2- Multifactorial origin of the COVID-19 epidemic
Like most diseases, COVID-19 exhibits large geographical variations which frequently remain unexplained 6. The COVID-19 epidemic is multifactorial, and factors like climate, population density, age, phenotype and prevalence of non-communicable diseases are also associated to increased incidence and mortality7. Diet represents only one of the possible causes of the COVID-19 epidemic and its importance needs to be better assessed. Some risk factors for the COVID-19 epidemics are proposed at the individual and country levels in Table 1.
Ecological data on COVID-19 death rates
When comparing death rates, large differences exist between and within countries and the evolution of the pandemic differs largely between countries (Figure 1). Although there are many pitfalls in analyzing death rates for COVID-19, 2 the evolution of death rates between May 20 and July 18 shows a dramatic increase in Latin America and only some increase in European countries, certain African countries, the Middle East, India, Pakistan and some of the South East Asian countries. However, there is no change in the very low death rates of Cambodia, China, Japan, Korea, Lao, Malaysia, Taiwan, Vietnam and of many Sub-Saharan African countries, Australia and New Zealand. This geographical pattern is very unlikely to be totally due to reporting differences between countries.
In some high death-rate countries such as Italy (Figure 2), variations are extremely large from 50 per million in Calabria to over 1,600 in Lombardia. In Switzerland, the French- and Italian-speaking cantons have a far higher death rate than the German-speaking ones (Office fédéral de la santé publique,Switzerlandhttps://www.bag.admin.ch/bag/fr/home.html ) (Figure 3). It may be proposed that the high-death rate cantons were contaminated by French and Italian people. However, the Mulhouse airport serves the region of Basel (Switzerland), the Haut-Rhin department (France) and the region of Freiburg (Germany). There was a COVID-19 outbreak in the Haut-Rhin department, in particular in Mulhouse and Colmar. The death rate for COVID-19 (May 20, 2020) was 935 per million inhabitants in France but only 10 to 25 in Switzerland and 7 in Germany. It is important to consider these regional differences since reporting of deaths is similar within the country and many factors may be considered.
In many Western countries, large cities (e.g. London, Madrid, Milan, New York, Paris) have been the most affected. This seems to be true also for many countries in which the rural areas have much fewer cases.
The number of deaths is relatively low in Sub-Saharan Africa compared to other regions, and the low population density (which applies in rural areas but not in megacities such as Cairo or Lagos) or the differences in health infrastructure are unlikely to be the only explanation.8 It has been proposed that hot temperature may reduce COVID-19, but, in Latin American countries, death rates are high (e.g. Brazil, Ecuador, Peru and Mexico).
Is diet partly responsible for differences between and within countries?
Nutrition may play a role in the immune defense against COVID-19 and may explain some of the differences seen in COVID-19 between and within countries 2. In this concept paper, raw and fermented cabbage were proposed to be candidates.
To test the potential role of fermented foods in the COVID-19 mortality in Europe, an ecological study, the European Food Safety Authority (EFSA) Comprehensive European Food Consumption Database, was used to study the country consumption of fermented vegetables, pickled/marinated vegetables, fermented milk, yoghurt and fermented sour milk.9 Of all the variables considered, including confounders, only fermented vegetables reached statistical significance with the COVID-19 death rate per country. For each g/day increase in consumption of fermented vegetables of the country, the mortality risk for COVID-19 was found to decrease by 35.4% (Figure 4).
A second ecological study has analyzed cruciferous vegetables (broccoli, cauliflower, head cabbage (white, red and savoy cabbage), leafy brassica) and compared them with spinach, cucumber, courgette, lettuce and tomato 10. Only head cabbage and cucumber reached statistical significance with the COVID-19 death rate per country. For each g/day increase in the average national consumption of some of the vegetables (head cabbage and cucumber), the mortality risk for COVID-19 decreased by a factor of 11, to 13.6 %. The negative ecological association between COVID-19 mortality and consumption of cabbage and cucumber supports the a priori hypothesis previously reported. However, these are ecological studies that need to be further tested.
Another diet component potentially relevant in COVID-19 mortality may be the food supply chain and traditional groceries. 11The impact of the long supply chain of food on health is measurable by an increase in metabolic syndrome and insulin resistance.12 Therefore, areas that are more prone to short supply food and traditional groceries may have been able to better tolerate COVID-19 with a lower death toll. These considerations may be partly involved in the lower death rates of Southern Italy compared to the Northern part (Figure 2).
Fermented foods, microbiome and lactobacilli
The fermentation process, born as a preservation method in the Neolithic age, enabled humans to eat not-so-fresh food and to survive.13 Fermented foods are “foods or beverages made via controlled microbial growth (including lactic acid bacteria (LAB)) and enzymatic conversions of food components.” 14 Not all fermented foods contain live cultures, as some undergo further processing after fermentation: pasteurization, smoking, baking, or filtration. These processes kill or remove the live microorganisms in foods such as soy sauces, bread, most beers and wines as well as chocolate. Live cultures can be found in fermented vegetables and fermented milk (fermented sour milk, yoghurt, probiotics, etc.).
Most traditional foods with live bacteria in the low-death rate countries are based on LAB fermentation 15. A number of bacteria are involved in the fermentation of kimchi and other Korean traditional fermented foods, but LAB - including Lactobacillus - are the dominant species in the fermentation process16,17. Lactobacillus is also an essential species in the fermentation of sauerkraut, Taiwanese18, Chinese 19 or other fermented foods 20. Lactobacilli are among the most common microorganisms found in kefir, a traditional fermented milk beverage21, milk and milk products 22,23. During fermentation, LAB synthesize vitamins and minerals, and produce biologically-active peptides with anti-oxidant activity14,24-28.
Humans possess two protective layers of biodiversity, and the microbiome has been proposed as an important actor of COVID-1929. The environment (outer layer) affects our lifestyle, shaping the microbiome (inner layer). 30Many fermented foods contain living microorganisms and modulate the intestinal microbiome. 14,28,31-33
The composition of microbiomes varies in different regions of the world. 34 Gut microbiota has an inter-individual variability due to genetic predisposition and diet. 35As part of the gut microbiome, Lactobacillus  spp. contributes to its diversity and modulates oxidative stress in the GI tract. Some foods like cabbage can be fermented by the gut microbiota.36
Urbanization in western countries was associated with changes in the gut microbiome and with intestinal diversity reduction. 35,37-40 Westernized food in Japan led to changes in the microbiome and in insulin resistance.41 The gut microbiome of westernized urban Saudis had a lower biodiversity than that of the traditional Bedouin population.42 Fast food consumption was characterized by reduced Lactobacilli in the microbiome. 43
The links between gut microbiome, inflammation, obesity and insulin resistance are being observed but further large studies are needed for a definite conclusion. 44-46
Some COVID-19 patients have intestinal microbial dysbiosis47 with decreased probiotics such as Lactobacillus  and Bifidobacterium 48. Many bacteria are involved in the fermentation of vegetables but most traditional foods with live bacteria in the low-death rate countries are based on LAB fermentation. 15-17,20,27 Lactobacilli are among the most common microorganisms found in milk and milk products21-23.
Angiotensin-converting enzyme 2 (ACE2) and COVID-19
COVID-19 is more severe in older adults and/or patients with comorbidities, such as diabetes, obesity or hypertension, suggesting a role for insulin resistance.49 Although differences exist between countries, the same risk factors for severity were found globally, suggesting common mechanisms. A strong relationship between hyperglycemia, impaired insulin pathway, and cardiovascular disease in type 2 diabetes is linked to oxidative stress and inflammation.50 Lipid metabolism has an important role to play in obesity, in diabetes and its multi-morbidities, and in ageing.51 The increased severity of COVID-19 in diabetes, hypertension, obese or elderly individuals may be related to insulin resistance, with oxidative stress as a common pathway.52 Moreover, the severe outcomes of COVID-19 - including lung damage, cytokine storm or endothelial damage - appear to exist globally, again suggesting common mechanisms.
The angiotensin-converting enzyme 2 (ACE2) receptor is part of the dual system – the renin-angiotensin-system (RAS) - consisting of an ACE-Angiotensin-II-AT1R axis and an ACE-2-Angiotensin-(1-7)-Mas axis. AT1R is involved in most of the effects of Ang II, including oxidative stress generation,53 which in turn upregulates AT1R 54. In metabolic disorders and with older age, there is an upregulation of the AT1R axis leading to pro-inflammatory, pro-fibrotic effects in the respiratory system, and to insulin resistance.55SARS-CoV-2 binds to its receptor ACE2 and exploits it for entry into the cell. The ACE2 downregulation, as a result of SARS-CoV-2 binding, enhances the AT1R axis 56 likely to be associated with insulin resistance 57,58 but also to severe outcomes of COVID-19 (Figure 5A).
Anti-oxidant activities of foods linked with COVID-19
Many foods have an antioxidant activity 59-61 and the role of nutrition has been proposed to mitigate COVID-1962. Many antioxidant mechanisms have been proposed, and several foods can interact with transcription factors related to antioxidant effects such as the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2). 3 Some processes like fermentation increase the antioxidant activity of milk, cereals, fruit, vegetables, meat and fish. 26
7-1- Nrf2, a central antioxidant system
Reactive oxygen species (ROS), such as hydrogen peroxide and superoxide anion, exert beneficial and toxic effects on cellular functions. Nrf2 is a pleiotropic transcription factor at the centre of a complex regulatory network that protects against oxidative stress and the expression of a wide array of genes involved in immunity and inflammation, including antiviral actions.63 Nrf2 activity in response to chemical insults is regulated by a thiol-rich protein named KEAP1 (Kelch-like ECH-associated protein 1). The KEAP1-Nrf2 system is the body’s dominant defense mechanism against ROS.64Induction of the antioxidant responsive element and the ROS mediated pathway by Nrf2 reduces the activity of nuclear factor kappa B (NF-κB),  65 whereas NF-κB can modulate Nrf2 transcription and activity, having both positive and negative effects on the target gene expression 66.
Natural compounds derived from plants, vegetables, fungi and micronutrients (e.g. curcumin, sulforaphane, resveratrol and vitamin D) or physical exercise can activate Nrf2.67,68 However, sulforaphane is the most potent activator of Nrf2.3,34 “Ancient foods”, and particularly those containing Lactobacillus, activate Nrf2. 69
Nrf2 may be involved in diseases associated with insulin-resistance.57,70-72 Nrf2 activity declines with age, making the elderly more susceptible to oxidative stress-mediated diseases.73 Nrf2 is involved in the protection against lung74 or endothelial damage. 75 Nrf2 activating compounds downregulate ACE2 mRNA expression in human liver-derived HepG2 cells.76 Genes encoding cytokines including IL-6 and many others specifically identified in the ”cytokine storm” have been observed in fatal cases of COVID-19. ACE2 can inhibit NF-κB and activate Nrf2.77
7-2- Sulforaphane, the most potent Nrf2 natural activator
Isothiocyanates are stress-response chemicals formed from glucosinolates in plants often belonging to the cruciferous family, and more broadly to the Brassica genus including broccoli, watercress, kale, cabbage, collard greens, Brussels sprouts, bok choy, mustard greens and cauliflower .78 The formation of isothiocyanates from glucosinolates depends on plant-intrinsic factors and extrinsic postharvest factors such as industrial processing, domestic preparation, mastication, and digestion. 79
Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)butane] is an isothiocyanate occurring in a stored form such as glucoraphanin in cruciferous vegetables 80,81. Sulphoraphanes are also found in fermented cabbage 28,82. Present in the plant as its precursor, glucoraphanin, sulforaphane is formed through the actions of myrosinase, a β-thioglucosidase present in either the plant tissue or the mammalian microbiome 83,84.
Sulforaphane is a clinically relevant nutraceutical compound used for the prevention and treatment of chronic diseases and may be involved in ageing.85 Along with other natural nutrients, sulforaphane has been suggested to have a therapeutic value for the treatment of coronavirus disease 2019 (COVID-19).86
One of the key mechanisms of action of sulforaphane involves the activation of the Nrf2-Keap1 signaling pathway.87Sulforaphane is the most effective natural activator of the Nrf2 pathway, and Nrf2 expression and function is vital for sulforaphane-mediated action.88,89 Sulforaphanes were suggested to be effective in diseases associated with insulin resistance1,90-92 It has been proposed that SARS-CoV-2 downregulates ACE2 and that there is an increased insulin resistance associated with oxidative stress through the AT1R pathway. Fermented vegetables and Brassica vegetables release glucoraphanin, converted by the plant or by the gut microbiome into sulforaphane, which activates Nrf2 and subsequently reduces insulin intolerance (Figure 5B).
7-3- Lactic acid bacteria