kinase Akt, an enzyme with important roles in SARS-COV-2 propagation in its host. In light of this finding, the same group further investigated the effect of αKG supplementation on host immune response against COVID-19 disease progression.9 The authors found that supplementation of octyl-αKG at concentrations of either 0.75 or 1 mM significantly inhibited replication of SARS-COV-2 in vitro in the Vero E6 cell line and in the human monocytic U937 cell line, with downmodulation of pAkt at a similar level to the effect of triciribine, the Akt inhibitor. With knockdown of PHD2, supplementation with octyl-αKG lost its effect on Akt and viral load control, further confirming that the PHD2–pAkt cascade is the target of αKG. In another set of experiments, oral supplementation with αKG up to 4 days after SARS-COV-2 infection downmodulated pAkt and significantly reduced viral load in hamster lungs. Additionally, αKG supplementation reduced accumulation of inflammatory cells and pro-inflammatory cytokines, and there were fewer clots and less apoptotic damage to lung tissues. These effects could be linked to a lower rate of acute respiratory distress syndrome (ARDS) and a higher level of oxygen pressure saturation in infected hamsters and mice, which favours their recovery from infection. Importantly, αKG supplementation did not alter the adaptive immune response in mice and hamsters against SARS-COV-2. Compared with the infected group without supplementation, the infected plus αKG group showed similar levels of immunoglobulin G and antibody responses. The antiviral activity of T lymphocytes is also not altered by αKG supplementation. This suggests that αKG could reduce viral load and prevent inflammation-related damage to lung tissue without interfering with the host adaptive immune system, making it a promising therapeutic candidate for treatment of SARS-COV-2 infections. In summary, the study by Agarwal et al. shows the effect of αKG in modulating the host signalling pathways and immune responses against SARS-COV-2. Its ability to suppress viral replication as well as host inflammatory response illustrates its potential as a nutrient adjuvant for treatment of SARS-COV-2 and reduction of ARDS-induced tissue damage. Considering the development of ARDS and reduced oxygen pressure saturation as common symptoms in bacterial and viral pneumonia and other types of respiratory diseases,10 αKG may also have the potential to reduce these symptoms and protect patients from long-term lung damage due to other infections. This work by Agarwal et al. provides us with new insight into nutrient therapy during the current COVID-19 pandemic as well as against other respiratory diseases and should encourage further studies in this area. The authors would like to thank Dr. Brian Robertson, Imperial College London for careful reading of this commentary. The authors declare they have no conflicts of interest.