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\begin{document}

\title{Sulforaphane: from death rate heterogeneity in countries to candidate
for prevention of severe COVID-19}



\author[1]{Jean Bousquet}%
\author[2]{Josep Anto}%
\author[3]{Wienczyslawa Czarlewski}%
\author[4]{Tari Haahtela}%
\author[5]{Susana Fonseca}%
\author[6]{Guido Iaccarino}%
\author[7]{Hubert Blain}%
\author[8]{Cezmi Akdis}%
\author[9]{Torsten Zuberbier}%
\affil[1]{Université Versailles, St-Quentin-en-Yvelines}%
\affil[2]{ISGLoBAL}%
\affil[3]{Medical Consulting }%
\affil[4]{Helsinki University Hospital}%
\affil[5]{GreenUPorto - Sustainable Agrifood Production Research Centre}%
\affil[6]{Federico II University Hospital}%
\affil[7]{CHU Montpellier}%
\affil[8]{University of Zurich}%
\affil[9]{Charité Universitätsmedizin Berlin}%


\vspace{-1em}



  
  \date{May 15, 2024}


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To the Editor,

Sulforaphane {[}1-isothiocyanato-4-(methylsulfinyl)butane{]} is a
clinically relevant nutraceutical compound present in cruciferous
vegetables (Brassicaceae). It is used for the prevention and treatment
of chronic diseases and may be involved in
ageing.\textsuperscript{1}Along with other natural nutrients,
sulforaphane has been suggested to have a therapeutic value for the
treatment of the coronavirus disease 2019 (COVID-19).\textsuperscript{2}
Sulforaphane is an isothiocyanate stored in its inactive form
glucoraphanin.\textsuperscript{3} The enzyme myrosinase, found in plant
tissue and in the gut microbiome, is involved in the conversion of
glucoraphanin to its active form sulforaphane.\textsuperscript{4}

\textbf{Heterogeneity of COVID-19 death rates in countries and relation
to diet}

When comparing death rates, large differences exist between and within
countries (Figure 1). Although many factors are involved in COVID-19
mortality,\textsuperscript{5-11} a recent hypothesis has proposed that
differences between countries may partly be explained by diet: the diet
of low-death rate countries often includes certain vegetables that are
potent anti-oxidants.\textsuperscript{12} Two studies have examined the
association between the COVID-19 mortality rate in EU countries and
diet. Fermented vegetables, head cabbage and cucumber have been
associated with lower death rates.\textsuperscript{13,14} Even though
these are ecological studies, they support the association between diet
and fatality. A healthy diet, rich in antioxidants, has been proposed as
a therapeutic strategy to mitigate the cytokine storm that developed in
COVID-19.\textsuperscript{15} In Asia and the Middle East, a diet high
in fermented cruciferous vegetables is common, and these countries have
a lower COVID-19 mortality rate. Fermentation food processing is known
to increase the antioxidant activity of
foods.\textsuperscript{16}Certain compounds found in the diet can
interact with Nrf2 (nuclear factor erythroid 2 p45-related factor 2), a
transcription factor involved in the protection against oxidative
stress.\textsuperscript{17}

\textbf{Insulin resistance and COVID-19}

COVID-19 is more severe in elderly adults and/or patients with
comorbidities, such as diabetes, obesity or hypertension, suggesting a
role for insulin resistance.\textsuperscript{18} 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.\textsuperscript{19} Lipid metabolism has an important role
to play in obesity, in diabetes and its multi-morbidities, and in
ageing.\textsuperscript{20} 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.\textsuperscript{21}

\textbf{ACE2 and COVID-19}

The angiotensin-converting enzyme 2 (ACE2) receptor is part of the dual
system - renin-angiotensin-system (RAS) - consisting of an
ACE-Angiotensin-II-AT\textsubscript{1}R axis and an
ACE-2-Angiotensin-(1-7)-Mas axis. AT\textsubscript{1}R is involved in
most of the effects of Ang II, including oxidative stress
generation,\textsuperscript{22} which in turn upregulates
AT\textsubscript{1}R \textsuperscript{23}. In metabolic disorders and
with older age, there is an upregulation of the AT\textsubscript{1}R
axis leading to pro-inflammatory, pro-fibrotic effects in the
respiratory system, and to insulin
resistance.\textsuperscript{24}SARS-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 AT\textsubscript{1}R axis.
\textsuperscript{25}

\textbf{Nrf2, a central mechanism in insulin resistance, and severity of
COVID-19}

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.\textsuperscript{26} Nrf2 may
be involved in diseases associated with
insulin-resistance.\textsuperscript{27,28} Nrf2 activity declines with
age, making the elderly more susceptible to oxidative stress-mediated
diseases. Nrf2-activating compounds downregulate ACE2 mRNA expression in
human liver-derived HepG2 cells,\textsuperscript{29} and in genes
encoding cytokines including IL-6 and many others specifically
identified in the ''cytokine storm'' observed in fatal cases of
COVID-19.

Natural compounds derived from plants, vegetables, fungi and
micronutrients (e.g. curcumin, sulforaphane, resveratrol and vitamin D)
can activate Nrf2.\textsuperscript{30} ACE2 can inhibit NF-\selectlanguage{greek}κ\selectlanguage{english}B and
activate Nrf2.\textsuperscript{31}

\textbf{Sulforaphane: the most potent natural Nrf2 activator}

A key mechanism of action of sulforaphane involves activation of the
Nrf2-Keap1 signalling pathway.\textsuperscript{32} Sulforaphane is the
most effective natural activator of the Nrf2 pathway, and Nrf2
expression and function is vital for sulforaphane-mediated
action.\textsuperscript{33,34} It has been proposed that SARS-CoV-2
downregulates ACE2 and that there is an increased insulin resistance
associated with oxidative stress through the AT\textsubscript{1}R
pathway. Cruciferous vegetables release glucoraphanin, converted by the
plant or by the gut microbiome, into sulforaphane which activates Nrf2
and subsequently reduces insulin intolerance (Figure 2).

\textbf{Complementing herd immunity with a sulforaphane-based diet}

Although nutritional epidemiology has been criticized on several fronts,
including the inability to measure diet accurately, and for its reliance
on observational studies to address etiologic
questions\textsuperscript{35}, there seems to be sufficient evidence to
raise some conclusions that will require appropriate testing.

Great hope has been placed on herd immunity, cross-immunity and
vaccination to provide protection against COVID-19. Unfortunately, herd
and cross-immunity may not be very effective, and the development of
vaccines is a long process. Until vaccines become available, a simple
solution would be to complement the diet with food that may have
positive metabolic regulatory and anti-inflammatory effects. It is clear
that the ecological studies available in Europe should be confirmed by
global studies and by adequate epidemiologic studies. However, proposing
a modification of diet before scientific evidence is available is not
harmful since these foods are usually, but not always, well-tolerated.
An alternative approach would be to evaluate the value of sulforaphane
in clinical trials, as recently proposed (Text box
1).\textsuperscript{2}

In conclusion, many factors may play a role in the difference of
severity and death rates in COVID-19 in different parts of the world.
These factors include trained immunity, cross reactivities with
different viruses and other coronaviruses as well as many different
dietary measures such as vitamin D levels, short-chain fatty acids,
omega 3-rich nutrition. \textsuperscript{36,37} Here, the authors
propose an additional dietary factor, a suphoraphane-based diet. Further
research is required to identify the synergistic effects between all of
these anti-inflammatory dietary factors, especially those acting on
insulin resistance and Nrf2.

Text Box:

\textbf{Future research areas:}

\begin{itemize}
\tightlist
\item
  Mouse models of COVID-19 to investigate the effects of diet,
  sulforaphane and similar compounds.
\item
  Cellular experiments for the \emph{in-depth} investigation of
  sulforaphane.
\item
  Case control studies.
\item
  Investigation of synergistic effects with other dietary factors and
  vitamins such as short-chain fatty acids, omega 3, and vitamin D.
\item
  Multiple omics metabolome analyses of the different stages of COVID-19
  patients.
\item
  Clinical trials with sulforaphane to prevent severe COVID-19.
\item
  Clinical trials with sulforaphane to reduce the severity of COVID-19.
\end{itemize}

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Jean Bousquet, MD, Charit\selectlanguage{ngerman}é, Universitätsmedizin Berlin,
Humboldt-Universität zu Berlin, and Berlin Institute of Health,
Comprehensive Allergy Center, Department of Dermatology and
MACVIA-France, Montpellier, France Allergy, Berlin, Germany

Josep M Anto, MD, ISGlobAL, Centre for Research in Environmental
Epidemiology (CREAL), IMIM (Hospital del Mar Research Institute),
Universitat Pompeu Fabra (UPF), CIBER Epidemiología y Salud Pública
(CIBERESP), Barcelona, Spain

Wienczyslawa Czarlewski, MD, Medical Consulting Czarlewski, Levallois,
and MASK-air, Montpellier France.

Tari Haahtela, MD, Skin and Allergy Hospital, Helsinki University
Hospital, Helsinki, Finland.

Susana C Fonseca, PhD, GreenUPorto - Sustainable Agrifood Production
Research Centre, DGAOT, Faculty of Sciences, University of Porto, Campus
de Vairão, Rua da Agrária, Porto, Portuga

Guido Iaccarino, MD, Federico II University, Department of Advanced
Biomedical Sciences, Napoli, Italy.

Hubert Blain, MD, Pole Gérontologie, University Hospital, Montpellier
University, MUSE, Montpellier.

Cezmi A Akdis, MD, Swiss Institute of Allergy and Asthma Research
(SIAF), University of Zurich, Davos, Switzerland

Torsten Zuberbier, MD, Charité, Universitätsmedizin Berlin,
Humboldt-Universität zu Berlin, and Berlin Institute of Health,
Comprehensive Allergy Center, Department of Dermatology, Berlin Germany

\textbf{Figure 1:} \textbf{COVID-19 deaths per million inhabitants (May
20, 2020)}\selectlanguage{english}
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\textbf{Figure 2: Putative mechanisms of \emph{Brassica} (cruciferous)
vegetables against COVID-19}\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/Figures/Figures}

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