Nutritional Interventions for COVID-19: A Role for Carnosine?

As COVID-19 continues to take an enormous toll on global health, the effort to find effective preventive and treatment strategies has been unparalleled in recent history [...].

without initiating an excessive inflammatory response. This excessive response, known as a cytokine storm, is central to many of the most damaging and potentially life-threatening consequences of COVID-19 [13]. This cytokine storm is characterized by a significant upregulation of inflammatory cytokines, notably interleukin (IL)-1, IL-6, and tumor necrosis factor alpha, as well as being associated with a high neutrophil to lymphocyte ratio [13]. Carnosine has been demonstrated to ameliorate these markers of immune hyperactivity in models of lipopolysaccharide and bleomycin-induced lung injury [14,15], indicating that it may prevent the excessive immune response in patients with COVID-19. This is likely to occur through its anti-inflammatory and anti-oxidant actions [16], as COVID-19 patients have been shown to be under significant inflammation and oxidative stress, which has been suggested to influence the hyperinflammatory response [17]. The cytokine storm of COVID-19 can also lead to acute respiratory distress syndrome (ARDS). Patients with ARDS due to COVID-19 have a higher mortality rate than those without and are commonly not responsive to ventilation and other supportive treatments [18]. Carnosine has been shown to protect against lung injury associated with ARDS, through its powerful antioxidant effects, reducing reactive oxygen species -mediated toxicity to the lung cells in animal models of lipopolysaccharide-induced pulmonary injury [14] and H9N2 swine influenza [9]. The combined anti-inflammatory and anti-oxidative effects of carnosine make it particularly suited to be considered as supportive treatment in patients with COVID-19. While carnosine supplementation may have a beneficial impact alone, there is also potential for its use alongside other nutritional interventions in patients with COVID-19. Several other nutrients have been investigated for use in patients infected with COVID-19, with potentially synergistic immune effects. Vitamins D, C, and B are all known to be immunomodulatory, and have been suggested to have potential in dampening the aggressive immune response and cytokine storm associated with COVID-19 [3,4]. Other trace minerals such as zinc and selenium, as well as omega-3 fatty acids, have also been shown to have some benefits which may improve the outcomes of patients with COVID-19, improving outcomes in respiratory infection, which has led many to recommend their use [29]. Interestingly, others have recommended pre-and pro-biotic interventions, as they also improve respiratory symptoms [30]. A "multi-nutrient" intervention, consisting of carnosine, alongside these additional immune-enhancing vitamins and minerals, could be used to enhance patient outcomes.
While research into these potential effects is preliminary, the role of carnosine in patients with COVID-19 is promising and therefore there is a need for trials to test the effi- While the anti-inflammatory and anti-oxidant properties of carnosine are well established, there are some other potential avenues by which it may aid in the treatment of COVID-19. While originally thought to be a primary respiratory pathology, it is now known that COVID-19 is a system-wide disease, leading to multi-organ failure, and cerebrovascular events. This is at least partially due to the increase in coagulation associated with the infection, which leads to microvascular damage, and stroke [19]. It has been proposed that the anti-oxidant and anti-glycating properties of carnosine may provide protection from this hypercoagulability, particularly in patients with altered glucose metabolism, who are known to have increased COVID-19 morbidity and mortality [16,17]. Others have suggested that carnosine may in fact prevent binding and internalization of SARS-CoV-2, potentially reducing both the incidence and severity of disease [20]. The SARS-CoV-2 spike protein has high binding affinity for angiotensin-converting enzyme 2 (ACE2), using this as a means of attachment and entry to the host cell [21]. In silico modelling of known pharmaceutical and therapeutic compounds revealed that carnosine is also able to bind to ACE2 as an inhibitor, potentially competing with the SARS-CoV-2 spike protein and reducing effective entry to host cells [20].
A new and concerning development in the management of patients with COVID-19 is the newly understood syndrome of "long COVID" in which symptoms develop and evolve over weeks and months following the infection [22]. Symptoms of long COVID are varied between individuals, but commonly include fatigue, physical pain, reduced exercise tolerance, dyspnea, gastrointestinal symptoms, headaches, memory and concentration difficulties, and psychological disturbance [22,23]. While research into the underlying cause of long COVID syndrome is in its infancy, it is currently thought to be the result of widespread, chronic multi-system inflammation, secondary to significant inflammatory activation, and cytokine storm [24,25]. This inflammation is thought to affect the lungs and cardiovascular, central nervous, and gastrointestinal systems [25][26][27], however, many questions remain. As patients with long COVID report significant decreases in quality of life [22], identifying strategies to manage it are critical. Given its inflammatory and anti-oxidative properties as well as its effects on exercise performance [28] and cardiac and cognitive function [3], carnosine supplementation could prevent or at least reduce symptoms related to long COVID. In addition, if the cytokine storm due to COVID-19 is rapidly suppressed, it is possible that ongoing symptoms may be decreased, or avoided entirely. Carnosine should therefore be evaluated for use in these patients.
While carnosine supplementation may have a beneficial impact alone, there is also potential for its use alongside other nutritional interventions in patients with COVID-19. Several other nutrients have been investigated for use in patients infected with COVID-19, with potentially synergistic immune effects. Vitamins D, C, and B are all known to be immunomodulatory, and have been suggested to have potential in dampening the aggressive immune response and cytokine storm associated with COVID-19 [3,4]. Other trace minerals such as zinc and selenium, as well as omega-3 fatty acids, have also been shown to have some benefits which may improve the outcomes of patients with COVID-19, improving outcomes in respiratory infection, which has led many to recommend their use [29]. Interestingly, others have recommended pre-and pro-biotic interventions, as they also improve respiratory symptoms [30]. A "multi-nutrient" intervention, consisting of carnosine, alongside these additional immune-enhancing vitamins and minerals, could be used to enhance patient outcomes.
While research into these potential effects is preliminary, the role of carnosine in patients with COVID-19 is promising and therefore there is a need for trials to test the efficacy of carnosine for prevention, as a supportive measure during the infection as well as in long COVID (Figure 1). Given the high tolerability and absence of significant side effects, alongside its anti-inflammatory and an antioxidant effects, it could provide a low-cost, scalable solution for this indication. This is particularly noteworthy given carnosine's well-known benefits in patient demographics who are at increased risk from COVID-19, including the elderly and those living with diabetes.
Author Contributions: J.F., writing-original draft; writing-review and editing; M.d.C., conceptualization; writing-review and editing; B.d.C., conceptualization; writing-review and editing; V.A., conceptualization; supervision; writing-review and editing. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding. and The Greek Orthodox Archdiocese of Australia. J.F. is a recipient of a University of Melbourne PhD scholarship.

Conflicts of Interest:
The authors declare no conflict of interest.