The globe is facing a new pandemic respiratory illness caused by the severe acute

respiratory syndrome coronavirus 2 (SARS-CoV-2) known as “COVID-19”. It is

extremely contagious and spreads from person to person via direct contact, droplets, or
fomites. It begins in December 2019 in Wuhan, China, and has since spread to over
213 countries, with over 300 million confirmed cases worldwide by January 26, 2022.

Introduction:

For over two years, COVID-19 has been threatening the economy and health. Despite
its ability to mutate, has alarmed scientists; its genotype is very close to the original
strain from Wuhan, China. Therefore, a need has arisen to develop effective vaccines
and targeted drug treatment regimens without neglecting adverse immune responses.

The SARS-CoV and SARS-CoV-2 enter the cell through binding to the angiotensin-
converting enzyme 2 (ACE2) receptor. SARS-CoV-2 damages the epithelial cells of the
human respiratory system, causing a pro-inflammatory cytokine storm and persistent
lung inflammation. With high mortality rates, scientists have been looking for solutions to
ease compromised immunity. Because of the coronavirus’s capacity to elude the
immune response, potentially spreads to cells other than the respiratory tract’s epithelial
cells. This directed eyes to probiotics because of their ability to improve human health
and boost immunity.

Discussion:

We attempt to summarize experimental research published in the last ten years that
provides the impact of probiotic use as a preventative strategy for respiratory viral
infections. We identified potential microbial strains depending on these experimental
data that may serve as lead preventive and immune-boosting probiotics in COVID-19
treatment. 3–6 days after the onset, COVID-19 symptoms may include fever, dyspnea,
dry cough, upper and/or lower respiratory tract complaints, myalgia, lethargy, diarrhea,
or a combination of these. Other symptoms include a headache, a sore throat,
rhinorrhea, and intestinal issues. However, it’s crucial to put the virus under the
microscope, to better understand the targeting strategies. SARS-CoV-2 is an RNA-
enveloped single-stranded virus. To analyze its whole genome, which is 29,881 bp in
length, researchers used an RNA-based metagenomic next-generation sequencing
technique (GenBank no. MN908947) encoding 9860 amino acids. Gene fragments
express structured and nonstructural proteins. The S, E, M, and N genes code for
structural proteins, whereas the ORF area codes for nonstructural proteins including 3-
chymotrypsin-like protease, papain-like protease, and RNA-dependent RNA
polymerase.)

SARS-CoV-2 has a significant number of glycosylated S proteins that bind to the host
cell receptor angiotensin-converting enzyme 2 (ACE2) and mediate viral cell entrance.
TM protease serine 2 (TMPRSS2), a type 2 TM serine protease found on the host cell
membrane, provokes virus entrance into the cell by stimulating the S protein when the S
protein attaches to the receptor. Once the virus penetrates the cell, it released the viral
RNA. The RNA genome is transcribed into a polyprotein, and the replicase–
transcriptase complex is formed by cleaving proteins and assembling the replicase–
transcriptase complex. In the host cell, viral RNA is reproduced, and structural proteins
are created, combined, and encoded before viral particles are liberated.

Probiotics

Probiotics are "nonpathogenic live bacteria that assist the human host in a variety of
".ways
Probiotics, which are commonly used to treat diarrhea, are live microorganisms or
components of dead bacteria that can control immunity by exerting resistance to
.antibiotics, xenobiotics, and pathogenicity or toxicity factors through the gut pathway

Probiotics have recently been discovered to be effective as co-adjuvants in the

treatment of metabolic illnesses such as type 2 diabetes, obesity, and metabolic
syndrome

Probiotics boost the Immune system, Microbiota and fight Covid-19.

Active components of probiotics have lately been researched in order to determine the
+3effectors of probiotic activity. The investigation of Bifidobacterium animalis subsp.
lactis BB-12 secreted proteins using two-dimensional gel combined with matrix-assisted
laser desorption ionization time-of-flight mass spectrometry showed 74 unique proteins.
Thirty-one proteins are projected to play physiological roles either within or outside the
cell, including solute-binding proteins for oligosaccharides, amino acids, and
manganese, as well as cell wall-metabolizing proteins. Interaction with human host
epithelial cells or extracellular matrix proteins is mediated by eighteen proteins.
Plasminogen binding, fimbria development, collagen adhesion, attaching to mucin and
intestinal cells, and activation of immunomodulatory responses are all possible
activities. These findings point to bacterial proteins playing a role in gastrointestinal tract
colonization, attachment to host tissues, or immune regulation of the host immune
system[1].
A Lactobacillus rhamnosus GG-derived soluble protein, p40, has already been found to
prevent and treat dextran sulfate sodium-induced intestinal damage and acute colitis, as
well as oxazolone-induced colitis. In mice models of colitis, p40 therapy decreased
intestinal epithelial apoptosis and impairment of barrier function in the colon epithelium
in such an epidermal growth factor receptor-dependent way. Furthermore, in dextran
sulfate sodium-treated animals, p40 reduced tumor necrosis factor (TNF), Interleukin-6,
keratinocyte chemoattractant, plus interferon (IFN)-production but hardly IL-1, IL-10, or
IL-17 expression, nor did it impact IL-13 production in oxazolone-treated mice. These
data indicate that p40 regulates innate immunity and also the Th1 immune response [2].

Two active compounds by Lactobacillus reuteri (RC-14), (cyclic dipeptides cyclo) (L-
Tyr-LPro) and cyclo (L-Phe-LPro), have been shown to suppress the staphylococcal
quorum-sensing system agr and reduce the expression of toxic shock syndrome toxin-1
in Staphylococcus aureus MN8, a type of bacteria in menstrual toxic shock syndrome
[3]. As a result, the chemicals produced from probiotics that have been identified may
be candidates for therapeutic applications for illness prevention and therapy.

Modification of the bacterial genome has been demonstrated as a method for enhancing
the regulatory effects of probiotics. The knockout of the phosphoglycerol transferase
gene, which modulates lipoteichoic acid biosynthesis, decreased IL-12 and TNF
production but increased IL-10 production in dendritic cells and managed the
costimulatory functions of dendritic cells, resulting in their incapability to induce CD4+ T-
cell stimulation. Furthermore, treatment with all these mutant bacteria reduced dextran
sulphate sodium and CD4+CD45RBhighT cell-induced colitis in rats. The induction of
IL-10 and CD4+FoxP3+ T regulatory cells through these mutant bacteria was linked to
reduced mucosal inflammation [4]. Thus, a better knowledge of the structure–functional
connection of probiotics with intestinal cells would improve the specific effects of
probiotics.

Probiotics help to define and manage the delicate balance between required and
excessive defensive mechanisms, such as innate and adaptive immunological
responses. Probiotics communicate with the immune system by direct interactions with
intestinal epithelial cells or through interactions with dendritic cells and follicle-
associated epithelial cells after internalization by M cells, triggering reactions mediated
by macrophages and T and B lymphocytes. Two important mechanisms behind
probiotic activity leading to immunomodulation are gene expression control and
signaling pathways in host cells.

Probiotics may help restore a healthy gut microbiota in the colonic environment and
prevent pathogenic organism colonization through a variety of processes. Probiotics, for
example, can adhere to gut epithelial cells, inhibiting pathogenic germs from sticking to
the gut wall [5]. Probiotics, once attached to gut epithelial cells, release chemicals that
inhibit pathogen growth and regulate intestinal permeability. Probiotics can also help to
restore gut health by reducing inflammation and strengthening the epithelial barrier[6].

Firstly, probiotics can improve the intestinal barrier function and prevent harmful
microorganism invasion by boosting mucin secretion[7]. Mucin is a highly glycosylated
material that is secreted into the intestinal cavity to form a mucus layer. It is distributed
in the cell membrane. Pathogenic bacteria would not be able to access the gut epithelial
cells without breaking through the mucus layer, which is the first line of defense for
maintaining the integrity of the intestinal barrier.

Second, by secreting antibacterial substances such as antibacterial peptides,

defensins, short-chain fatty acids, and bacteriocins, probiotics may directly limit
pathogen growth[8]. Finally, probiotics may improve the barrier function of the intestinal
epithelium by boosting the expression of tight junction proteins, and depletion of
essential gut commensals such as Lactobacillus and Bifidobacterium has been
frequently documented in some COVID-19 patients. These gut bacteria are recognized
to play an important-role-in-colonic-homeostas.

improving the intestinal barrier function and

prevent harmful microorganism invasion

Probiotics &Gut
microbiota

may improve the barrier function of the intestinal

epithelium by boosting the expression of tight
secreting antibacterial substances such
junction proteins as antibacterial peptides

Figure 1: How Probiotics Restore Healthy Gut microbiota.

Due to high SARS-CoV-2 infectivity, opportunistic pathogens such as Collinsella

aerofaciens, Collinsella tanakaei, Streptococcus infantis, and Morganella morganii were
found, along with an increased functional capacity for nucleotide de novo biosynthesis,
amino acid biosynthesis, and glycolysis.While the faecal metagenomes of patients with
low to no SARS-CoV-2 infectivity were characterised by abundant short-chain fatty acid
producing bacteria such as Parabacteroides merdae, Bacteroides stercoris, Alistipes
onderdonkii, and Lachnospiraceae bacterium[9].

In response to the COVID-19 epidemic, a Chinese infectious disease scientist

suggested the "four-antibody, two-balance" therapy approach, which has been
effectively adopted for treating SARS-CoV-2-associated acute respiratory distress
syndrome. The four antibodies signified antiviral, antishock, antihypertension, and anti-
infection treatment, whereas the "two-balance" related to water electrolysis acid-base
balancing and microecological balance. The microecological balancing was thought to
be especially important in the treatment because it might lead to subsequent infection of
bacteria after healing out from viral infection[10].

According to a case study report, some COVID-19 sufferers had microbial dysbiosis,
which was characterized by low levels of intestinal Lactobacillus (L.) and
Bifidobacterium (B). the majority of COVID-19 patients with mild symptoms had
received probiotics. Baud et al. summarized data from a large body of human studies
and listed various probiotics that may be relevant to trying to lower COVID-19 burden,
such as Lactobacillus casei, Lactobacillus plantarum, Lactobacillus rhamnosus,
Lactobacillus gasseri, Bifidobacterium bifidum, Bifidobacterium longum, Bifidobacterium
breve, Leu.

Gut- Lung Axis

The respiratory and gastrointestinal tissues develop from the same embryonic tissue
and have a comparable structure. While they serve different purposes, they both serve
as a physical barrier against foreign diseases. Both have their own set of commensal
microorganisms that operate as a barrier to the active spread of diseases. They have
mucosal-associated lymphoid tissue (MALT), which is essential for the immunological
function of their respective tissues. This can serve as a foundation for understanding
lung-gut interactions in health and sickness.

Both gut microbiota and the gut constitute a symbiotic whole, with microbial metabolites
benefitting the host in a range of methods and being involved in a variety of signalling
and feedback loops.
 Lung
microbiota Microbiota
dysbiosis

lymphatic lymphatic
system system

Circulatory circulatory
system system

Microbiota dysbiosis of
intestinal flora Figur
e 2: depicts a bidirectional gut-lung axis. When the content and diversity of the gut
microbiota alter, which is referred to as microbial dysbiosis, the lung immunological
might be affected via the lymphatic or circulatory systems. Likewise, the lung microbiota
can influence the gut microbiota via the lymphatic or cardiovascular system, and
intestinal flora dysbiosis can be produced by lung microbial dysbiosis and inflammatory
cytokines via the lymphatic or circulatory systems.

An abnormality in the gut microbiome (gut dysbiosis) can encourage the growth of
opportunistic infections, altering metabolic and immune responses and ultimately
leading to inflammation. Asthma and cystic fibrosis have both been related to gut
dysbiosis. Influenza was linked to alterations in gut microbial species in mice. Again,
after delivering lipopolysaccharide (LPS) to mice, which caused a change in the lung
microbiota, the gut flora revealed a matching alteration as bacteria travelled from the
lungs into the systemic circulation. This demonstrates how bacteria play a role in
mediating gut-lung connections and how dysbiosis in one arm of this axis impacts the
other[11].
Dysbiosis, including several bacterial infections, has been discovered in COVID-19
patients. According to certain researchers, some Clostridium species are more
prevalent in severe COVID-19, but Faecalibacterium Prausnitzii is diminished.

The increased severity of COVID-19 in the elderly may be due to a decrease in gut flora
variety, with decreased amounts of 'good' bacteria such as Bifidobacterium, which plays
a preventive function. These data imply that in severe COVID-19, dysbiosis treatment
with prebiotics and probiotics is critical. A mouse experiment in which transplanted
donor B lymphocytes from the stomach lymph nodes were distributed to practically
every mucosal tissue was highlighted by scientists. B lymphocytes from peripheral
lymph nodes, on the other hand, remained peripheral in their circulation. This is
characterised as the activity of all mucosal surfaces in the body working together as one
organ to guard against external infections. It might be the mechanism by which
immunisation at one mucosal location prevents infection at other mucosal interfaces[7].

Because of their gut-associated lymphoid tissue (GALT) and bronchial-associated

lymphoid tissue (BALT), the gut and lung appear to be one such interconnected
mucosal immune system (BALT). The former is densely packed with innate and
adaptive immune cells. Its abundant circulatory supply transports immune cells and
immunological components to the BALT, where they help to increase resistance to
respiratory infections. Again, a mouse experiment shown that injected lymphoid cells in
the gut were subsequently identified in the lung following activation, suggesting that
when one of these locations is stimulated, both lymph and blood interact.

The angiotensin-converting enzyme II (ACE2) enzyme controls the renin-angiotensin

system (RAS), which is essential for cardiovascular, kidney, and pulmonary blood flow
in health or sickness. It is also the receptor by which SARS-CoV-2 enters the host cell,
and it is found on lung cells as well as in the heart, blood vessels, brain, kidney, and
gut[12].

ACE2 is associated with amino acid transport in the gut and immunological
homeostasis. With SARS-CoV-2 infection, ACE2 is negatively regulated, which may
result in gut dysbiosis and, as a result, lung inflammation. Administration of particular
strains of Lactobacillus spp. in the respiratory and/or digestive system may protect
against certain illnesses including such cystic fibrosis or nosocomial pneumonitis.In an
animal model, Liu et al. discovered that generic Lactobacillus plantarum had antiviral
activity against coronavirus infection in epithelial cells of the colon[13].Many studies
found Lactobacillus rhamnosus GG to be beneficial in maintaining intestinal as well as
lung barrier homeostasis, lowering apoptosis, boosting regulatory T cells, and
decreasing proinflammatory cytokines in the gut as well as lung.

Effects of Probiotics upon Upper Respiratory Tract Infections Clinical and

preclinical trials).

We found 21 clinical studies examining the efficacy of probiotics on URTIs and otitis.
Four studies found no statistically significant difference in outcome metrics between the
probiotic and placebo groups[14]. Furthermore, Hatakka and colleagues' clinical
research revealed an increase in the prevalence of Moraxella catarrhalis in the probiotic
group. All of the other trials found that the probiotic had a favourable impact and
improved particular sickness-related outcome markers.

In these clinical studies, a variety of probiotic strains were utilised. We opted to include
three probiotic species in our study (Lactobacillus casei, Lactobacillus helveticus, and
Lactococcus lactis) that have not yet been studied in clinical trials for their effect on
URTIs. In vitro investigations, however, have revealed that they have mechanical
qualities that allow them to inhibit respiratory tract infections. As a result, they might be
viable probiotic candidates for future clinical trials.

Lactobacillus rhamnosus;

GG is the most widely utilised Lact. rhamnosus strain in URTI studies. This probiotic,
alone or in combination with Bifidobacterium animalis subsp. lactis Bb-12, decreased
the occurrence of respiratory infections and acute otitis media in children, as well as the
usage of antibiotics, The combination of these two probiotics may minimise respiratory
pathogen colonisation through local reduction as well as immunomodulation throughout
the general mucosa-associated immune system[15]. Lact. rhamnosus GG was
demonstrated to prevent nasal colonisation with pathogens such as Staph. aureus as
well as Strep. pneumoniae in adults when combined with Strep. thermophilus, Lact.
acidophilus 145, and Bifidobacterium sp B420. An immunomodulating mechanism might
be at work.

Lactobacillus acidophilus;

According to a clinical investigation employing Lact. acidophilus NCFM alone or in

combination with Bif. animalis subsp. lactis Bi-07, this probiotic lower influenza-like
complications (fever, rhinorrhoea, cough incidence and duration of antibiotic
prescription). The authors provided no explanations for this impact. Lactobacillus
acidophilus strain 145, together with Lactobacillus rhamnosus GG, Strep. thermophilus,
and Bifidobacterium sp B420, decreased nasal colonisation with pathogens such as
Staph. aureus and Strep. pneumoniae in adults, probably through an
immunomodulatory mechanism.

Auto-aggregation is one of the mechanical features of Lactobacillus acidophilus strains.

Strain CCUG 5917 has the ability to co-aggregate with microbial pathogens
(Streptococcus mutans and Streptococcus sobrinus[16]. Strains obtained from a healthy
woman's vagina may co-aggregate with vaginal microorganisms (E. coli, G. vaginalis,
and C. albicans) and compete for binding to sexual cell glycogen receptors.
Lactobacillus acidophilus CRL 1259 attaches to vaginal epithelial cells as well as
competes with Staph. aureus for survival. In culture, the isolates LB, BG2FO4, LA-1,
HNO17, LC1, and NCFM/N2 attach to human epithelial intestine cells . The strains
BG2FO4, LA-1, and HNO17 bind to intestinal mucous as well. Strain LB inhibits
diarrhoeagenic enterotoxic E. coli adherence to the brush edge of intestinal cells as well
as competes with this pathogen for attaching to enterocytic pathogen receptors via
steric hindrance. E. coli colonisation of the intestinal monolayer is inhibited by strain
HN017. Certain enteropathogens are inhibited by Lactobacillus acidophilus strain UO
001.

Bifidobacterium bifidum;

Bifidobacterium bifidum MF20/5, in combination with Lact. gasseri PA 16/8 and

Bifidobacterium longum SP 07/3, decreased the length and intensity of cold virus
symptoms through an immunostimulatory effect.In vitro, Bifidobacterium bifidum I4 has
the ability to auto-aggregate and co-aggregate alongside Clostridia[17].

Corynebacterium Co304;

Coryne. Co304, isolated from the nares of a healthy subject, inhibited and eradicated
colonisation of the nasal cavity by pathogens such as Staph. aureus utilizing a quasi-
mechanism, according to a research on volunteers followed by in vitro analysis. This
strain is capable of aggregation and may compete with Staph. aureus for such an attach
molecule[18].

Lactobacillus paracasei;

Lactobacillus paracasei 8700:2, when combined with Lactobacillus plantarum HEAL 9,

decreased the frequency of cold virus episodes and the degree of pharyngeal
symptoms. The authors provided no reason for this impact[19]. Lactobacillus casei DN-
114001, also known as Lact. paracasei subsp. paracasei in present nomenclature, is
found in Actimel with Strep. thermophilus and Lact. delbrueckii sp. paracasei. This
commonly produced fermented probiotic dairy drink decreased the length of URTIs,
notably rhinopharyngitis. Despite the fact that the researchers provided no reason for
any alteration of immunological markers (natural killer cell activity, cytokine production)
[20].

Lactobacillus plantarum;

A clinical study using Lact. plantarum HEAL 9 in conjunction with Lact. paracasei
8700:2 revealed a decrease in the occurrence and length of cold virus episodes, as well
as a decrease in the intensity of pharyngeal symptoms. The authors provided no reason
for this impact[19].

Lactobacillus plantarum 299v forms clusters with microbial pathogens (Strep. mutans
and Strep. sobrinus). Strain 299v also attaches to mucosal colonic cells and human
rectal mucosa in vitro. BFE 1685 may auto-aggregate, attach to human epithelial
intestinal cells, and co-aggregate with pathogenic microbes[21]. Lactobacillus plantarum
Bar10 competes with Salmo typhimurium and E. coli for survival. Strain 423 binds to
human epithelial intestinal cells and fights with Clostridium sporogenes and
Enterococcus faecalis for adherence.

Streptococcus thermophiles;

Strep. thermophilus OLS3059, in combination with Lact. delbrueckii subsp. bulgaricus

OLL1073R-1, lowered the chance of contracting the cold virus in healthy persons and
the elderly. Subsequent in vitro research revealed that this probiotic possesses
immunomodulating properties (Makino et al. 2010). Streptococcus thermophilus in
conjunction with Lactobacillus rhamnosus GG, Lactobacillus acidophilus 145, and
Bifidobacterium sp B420 decreased pathogenic bacterial colonisation in the nasal
cavity. This activity is thought to have an immunomodulatory impact.[22] .Streptococcus
thermophilus CHCC 3534 binds to intestinal epithelial cells and mucus pretty effectively.

Streptococcus sanguinis;

Seven clinical studies have been conducted using Streptococcus sanguinis. A total or
nearly complete disposal of middle ear fluid was seen in one clinical experiment using
strain 89a, NCIMB 40104, in children with secretory otitis media. The authors
hypothesised that the associated with clinical impact may be attributed to the activation
of antibacterial immune effector systems instead of bacterial interaction[23]. Strep.
sanguinis, when combined with Strep.mitis, reduced the frequency of group A
streptococci in individuals with early streptococcal pharyngotonsillitis. This probiotic
mixture also reduced the recurrence of tonsillitis in individuals with causes of acute
streptococcal tonsillitis or pharyngotonsillitis.

A collection of Strep. sanguinis, Strep. mitis, and Strep. oralis strains isolated from the
entrance of healthy children's Eustachian tubes reduced the recurrent of otitis media. In
another clinical experiment, the identical mix of probiotic genera isolated from healthy
children's nasopharynges showed no positive impact. Strep sanguinis strains obtained
first from entrance of healthy children's Eustachian tubes have had the ability to
antagonise pathogens such as Strep. pneumoniae, H. influenza, Mor. catarrhalis, and
Strep. pyogenes in vitro. SK36 attaches to human oral epithelial cells as well as saliva.
Aggregatibacter actinomycetemcomitans, an oral bacteria prevalent in infectious
diseases of the oral cavity, primarily periodontitis, is inhibited by strain KTH-4.

Lactobacillus helveticus;

In vitro, Lactobacillus helveticus MIMLh5 attaches to human pharyngeal cells. It fights

Strep. pyogenes by excluding and competing for cell attachment sites[24]. This probiotic
has not been tested in clinical studies for upper respiratory tract infections.

Lactococcus lactis;

Lactococcus lactis subsp. cremoris Viili has a strong affinity for human pharyngeal cells
and inhibits Strep. pyogenes. NIAI527 attaches to colonic cells as well as human
intestinal mucus. The researchers used an unspecified strain to minimize Staph. aureus
adhesion and vitality. Up to this point, no clinical studies have been done with this
probiotic[24].

Streptococcus oralis;

Strep. oralis's impact has been evaluated in two clinical studies, both of which included
a combination of Strep. oralis, Strep. sanguinis, and Strep. mitis. One of the clinical
studies yielded a favorable result, with a substantial reduction in the incidence rates of
group Some streptococci in the groups treated. Strains obtained from the entrance of
healthy children's Eustachian tubes were employed in this study. The second clinical
experiment used strains derived from normal children's nasopharynges and yielded no
good results[25]. Strep. oralis strains Parker and Booth were studied in vitro after being
isolated from the nasopharynges of individuals having adenoidectomy with hypertrophy
or recurrent otitis media. These genotypes have the ability to antagonize and decrease
the growth of harmful bacteria in the nasopharynx such as Streptococcus pneumonia,
Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pyogenes.

Streptococcus salivarius;

Streptococcus salivarius BLIS K12 Throat Guard is a probiotic supplement that is

advertised as a natural cure for the colds and the flu. Streptococcus salivarius K12
lowers halitosis and is marketed as an anti-oral malodour probiotic. In vitro, strain K12
may attach to human epithelial pharyngeal cells. It fights Strep. pyogenes via exclusion
and competitiveness. This strain significantly suppresses C. albicans development in
vitro and protects mice against oral cadidosis. Strain ST3 attaches to pharyngeal
epithelial cells in vitro, either alone or in combination with Lact. helveticus MIMLh5, and
antagonises Strep. pyogenes affects innate immunity in the host by eliciting
therapeutically preventive properties[26]. In vitro, strain NCC1561 regulates the
proliferation of oral bacteria.

Conclusion:

Probiotics are thought to change the basal and provoked inflammatory balance in
response to viral infections by adjusting the interaction between commensal
microorganisms and the mucosal immune system after delivery.
Some probiotics have antiviral preventive and therapeutic effects in upper respiratory
tract disorders, reducing the degree and amount of tissue damage caused by infection
and inflammation.
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