Probiotics and COVID-19

I Nengah Sujaya
School of Public Health Faculty of Medicine
Pusat Kajian Gut Microiota and Health,
Universitas Udayana
24 April 2020
nsujaya@unud.ac.id

Taki takining sewaka guna widya Megejar ilmu pengetahuan dan kebajikan
Topik
• Sepintas kasus COVID-19
• Pulmonary Microbiota
• Komunikasi antar Gut Microbiota dan Pulmonari
Microbiota
• Lesson learned Gut Microbiota pada kasus infeksi sal.
pernafasan oleh virus Influenza
• Modulasi sistem imun oleh Gut Microbiota
• COVID-19 –dysbiosis – pemulihan gut microbiota
• Ringkasan
COVID-19 Situation (WHO, April 21 ,
st 2020)
Spatial and temporal aspects of intestinal microbiota composition. A: variations in microbial numbers and
composition across the length of the gastrointestinal tract. B: longitudinal variations in microbial composition
in the intestine. C: temporal aspects of microbiota establishment and maintenance and factors influencing
microbial composition. Sekirov I, Russell SL, Antunes LC, Finlay BB.
Physiol Rev. 2010 Jul;90(3):859-904. doi: 10.1152/physrev.00045.2009. Review.

(C) In a healthy individual, the load of micro-organisms in the
lungs is equivalent to 103–105 bacteria per gram.
Proteobacteria, Firmicutes, and Bacteroidetes are the main
phyla present. Asthma is associated with a shift in the lung
microbiota toward greater diversity and species richness.
The lungs should be considered as an
ecosystem with its own microbiota.
(A) Maintenance of balance in the
lung microbiota: the communities of
micro-organisms in the lungs are
shaped by microbial immigration and
elimination [adapted from (Dickson et
al., 2014)].
(B) From birth onwards, the lungs are
continually exposed to diverse micro-
organisms. This diversity of bacterial
exposure, the environment and any
treatments administered may play a
fundamental role in determining
susceptibility to pulmonary disease.
Mathieu et al. Front Physiol. 2018; 9: 1168
Paradigms of Lung Microbiota Functions in Health and
Disease, Particularly, in Asthma
Eshetie and Soolingen. BMC Infectious Diseases (2019) 19:92
https://doi.org/10.1186/s12879-019-3712-1
 Intestinal–pulmonary cross-talk during respiratory health and disease
• In healthy individuals, the intestinal
and airway microbiotas harbor
diverse communities, which are
predominated by the phyla,
Bacteroidetes and Firmicutes.
• During respiratory disease a
dysbiosis of both the intestinal and
airway microbiota has been reported,
commonly presenting as an
outgrowth of Proteobacteria and
Firmicutes.
• A cross-talk between these two
microbiota compartments has been
proposed. The intestinal microbiota
influences pulmonary microbial
composition and immune responses
by both direct seeding of the
respiratory tract with bacteria and the
distribution of bacterial metabolites,
such as short-chain fatty acids
(SCFAs), which promote the growth
of certain SCFA-producing bacteria
(e.g., Bacteroidetes) and/or act
directly as immunomodulatory
,
Marsland et al, Annals ATS Volume 12 Supplement 2 November 2015 molecules.
 Link between Viral Respiratory Tract Infections and Gut Microbiota
Viral Infections
Modified from Hanada et al, 2018,
Frontiers in Immunology, Vol. 9
Local and Systemic
Immune Response
• ↑ IFNs (type I, II, III)
• ↑ Mucus Responses
• Loss of ciliary function
• Epithelial Cell death
• Cytokines (↑ IL-10 and IL-27)

Respiratory Tract
Dysbiosis
Gut Dysbiosis Alterations in Pulmonary
Immune Response
• ↑ Firmicutes (S. pneumoniae, S.
• ↑ Proteobacteria • ↓ Macrophage and aureus)
• ↓ Firmicutes neutrophil function • ↑ Proteobacteria (Haemophilus
• ↓ Anaerobic bacteria • ↓ Inflammatory cell influenza, Pseudomonas)
recruitment • ↑Actinobacteria
Influenza A Virus Infections
Shifts in the mouse gut microbiome in the setting of
influenza infection.
During an acute respiratory viral infection, changes in the
bacterial composition of the gut microbiome can be observed
despite the absence of detectable virus in the gastrointestinal
compartment. This suggests that systemic immune signals,
physiologic changes (e.g., weight loss), and other still
unknown factors are disrupting the normal ecology of the
gut, thereby leading to dysbiosis.

Hanada et al, 2018, Frontiers in Immunology, Vol. 9

 Representative mechanism of the influence of the
microbiota on influenza infection.

• (A) The migration of (B) Influenza infection

dendritic cells from changes the intestinal
the lung induced by microbiota
inflammasome composition
activation acts on mediated by IFN-γ
influenza-specific T- produced by lung-
cell responses derived T-cells
characterizing a recruited into the
mechanism of intestine.
microbiota-mediated
protection against the
influenza.
 Link between gut microbiota and viral
infections: Lesson from Influenza Virus
Infections
• During the influenza virus infection, organisms of the
[cytosolic multiprotein commensal microbiota, as well as their components
oligomers of the innate activate the inflammasome, resulting in IL-1β and IL-18
immune system ] production.

• The production of cytokines induces the migration of

dendritic cells from the lung to the draining lymph nodes,
where they act as antigen-presenting cells to prime
virus-specific B cells, CD4+ T cells, CD8+ T cells, and
macrophages.
IFN Alfa (α), Beta (β),
IFN Gamma (γ)
• Dendritic cells also secrete type I and type II interferons
to stimulate the activation of T cells or macrophages.
Limposit
(Antibodi)
• As a result, these effector cells secrete virus-specific
antibodies or inflammatory cytokines or exert direct
virus-killing effects to suppress the infection process of
the influenza virus.
Li et al, Frontiers in Immunology, vol. 10, July 2019
 • A respiratory pathogen causes
dysbiosis where the commensal
bacterial diversity is perturbed
• As a consequence of dysbiosis,
there is a disturbance of the
level and activation of
leucocytes, potentially leading to
lung damage.
• Reintroduction of beneficial
microbial strains (i.e.,
probiotics) may help to recover
a healthy status (e.g., microbiota
function and composition,
leucocyte homoeostasis, and/or
activation to control infection
and immunopathology) through
microbiota‐derived (e.g., short
chain fatty acids) or host‐derived
products (e.g., cytokines and
chemokines) at the local (lung)
or distal (gut) level.
Dumas et al, Cellular Microbiology.
2018;20:e12966.

Model of the host–microbiota interaction during dysbiosis (and microbiota restoration)

within the context of pulmonary infectious disease: the gut–lung axis
Mechanisms of
immunomodulation by
beneficial microbes.

Probiotics can modulate the immune

system in the intestine through the
luminal conversion process.

The bacteria produce secreted soluble

factors and metabolites, such as short-
chain fatty acids (SCFAs) and vitamins
using substrates from the diet. These
bioactive compounds affect the
function of intestinal epithelium and
mucosal immune cells, resulting in
production of cytokine and related
factors

Hemarajata et al, Therapeutic Advances in

Gastroenterology · December 2012
 Promotion of Immune Regulation by
the Microbiota during Steady State
and Inflammation

(Left) Commensals promote the induction of

regulatory T cells via direct sensing of
microbial products or metabolites by T cells
or dendritic cells. Further commensals
promote the induction of Th17 cells that can
regulate the function and homeostasis of
epithelial cells. In the context of
inflammation, similar mechanisms may
account for the regulatory role of the
microbiota.

(Right) Commensal-derived metabolites can

also have a local and systemic effect on
inflammatory cells. For example, SCFA can
inhibit neutrophil activation. Upon entrance in
the tissue, inflammatory monocytes can also
respond to microbial-derived ligands by
producing mediators such as PGE2 that limit
neutrophil activation and tissue damage.

Belkaid et al, Cell 157, March 27, 2014

 SARS-CoV2 (the causative agent of Covid-19)

Receptor for Covid-19 is ACE2

Speculation 1: Covid-19 related to the gut
ACE2 is known to be abundant in the
epithelia of the lungs and intestine in microbiota
humans (primarily located on the
luminal surface of differentiated
small intestinal epithelial cells) Speculation 2: Targeting gut microbiota may
be a new therapeutic option or at least an
Linked the amino acid transport function of ACE2 adjuvant therapeutic choice
to the microbial ecology in the gastrointestinal
tract
It is well known that the Speculation 3: probiotics may modulate the gut
respiratory tract has own microbiota, but patients with microbiota to alter the gastrointestinal symptoms
respiratory infections generally have gut dysbiosis, which favorably and may also protect the respiratory system
are related to a more severe clinical course of the disease,
thus indicating gut– lung crosstalk

(J Dig Dis. 2020;21:125–126)

SARS-CoV-2: a storm is raging

Cytokines storm (severe case) in Covid-

19: release of large amounts of pro-
inflammatory cytokines (IFN-α, IFN-γ,
IL-1β, IL-6, IL-12, IL-18, IL-33, TNF-α,
TGFβ, etc.) and chemokines (CCL2, CCL3,
CCL5, CXCL8, CXCL9, CXCL10, etc.) by
immune effector cells in SARS-CoV
infection

J Clin Invest DOI: 10.1172/JCI137647

Dumas et al, Cellular Microbiology.
2018;20:e12966.
 Summary
Probiotics may be a new therapeutic option or at least
an adjuvant therapeutic choice for COVID-19 via
microbiota restoration and immunomodulation.

The probiotic strain should be carefully selected to

avoid counter effects considering the state of diseases.
 Ucapan Terimakasih

Pusat kajian Gut Microbiota and Health, Fak. Kedokteran

Universitas Udaya, dr. Ni Ngh. Dwi Fatmawati, S.Ked., Ph.D.,
Sp.MK (K). yang telah menyiapkan dan memberikan
masukan kritis pada materi yang disampaikan.
Thank you
 Referensi

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