COVID-19 Pandemic and Dysbiosis: Can the Ivermectin Hysteria Lead to an Increase of Autoimmune Neuroinflammatory Diseases?

Abstract

The pandemic caused by the SARS-CoV-2 has made new treatments a goal for the scientific community. One of these treatments is Ivermectin. Here we discuss the hypothesis of dysbiosis caused by the use of Ivermectin and the possible impacts on neuroinflammatory diseases after the end of the pandemic.

Full text

COVID-19 Pandemic and Dysbiosis: Can the
Ivermectin Hysteria Lead to an Increase of
Autoimmune Neuroinflammatory Diseases?
J.P.S. Peron,a,b,c H.I. Nakaya,b,d M.A.M. Schlindwein,e & M.V.M. Gonçalvesf,*
aNeuroimmune Interactions Laboratory, Institute of Biomedical Sciences, Department of Immunology, University
of Sao Paulo, São Paulo, Brazil; bScientic Platform Pasteur, University of São Paulo (USP), São Paulo, Brazil;
cImmunopathology and Allergy Post Graduate Program, School of Medicine, University of São Paulo (USP), São Paulo,
SP CEP 01246-903 Brazil; dDepartment of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences,
University of São Paulo (USP), São Paulo, Brazil; eDepartment of Medicine, University of the Region of Joinville
(UNIVILLE) Joinville, Brazil; fProfessor of Neurology, University of the Region of Joinville (UNIVILLE), Joinville, Brazil
*Address all correspondence to: Marcus Vinicius Magno Gonçalves, MD, PhD, Department of Medicine, University of the Region of Joinville,
Rua Ministro Calógeras, 439, Bucarein, Joinville, Santa Catarina, Brazil, 89202-207; Tel.: +55 47 3431-0600; Fax: +55 47 3473-0131,
E-mail: mvmpesquisa@gmail.com
ABSTRACT: The pandemic caused by the SARS-CoV-2 has made new treatments a goal for the scientic community.
One of these treatments is Ivermectin. Here we discuss the hypothesis of dysbiosis caused by the use of Ivermectin and
the possible impacts on neuroinammatory diseases after the end of the pandemic.
KEY WORDS: SARS-CoV-2, COVID-19, ivermectin, dysbiosis, tolerance
I. COVID-19 AND IVERMECTIN
By September 9 2020, the SARS-CoV-2 pandemic
has infected around 27,400,000 people worldwide,
leading to more than 894,000 deaths (https://covid19.
who.int). Lethality may range from 0.3/1000 to
305/1000 among younger and older individuals, re-
spectively.1 This may even increase when associated
with comorbidities such as diabetes, hypertension,
and lung and heart diseases.2 Moreover, patients may
require many degrees of hospitalization, overcrowd-
ing the hospitals and resulting in a massive public
health issue. For these reasons, many countries are
rushing to nd an effective vaccine or antiviral drug to
treat COVID-19. Many proposals result from in silico
drug repositioning studies or in vitro high throughput
screening. Obviously, due to that, many lack a robust
clinical study to prove either safety or efcacy, possi-
bly leading to misinterpretation or excessive trust by
the public. In this sense, mass utilization of some of
these drugs must be taken with caution and possible
adverse effects and consequences must be considered.
In this context, ivermectin, a broad spectrum
antiparasitic drug that acts on nematodes, such as
Strongyloides stercoralis or Ascaris lumbricoides,
and larial parasites, has shown the capacity to re-
duce SARS-CoV-2 replication in VERO/hSLAM
cells in vitro has gained much attention.3 Although
it has been already demonstrated that ivermectin
reduces HIV replication by blocking importins α/β
that transport HIV integrase to the cell nucleus, the
mechanisms by which ivermectin acts on other vi-
ruses, including SARS-CoV-2, are far from being
elucidated. There are currently 34 clinical studies
registered at www.clinicaltrials.gov using the terms
ivermectin + COVID-19. The studies are being per-
formed in Brazil, Egypt, Colombia, Singapore, Ban-
gladesh, the United States, and Italy. Unfortunately,
only four studies have been completed, but none
have deposited the results or published an article in
peer-reviewed journals. This leads us to question the
real efcacy of the drug for the treatment of SARS-
CoV-2 infection, and calls attention to its indiscrimi-
nate use and impact on people´s health, especially in
developing countries. We suggest here that the mas-
sive indiscriminate use of ivermectin for supposedly
protecting against COVID-19 can potentially harm
the population and must be taken seriously.
Many studies have associated microbial im-
balance (dysbiosis) with the development of
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540 Peron et al.
autoimmune diseases.4 Thus, with the illusion of pro-
tection against SARS-CoV-2 using ivermectin, indi-
viduals may be depleting key microbes that promote
immune tolerance and thus prevent autoimmune dis-
eases. How this mass treatment will impact the in-
cidence of neuroinammatory autoimmune diseases,
particularly multiple sclerosis (MS), is unknown.
MS prevalence in Brazil follows the global trend
of being associated with locations at higher lati-
tudes.5 Santa Maria, for instance, a city in the south-
ern state of Rio Grande do Sul (latitude of 29° 41’
S), has the highest prevalence known in the country,
with 27.2 per 100,000 inhabitants.6 Interestingly,
however, other countries at similar latitudes have
different MS prevalence; the state of Queensland
(Brisbane, its capital, latitude of 27° 47’ S) in Aus-
tralia has a prevalence of 74.6 per 100.000 inhabi-
tants.7 In the Italian city of Catania (latitude of 37.49
N), from which a great share of Santa Maria’s pop-
ulation originates,6 the prevalence of MS is 127.1
per 100,000 inhabitants.8 The distinct prevalence
but similar genetic traits between the populations
of Santa Maria and Catania clearly indicates that
other factors play a key role in MS development.
Although many possibilities must be considered,
the importance of intestinal microbiota has been un-
questionably relevant, and must be further consid-
ered. Thus, we wonder if the dysbiosis induced by
the massive misuse of ivermectin or other antibiotic/
antiparasitic drugs may increase MS prevalence in
the postpandemic world.
The Human Microbiome Project, a collabora-
tive multicenter research project aimed at under-
standing and characterizing the human microbiota,
published its rst ndings in 2012.9 This started to
unravel its complexity, heterogeneity, and correla-
tion with other diseases, as we learn more and more
that the interplay between the microbiota and its
products with host immune cells impact not only
local resident cells, but also systemic immunity.4,10
The idea that exposure to microorganisms would af-
fect our immunity was proposed for the rst time by
Strachan, who showed the prevalence of hay fever
with contact with older siblings.11 The so-called hy-
giene hypothesis states that the reduced exposure to
microorganisms during childhood, due to improved
sanitation in industrialized countries, leads to an
increase in immune reactivity and higher incidence
of allergic and autoimmune diseases, as reviewed.12
How this childhood acquired microbiota evolves
throughout adult life, and how they orchestrate
the immunity in adulthood is of great relevance to
understand the etiology of many diseases, mostly
autoimmunity. It is noteworthy to mention that, if
autoimmunity were solely a genetic-related phe-
nomenon, autoimmune diseases such as MS and
many others would always start during childhood,
which is not the case. Thus, it is suitable to think
that alterations in gut microbiota would impact the
regulatory immune network, resulting in breaking of
self-tolerance and further autoimmunity.4,10
Although we are a long way from unequivocally
understanding the complex and intricate network of
molecular and cellular interactions happening be-
tween host and microbiota, some mechanisms have
started to become clear. It was shown, for instance,
by 16s meta-genomics analysis of 46 MS patients,
that bacteria of the genus Methanobrevibacter,
Akkermansia, and Verrucomicrobia were signi-
cantly increased compared with healthy control in-
dividuals. Noteworthy, these microorganisms have
already been associated with systemic inamma-
tion. Conversely, butyrate secreting Butyricimonas
were reduced in MS patients. Butyrate, as well as
other short-chain fatty acids (SCFA), have already
been demonstrated to potently modulate host im-
mune cells, mostly promoting suppression and
tolerance.13,14
Microbiota-attenuated inammation is orches-
trated by many different mechanisms, such as by
inducing anti-inammatory cytokines such as IL-10
and TGF-β10,15–17; expansion of T regulatory cells
(Tregs)18; reduction of antigen presentation and co-
stimulatory molecules in antigen presenting cells,
such as dendritic cells and macrophages16; decrease
in pro-inammatory cytokines such as IL-1β, IL-2,
IL-6, IL-12, IFN-γ, TNF-α; and many others.19,20
Corroborating these clinical ndings, the
amount of experimental research that correlates
microbiota with autoimmune diseases is vast, as
shown for experimental autoimmune encephalomy-
elitis (EAE), the experimental model for MS.13,21,22
In fact, the Th17 population of T CD4+ cells, asso-
ciated with autoimmunity and pathology in many
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COVID-19 Pandemic and Dysbiosis 541
diseases, was shown to be tightly regulated by seg-
mented lamentous bacteria (SFB) in the gut.21,23
The importance of this microorganism population is
noteworthy, as it was demonstrated that mice from
two mouse suppliers, i.e., Jackson and Taconic, har-
bor different microbiota, specially SFB, and this
would impact the overall results, mainly concerning
the expansion of Th17 CD4+ lymphocytes.23 This
would render animals as more susceptible to EAE
and, more recently, to autistic-like behavior in mice
neonates.24,25 Conversely, it is worth mentioning that
Th17 and Th17-related molecules were upregulated
in COVID-19 patients.26
Besides bacteria, the role of other microorgan-
isms, such as viruses and worms, in the development
of autoimmune diseases has also been addressed.
Helminths may also be considered major actors in
this hypothesis, by promoting T-helper-2 (Th2) and
suppressing T-helper-1 (Th1), as well as Th17 lym-
phocytes.12,27 This was supported by a 4.6-year fol-
low-up study in 12 MS patients naturally infected
with parasites compared with noninfected controls.
Infected patients had reduced exacerbations and
lower disease activity, as evaluated by brain imaging,
although with minimal changes in total disability.
Similarly, as observed in EAE, this was associated
with higher levels of regulatory T-cells (Treg), IL-10,
TGF-β, and lower levels of IL-12 and IFN-γ.27
Along with their dynamic role in interacting with
and orchestrating physiological immune response,
the immunomodulatory role of worms or worm-de-
rived molecules has also been considered. A recent
randomized double-blinded placebo-controlled trial
using living Necator americanus hookworm as ther-
apeutic intervention in MS patients showed that al-
though it failed to reduce the appearance of newer
lesions on the T2 magnetic resonance image (MRI),
it showed an increment in Treg cell markers in in-
fected patients.28 Despite the failure as a therapy,
it clearly shows that worm infections modulate the
immune response. Thus, it is reasonable to think that
parasite infections may also impact both children’s
and adults’ immune systems and thus promote toler-
ance and immunomodulation.
Studies evaluating the prevalence of parasite
infections in Brazil showed 57% prevalence in 962
children between 3 and 12 years old.29 Another
study found a prevalence of 29% with a variation of
7–83% from the least infected to the most infected
school.30 In India, a recent systematic review identi-
ed six states with prevalence higher than 20% and
another with prevalence higher than 50%.31 Sim-
ilarly, the prevalence of parasitism in the French
West Indies was high in 1978, when the intestinal
parasitism was 70% in Martinique; by 1994 this
prevalence had dropped to just 8%. Conversely,
these changes in parasitic prevalence were asso-
ciated with rising prevalence of MS in the French
West Indies. The MS prevalence in 1999 was calcu-
lated at 14.8 per 100,000 inhabitants, and although
previous prevalence studies are lacking, the authors
assume from past accounts that MS was a rare entity
in the French West Indies. Interestingly, the authors
capture a trend of change in demyelinating disease
prevalence from recurrent neuromyelitis optica to
more typical MS.32
Unfortunately, there are very few studies fo-
cused on the impact of ivermectin on human micro-
biota. One study of 144 adolescents from 15 to 18
years of age treated with tribendimidine (400 mg),
tribendimidine (400 mg) plus ivermectin (200 μg/
kg), tribendimidine (400 mg) plus oxantel pamoate
(25 mg/kg), and albendazole (400 mg) plus oxan-
tel pamoate (25 mg/kg) evaluated the microbiota
by 16s sequencing.33 Although there was no group
treated with ivermectin alone, the results clearly
show an impact in microbiota composition, mainly
decreasing the abundance of bacteria from the Bac-
teroidetes phylum, the most abundant phylum of the
microbiota, 24 hours after treatment. More import-
ant, this change was maintained for up to 3 weeks
after treatment.
It is noteworthy that changes in the abundance
of Bacteroidetes have already been correlated to au-
toimmune diseases.34 In fact, RRMS patients have a
reduction in the abundance of intestinal Bacteroide-
tes.35,36 This may correlate to microbial products that
actively suppress or modulate the immune response,
such as butyrate and lipid 654, a TLR-2 ligand that
actively shifts intestinal immune response and pro-
motes tolerance. More interesting, and consistent
with this modulatory effect of Bacteroidetes or its
products over the immune response, RRMS patients
treated with disease modifying therapies (DMT)
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542 Peron et al.
have shown a restoration of Bacteroidetes levels.
Thus, despite the limitations, this study demon-
strated that ivermectin tribendimidine was able to
alter the microbiota of young subjects, which takes
around 3 weeks for full restoration.
It has also been shown that ivermectin may also
alter animal microbiota. Ivermectin + fenbendazole
changed the composition of microbiota of Amur
tiger.37 Bacteria from the phyla Actinobacteria,
Bacteroidetes, Firmicutes, and Fusobacteria were
drastically changed. Moreover, there were higher
levels of Oscillibacter, Butyricicoccus, Falsipor-
phyromonas, and Intestinimonas, and lower levels
of Clostridium XI, Staphylococcus, Saccharibacter,
Canibacter, and Megamonas. As expected, this was
associated with a concomitant change in fecal me-
tabolome in these tigers.
In summary, we highlight some relevant research
that correlates the use of ivermectin with alteration
of gut microbiota. Thus, could the indiscriminate use
of ivermectin reduce parasite prevalence or cause
dysbiosis and thus impact autoimmune diseases as
MS, postpandemically? (Fig. 1). We still don’t know.
But, we would like to call attention to the fact that
panic caused by the COVID-19 pandemic may pro-
mote self-medication with antiparasitic drugs like
ivermectin in developing countries like Brazil, and
this could impact the prevalence of neuroinamma-
tory autoimmune diseases by disrupting tolerance
mechanisms and immune regulatory mechanisms in
these populations. Although we know that dysbiosis
may be a transient phenomenon, it is possible that
even in a small window of treatment, these changes
could blunt immune tolerance and facilitate the ap-
pearance of autoimmunity.
ACKNOWLEDGMENTS
JPSP is funded by FAPESP (Grant Nos. 2017/26170-
0 and 2017/22504-1) and CNPq (301287/2016-3).
HN is funded by FAPESP (Grant Nos. 2017/50137-
3, 2012/19278-6, 2018/14933-2, 2018/21934-5 and
2013/08216-2) and CNPq (313662/2017-7). ASF is
funded by FAPESP (Grant Nos. 2017/21363-5 and
2019/06372-3).
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FIG. 1: Ivermectin use and dysbiosis. Illustrative scheme indicating that the use of ivermectin, supposedly to protect
against COVID-19, may alter gut microbiota (dysbiosis) and thus favor the expansion of bacteria that do not promote
tolerance and immune regulation, thus facilitating autoimmunity to appear.
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Critical ReviewsTM in Immunology