The COVID-19 pandemic has caused a global crisis, reminiscent of the Spanish flu of 1918, with severe consequences for the global economy. Pneumonia caused by coronaviruses is a zoonosis, and humans have experienced the emergence of three highly pathogenic CoV species over the past two decades: severe acute respiratory syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, and SARS-CoV-2 (1). Its strong infectivity has been verified through transmission from humans to cats, which may have served as intermediate hosts for the virus (2). Regarding the COVID-19 vaccine, some ecological studies have shown regional disparities in immunization coverage in the USA (3). There is concern regarding low vaccination rates despite the greater risk of infection in non-Hispanic Black and Hispanic populations. Data provided by the WHO as of June 17, 2024, showed that the COVID-19 deaths in Africa, the Americas, Europe, the Eastern Mediterranean region, and Asia (Western Pacific and South-East Asia) numbered 175,510 (2%), 3,020,756 (43%), 2,272,390 (32%), 351,975 (5%), and 1,229,712 (17%), respectively (4). Africa had the lowest proportion of cumulative deaths worldwide at 2%, accounting for 9,579,844 cumulative cases and only 1% of the global total.

Contrary to expectations, the number of COVID-19 deaths did not increase significantly in Africa despite the high rates of HIV, malaria, and other infectious diseases and the lack of developed healthcare systems. In contrast, in many developed countries in Europe and the USA, which have large elderly populations, COVID-19 resulted in high mortality rates, especially among the elderly and those with underlying medical conditions. Elderly individuals are more susceptible to pneumonia, with underlying conditions such as diabetes and obesity, which are metabolic conditions included in lifestyle-related diseases, and a weakened immune system due to various diseases. These susceptible populations prioritized vaccination and other preventive measures.

In Africa, an interesting phenomenon was observed: the number of deaths due to COVID-19 did not increase, as expected. However, this anomaly requires further investigation. One possible reason for this is the demographic structure of Africa, which has an overwhelmingly large number of children and a relatively small number of elderly individuals, who showed higher mortality rates from COVID-19. The median age on the African continent is 18.8 years, compared to the world average of 30.7 years and 49.5 years in Japan (5). In children, the innate immune response that eliminates the virus may be more effective than the speed at which the virus mutates (6, 7).

Another explanation is that Japan’s low mortality rate from COVID-19 compared to that in Western countries comes from its status as the country with the longest life expectancy in the world (8). Reports have shown that the nutritional situation in Africa has been adversely affected by the COVID-19 pandemic, particularly among children (9). In addition to economic development, a well-known factor contributing to Japan’s longevity is the healthiness of the Japanese diet. The Japanese diet, similar to the Mediterranean diet (10), has also been considered healthy, particularly around 1975, which is considered healthier than the current Japanese diet (11–13). Compared to the USA and other countries, Japan has lower rates of obesity and lifestyle-related diseases, including metabolic diseases, which are believed to be associated with the longevity of its population. The typical Western diet is high in energy density, leading to underlying and lifestyle-related diseases and impaired immunity due to chronic inflammation, which have been identified as risk factors for COVID-19 (14). This study investigated the effects of polyphenols, a class of phytochemicals abundant in the healthy diets of the Mediterranean region and Japan, on COVID-19.

It is also well-established that vitamin D deficiency is associated with a range of diseases, including those that impair immunity. A systematic review and meta-analysis conducted in Italy, a country severely affected by COVID-19, revealed a clear association between vitamin D deficiency and COVID-19 mortality (15). Blood vitamin D levels are categorized as follows: < 20 ng/mL deficient, 20–30 ng/mL, insufficient; and > 30 ng/mL, sufficient. A report showed the following blood vitamin D (25-OH-D) levels (ng/mL) in European countries: France 24.0, Germany 20.0, Italy 20.0, the UK 19.0, and Spain 17.0 (16). In Japan, only 2% of individuals have sufficient blood vitamin D levels, with an average value of 15.5 ng/mL (17). In Africa, because of the strong direct sunlight, over 40% of people have blood vitamin D levels above 30 ng/mL, with a mean value of 27.1 ng/mL, the highest among the compared regions (18).

Finally, the relationship between the gut microbiota and COVID-19, which is significantly influenced by diet and varies with the disease, was also examined.

Based on the above, this study tested the following hypotheses by examining COVID-19 responses in Japan and Africa: (1) a healthy diet is effective against COVID-19, (2) blood vitamin D levels are associated with COVID-19 mortality, and (3) COVID-19 is associated with the gut microbiota. To test these hypotheses, we conducted a series of literature searches and summarized the findings of a systematic review and meta-analysis.

This systematic review first examined whether a healthy diet was effective against COVID-19. Japan has the longest longevity in the world, and in recent years, there has been growing awareness of the need to reduce medical costs and prevent aging, particularly by detecting and curing non-disease conditions (ME-BYO) (80). Consequently, considerable research has been conducted on healthy longevity and diet (81). Unlike the typical high-fat, high-sugar Western diet, the Japanese diet, which is similar to the Mediterranean diet, is well-known worldwide as a healthy diet, making those who consume it less prone to metabolic-related diseases and obesity (82).

In developed countries, high infection and mortality rates owing to COVID-19 have been observed, particularly among the elderly and those with underlying diseases, who constitute a large proportion of the population. Consequently, these groups are prioritized for vaccination (83). A healthy Japanese diet may be associated with lower rates of COVID-19 due to the lower prevalence of underlying lifestyle-related diseases in the population.

Africa, on the other hand, is a region with a poor food situation, including hunger and water shortages, and the economic impact of COVID lockdowns and other problems was a major concern (84). However, contrary to our expectations, the reported number of deaths due to COVID-19 did not increase significantly. One reason is that since Africa’s situation cannot be compared with that of other regions owing to underdeveloped health systems, the COVID response in Africa has been underreported. In addition, regional differences exist between the urban and non-urban areas in Africa. However, the proportion of younger people is the highest in the world, and the proportion of patients with metabolic syndrome, lifestyle-related diseases, and diseases caused by overeating is lower than in developed and emerging countries (85). This is associated with the fact that COVID-19 mortality rates were low in Africa.

Vegetables and fruits have received attention in recent years because of their high phytochemical content (86). They are referred to as the seventh nutrient, following the three macronutrients—carbohydrates, proteins, and fats—the fourth and fifth nutrients—vitamins and minerals, and the sixth nutrient–dietary fiber. Phytochemicals have gained particular attention owing to their anti-inflammatory effects and well-known antioxidant properties. Numerous studies have investigated the antibacterial, anti-viral, and anti-cancer properties of these compounds. Grape phytochemicals such as resveratrol are among the most widely studied and used compounds (87). Many other plant-derived ingredients are extensively utilized not only in foods, but also in Kampo (traditional Japanese) and other herbal medications, from aspirin to the antimalarial drug artemisinin.

Next, we examined whether blood vitamin D levels were associated with COVID-19 mortality. Recently, there have been an increasing number of reports on the immune-boosting properties of vitamin D (88). Vitamin D was named after Elmer McCollum in 1922 as the fourth vitamin, with Vindaus et al. contributing to early research. It is well-known for its role as a bone hormone and its involvement in calcium absorption in the intestinal tract. Vitamin D deficiency is well known to be associated with rickets in children (89) and osteoporosis and osteomalacia in the elderly (90).

Vitamin D toxicity can lead to hypercalcemia and calcium accumulation in blood vessels caused by excessive vitamin D intake combined with calcium intake. This effect could be reversed by preventing excessive vitamin D intake. There are two types of vitamin D: plant-derived vitamin D2, produced in mushrooms, and animal-derived vitamin D3. Vitamin D3 is produced in the body from cholesterol precursors in the skin, but the activated form, 1α,25-(OH)2-D3, has a short half-life of a few hours and is not excessive in its natural state.

It is also well known that African Americans living in temperate regions are often deficient in vitamin D3, as its production in skin cells is inhibited by high melanin levels (91). For similar reasons, vitamin D supplementation is recommended, particularly in the UK and Scandinavian countries because of the high prevalence of vitamin D deficiency at higher latitudes (92). As mentioned previously, vitamin D deficiency is much less common in mainland Africa than in other countries. A study comparing East Africa and Finland found that East Africans had a higher vitamin D intake (93), with differences in diet and sunlight exposure across regions being associated (94).

It has also been suggested that in Africa, unlike in developed countries where the population is concentrated in urban areas, there are far more opportunities for exposure to direct sunlight owing to differences in living conditions. Therefore, sufficient vitamin D is synthesized despite the high melanin pigmentation in the skin (95). This phenomenon is attributed to the fact that people living at higher latitudes lose the need for pigments that protect their bodies from direct sunlight.

In recent years, it has been noted that vitamin D deficiency is associated with compromised immunity, since vitamin D receptors (VDRs) expressed in many cells, including immune cells (96). Active vitamin D, bound to the nuclear VDR, binds to the vitamin D response elements of genes and regulates their expression of various genes. This action is particularly prominent in proinflammatory cytokine genes such as TNF-α and IL-1β, thereby providing vitamin D with anti-inflammatory properties and making it deeply involved in immune regulation (97).

There were remarkable numbers of meta-analysis in PubMed search (65 results) associated with the keywords COVID-19 and vitamin D (98). Therefore, a meta-analysis was conducted from the references in Tables 3–5, 8, and the statistical analysis of blood 25-OH-D3 levels, hospitalization period, COVID-19 cases, and deaths in relationship to COVID-19 and vitamin D. Statistically significant differences (p < 0.01) in blood 25-OH-D3 levels and number of COVID-19 cases were observed in this study, similar to other meta-analyses. However, it is likely that vitamin D works as supplementary regimen for daily upregulation of immune responses to avoid infections rather than the treatment of severe COVID-19.

Contrary to prior predictions, there was no significant increase in the number of deaths from COVID-19 in Africa despite the high prevalence of other infectious diseases such as AIDS and malaria (99). Although vitamin D deficiency is common in Africa, it is less prevalent than that in other regions of the world. Therefore, it is highly likely that higher average blood vitamin D levels in Africa are associated with improved survival rates. In contrast, mortality from COVID-19 was associated with blood vitamin D levels, similar to trends observed in other regions.

Finally, we examined whether COVID-19 is associated with the gut microbiota. In recent years, gut microbiota have been found to be associated with various diseases (100). The gut microbiota of the Japanese people can be categorized into five types. The gut microbiota phenotype of healthy Japanese individuals is referred to as the rural type and is characterized by high levels of Prevotella, which is associated with a reduced risk of various diseases (101). A study of African children found that, compared to their European counterparts, children in rural African villages had an enrichment of Bacteroides and a reduction of Firmicutes, resulting in a more diverse and healthier gut microbiota (102). This was attributed to the primitive, fiber-rich diet of Africans with healthy low Firmicutes/Bacteroides (F/B) ratio and linked to the low COVID-19 infection rates and deaths in Africa, presenting a remarkably interesting finding.

Patients with COVID-19 show reduced diversity of microbiota in the lungs, including a reduction in Bacteroides (103). Focusing on the gut microbiota, it was found that short-chain fatty acid-producing bacteria, mainly from the class Clostridia decreased, whereas opportunistic pathogens increased, resulting in leaky gut syndrome (104). Short-chain fatty acids, such as acetic acid, propionic acid, and butyric acid, are crucial for the activation of regulatory T cells (Tregs) and upregulate immunity. Furthermore, an increase in opportunistic pathogens, including mycoplasmas, has been observed in the respiratory tracts of COVID-19 patients (105). Opportunistic pathogens are normally present in the body but become pathogenic when the immune system is weakened. Thus, a link between COVID-19 and the gut microbiota has been suggested.

In addition, vitamin D helps maintain healthy gut microbiota (106). The composition of the gut microbiota varies greatly depending on the diet and can be broadly classified into obese and lean types. Obese individuals contain more Firmicutes, whereas lean individuals often have more Bacteroides (107). A typical Western diet, which is high in fat, sugar, and red meat, increases the number of obese Firmicutes. In contrast, a high-fiber diet rich in vegetables and fruits, such as the Japanese diet, the Mediterranean diet, the Five-a-Day diet in the USA, and vegetarian and vegan diets, increases Bacteroidetes (108). The Mediterranean diet, a representative healthy diet, is characterized by low intake of sweets and red meat, daily consumption of whole grains with a low glycemic index (GI), extra virgin olive oil, and approximately one glass of red wine per day. Additionally, daily physical activity is recommended as part of the Mediterranean diet pyramid.

The Japanese diet is also characterized by a high intake of foods that maintain a healthy gut microbiota, including low fat intake, high fish protein, and fermented foods (109). On the other hand, it is interesting to note that African villages have a primitive diet very high in dietary fiber, which maintains the diversity of the intestinal microbiota and a low Firmicutes/Bacteroidetes (F/B) ratio, which is considered healthy (110).

Figure 5 summarizes the mechanisms underlying the improvement in COVID-19 responses by phytochemicals (polyphenols and flavonoids), vitamin D, and gut microbiota. Phytochemical effects against COVID-19 via various mechanisms. First, phytochemicals not only prevent the production of proinflammatory cytokine TNF-α production but also prevent cytokine storms caused by COVID-19. The suppression of chronic inflammation prevents obesity and metabolic syndrome-related diseases, which are responsible for the onset of underlying diseases. The anti-viral effects of phytochemicals are well known. Furthermore, phytochemicals function as prebiotics and maintain a healthy gut microbiota.

Recent findings on vitamin D have demonstrated its effects on the upregulation of the immune system. Since most immune cells express vitamin D receptors (VDRs), vitamin D suppresses the transcription pathways of inflammation-associated genes and cytokine storms observed in COVID-19. Vitamin D deficiency has been observed in many deadly diseases, and their supplementation boosts immune responses. Furthermore, vitamin D intake is associated with the maintenance of healthy gut microbiota.

Maintenance of a healthy gut microbiota is associated with systemic health conditions. The onset of COVID-19 is associated with dysbiosis. This induces leaky gut syndrome, which enables the penetration of bacteria and their toxins into the bloodstream and circulation around the body, thereby inducing inflammation. Malfunction of the intestine is one of the chief symptoms of COVID-19 that worsens the condition of patients. Furthermore, the gut microbiota is associated with the maintenance of the gut-brain axis and induces a parasympathetic-neuron-dominant state related to stress reduction. In addition, short fatty acids produced by the gut microbiota activate regulatory T cells (Tregs) and prevent the manifestation of symptoms even after infection with SARS-CoV-2.

Acute pneumonia due to COVID-19 resembles sepsis caused by various infections and viruses (111). In COVID-19, SARS-CoV-2 infection causes inflammation, primarily in the lower respiratory tract, and disseminated intravascular coagulation (DIC) occurs when a cytokine storm spreads throughout the body, leading to severe symptoms and death. The mechanism is an inflammatory response, such as septic shock, triggered by infections and not just viruses. Long-term COVID-19 continues to pose a problem (112). This condition is caused by an inflammatory response that affects various parts of the body, including nerve cells, resulting in an increase in the number of aging cells. The challenge in treating long COVID, as to sepsis, is the removal of senescent cells. The antimicrobial peptide LL-37 (113), which activates innate immunity, and K-FGF (114, 115), a functional food containing phytochemicals produced from Japanese grapes (fermented grape food from Koshu), are effective in this regard.

A limitation of this study is that the medical systems in developed countries such as Japan and Africa are very different, making it difficult to determine how well recorded figures capture the actual situation. Japan has also experienced a collapse in medical systems owing to COVID-19, such as a shortage of ambulances in Tokyo; however, the medical system has been well developed. By contrast, in Africa, the population with access to hospitals is much more limited. Some reports have indicated the possibility of underestimating the impact of COVID in Africa (116). The most conceivable reason derived from the serosurveillance data is significant underdetection and underreporting (117). However, it is possible that these phenomena are applicable only to limited areas, including conflict zones (118). Second, Japan has a long life expectancy and a declining population, while in Africa, the population continues to grow and there are many children, creating completely different population pyramids. Furthermore, ACE2, the receptor for SARS-CoV-2 infection, is less expressed in young people (119), and Africans have many genetic polymorphisms, the frequency of which differs from that of people in other regions (120).

Regardless of these differences, it is necessary to consider the possibility that directly applying findings obtained from one region to another may be difficult. Moreover, with predicted future developments, healthy features such as high blood vitamin D levels and diverse gut microbiota in Africa may be lost.

Notably, in this study, COVID-19 deaths in Africa were unexpectedly low, accounting for only 2% of the global deaths. This low mortality rate is attributed not only to the high proportion of children in the population, but also to the relatively low number of people with underlying metabolic and obesity-related diseases, which are mainly caused by overeating. Additionally, high average blood vitamin D levels and, more notably, a low Firmicutes/Bacteroidetes (F/B) ratio and a highly diverse gut microbiota are contributing factors. These factors may explain the lower incidence of COVID-19 and less severe disease outcomes in Africa than in developed and emerging countries. These results are indeed very interesting.

The authors have already shown that a healthy diet containing nutrients such as phytochemicals and vitamin D is associated with a healthy gut microbiota. In this context, the present study, based on an article review, shows that phytochemicals and vitamin D are involved in the improvement of COVID-19 and its sequelae by maintaining a healthy gut microbiota. Further epidemiological studies are required to confirm these findings and explore the potential of dietary interventions to mitigate the impact of COVID-19 and improve overall public health.

A comparison of the Japanese and African COVID-19 responses confirmed the importance of a healthy diet. Vitamin D is related to vitamins, and its deficiency threatens the health of the body. However, it is now recognized as an immune-related hormone. Phytochemicals have also become attractive as the seventh most important nutritional source for a healthy diet in recent years. Maintaining adequate blood vitamin D levels and taking phytochemicals are associated with maintaining a healthy and diverse gut microbiota and upregulation of immune responses, which are correlated with a low mortality rate from COVID-19. This study suggests that healthy dietary patterns and nutrients are important long-term protective factors against lung diseases, including COVID-19, and may also help prevent other diseases such as sepsis caused by infections. Promoting a diet rich in phytochemicals and ensuring sufficient vitamin D intake could serve as effective strategies to enhance public health and mitigate the global impact of infectious diseases.