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