1 s2.0 S1756464620303042 Main

Journal of Functional Foods 73 (2020) 104080
Contents lists available at ScienceDirect
Journal of Functional Foods

journal homepage: www.elsevier.com/locate/jff
Probiotics as an alternative antimicrobial therapy: Current reality and future T

directions
Diego Romário Silvaa, Janaína de Cássia Orlandi Sardib, Nayla de Souza Pitanguic,
Sindy Magri Roquee, Andréa Cristina Barbosa da Silvaf, Pedro Luiz Rosalena,d,
⁎
a
Department of Physiological Sciences, Piracicaba Dental School, University of Campinas (UNICAMP), Piracicaba, SP, Brazil
b
Faculty of Pharmaceutical Sciences, Food and Nutrition, Federal University of Mato Grosso do Sul, Campo Grande,MS, Brazil
c
Department of Cellular and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, SP, Brazil
d
Biological Sciences Graduate Program, Federal University of Alfenas, MG, Brazil
e
Faculty of Pharmaceutical Science, State University of Campinas, Campinas, SP, Brazil
f
Department of Pharmacy, Center of Biological and Health Sciences, State University of Paraíba, Campina Grande, PB, Brazil
ARTICLE INFO ABSTRACT
Keywords: Probiotics are defined as microorganisms that live in symbiosis with the human host. When ingested in adequate
Probiotics quantities, probiotics may modulate biological functions, with health benefits. Different biological properties
Antimicrobial activity have been reported for probiotics, including antimicrobial activity. However, there are few studies investigating
Pharmacology the use of probiotics as candidates for alternative antimicrobial therapy or as a source of new antibiotics. Thus,
in this review we provide a general approach to the current situation of probiotic antimicrobial research and
point out future directions in the field. Despite the promising benefits of probiotics on intestinal health, there
remains no consensus or standardization on the development of delivery systems and on the application of
probiotic formulations for antimicrobial therapy. Thus, further bioguided studies and clinical trials are needed to
address the existing gaps in the knowledge. Future research should focus on the isolation, doses, clinical efficacy,
safety and mechanisms of action of probiotics in humans.
1. Introdution Lactobacillus and Bifidobacterium) (Marco, Pavan, & Kleerebezem,

2006).
Immediately after birth, the human body is colonized by different The probiotics that colonize the human host are most numerous in
microorganisms, such as archaea, bacteria, fungi, viruses and micro- the intestines. The commensal intestinal microbiome contributes to
eukaryotes (Aagaard et al., 2014). Over time, colonization occurs so increased resistance against infections, host immune system differ-
intensely that the human microbiome of an adult individual contains entiation, and synthesis of nutrients (Ubeda & Pamer, 2012).
more bacterial cells than human cells (Sender, Fuchs, & Milo, 2016). There is evidence that probiotics may act in the treatment and
Different types of microorganisms can cause disease in humans and prevention of infectious diseases (Yang et al., 2019). Currently, in-
some of which have a high fatality rate (Peterson et al., 2009). For fectious diseases are commonly managed with the administration of
many years, scientific research has focused on understanding patho- antibiotics. However, an irrational use of antibiotics may cause con-
genic bacteria and finding ways to preventing and treating human sequences at the patient level, such as drug-specific adverse effects, and
diseases. Conversely, some bacterial species may bring benefits to the at the public health level, such as selection of multidrug-resistant bac-
host through a symbiotic relationship. These microorganisms are gen- teria (Yang et al., 2019). Thus, the search for new alternatives in an-
erally named probiotics (Fijan, 2014). timicrobial therapy is much needed, with a special interest in natural
Probiotics are living microorganisms that provide health benefits product-based therapies (Silva et al., 2019).
when ingested in adequate amounts (FAO/WHO, 2001). Most probiotic Clinical trials have shown that probiotics are effective against a
bacteria are Gram-positive, and their main functions are related to wide range of pathological conditions, such as constipation, diarrhea,
modulation and maintenance of the intestinal tract health (e.g., polycystic ovary syndrome, ulcerative colitis, stress and anxiety,
⁎
Corresponding author at: Department of Physiological Sciences, Piracicaba Dental School, State University of Campinas, Av. Limeira, 901 – Areião, Piracicaba, SP
CEP: 13414-018, Brazil.
E-mail address: rosalen@fop.unicamp.br (P.L. Rosalen).
https://doi.org/10.1016/j.jff.2020.104080
Received 29 December 2019; Received in revised form 15 June 2020; Accepted 22 June 2020
Available online 31 July 2020
1756-4646/ © 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
D.R. Silva, et al. Journal of Functional Foods 73 (2020) 104080
Fig. 1. Mechanisms of action of probiotics. (A) Competitive exclusion of pathogenic microorganisms. (B) Production of antimicrobial substances. (C) Increased
adhesion to the intestinal mucosa and improvement of the epithelial barrier. (D) Stimulation of the immune system.
inflammatory bowel disease, breast cancer and diabetes (Kechagia in different industrial food processes (König & Fröhlich, 2009).
et al., 2013). The main biological mechanisms of action of probiotics include
Despite the proven biological properties of probiotics, such as an- increased epithelial barrier, increased adhesion to the intestinal mucosa
timicrobial activity, research in this area is still incipient and needs and inhibition of microbial adhesion and competitive exclusion of pa-
further discussion. Thus, this review provides a general approach to the thogenic microorganisms, production of antimicrobial substances and
current situation of probiotic antimicrobial research and points out immune system modulation (Bermudez-Brito et al., 2012). Fig. 1 shows
future directions in the field. a schematic representation of how these mechanisms occur in the in-
testinal mucosa.
2. Probiotics Microorganisms of the LAB group produce lactic acid from different
carbon sources, such as simple carbohydrates (Carr, Chill, & Maida,
Ancient civilizations, such as Greeks and Romans, developed recipes 2002). In addition, they eliminate secondary metabolites (e.g., bacter-
for fermented milk, and the Bible mentions sour milk a few times. Thus, iocins, exopolysaccharides and enzymes) that inhibit the growth of
the beneficial effects of lactic acid fermentation on human health have other microorganisms. These factors are related to the different anti-
been long discussed (Hosono, 1992). microbial mechanisms of action of probiotics (Leroy & De Vuyst, 2004,
Probiotics are living microorganisms (yeast or bacteria) that provide de Melo Pereira et al., 2018). These mechanisms are well understood in
beneficial effects while colonizing the host. Lactic acid bacteria species improving bowel function, as shown in Fig. 1. However, the literature is
(Lactococcus, Lactobacillus, Streptococcus and Enterococcus) and still incipient regarding the potential of probiotics for alternative anti-
Bifidobacterium (Doron & Snydman, 2015; Prado & de Lindner, 2015; microbial therapy against infectious diseases.
Soccol et al., 2015) are among the best-known probiotics. These mi-
croorganisms have characteristics that give them the ability to with- 3. Methods for determining the antimicrobial activity of
stand adverse conditions in the host organism, such as enzymatic action probiotics against other microorganisms
and acidity. They can colonize the host and contribute to health by
regulating the microbiome and performing biological functions (de There are different in vitro methods for determining the anti-
Melo Pereira et al., 2018). microbial activity of a substance. In the case of probiotics, it is possible
There is mounting evidence on the biological efficacy of probiotics; to determine a direct antagonism between a probiotic culture and that
however, the indication of these microorganisms for clinical use should of a pathogenic strain or to determine the antimicrobial activity of a
be seen with caution (de Melo Pereira et al., 2018). In 2002, the United probiotic extract (planktonic cells) (Fijan, 2016). When the purpose of
Nations Food and Agriculture Organization/World Health Organization the analysis is merely to discover the antagonism of one microorganism
(FAO/WHO) published the “Guidelines for the Evaluation of Probiotics in relation to another, then microbial antagonism assays on solid media
in Food.” These guidelines established safety and efficacy standards for are most appropriate (Tagg, Dajani, & Wannmaker, 1976; Balouiri,
probiotics, systematizing their discovery and selection (Araya et al., Sadiki, & Ibnsouda, 2016). This approach involves the detection of
2002). Thus, the FAO/WHO guidelines suggest different criteria that growth inhibition of an indicator strain caused by the test culture. In
should be evaluated for the selection of probiotics, namely: resistance to this section, we make a critical analysis of the main methods currently
unfavorable conditions in the human body, ability to adhere to epi- available for in vitro evaluation of the antimicrobial activity of pro-
thelial tissues, antimicrobial activity, and safety for use (de Melo biotics.
Pereira et al., 2018). The safety of a probiotic strain is defined by its The Agar Spot Test was described by several authors (Tagg et al.,
origin and lack of association with pathogenic cultures, in addition to 1976; Tharmaraj & Shah, 2009; Choi & Chang, 2015; Macaluso et al.,
its antibiotic resistance profile (Markowiak Slizewska, 2017a,b). 2016), with several modifications over time. We describe here the
Lactobacillus is considered the oldest documented probiotic. It is a variation of this method that is mostly indicated to determine the an-
genus with Gram-positive bacteria of the LAB group. These rod-shaped timicrobial activity of probiotics. There are two variations of this
bacteria comprise about 183 known species and are commonly applied method that are commonly used, namely: simultaneous (or direct) and
2
deferred antagonism. In the direct assay, the test and indicator cultures activity of a substance. Several approaches have been standardized for
are grown simultaneously, and the demonstration of antagonism de- this purpose, such as modified Robbins device, Calgary biofilm device,
pends on the release of a diffusible inhibitor at the beginning of the test disk reactor, Centers for Disease Control (CDC) biofilm reactor, per-
culture growth (Tagg et al., 1976). In deferred antagonism, the pro- fused biofilm fermenter, and bladder model (Kırmusaoğlu, 2019). The
biotic microorganism under test is grown on agar media for a certain analysis of biofilms involves many techniques ranging from older es-
period and then inactivated; next, an overlap of the indicator strain is tablished methods – such as counting of bacterial colonies – to more
placed on the surface of the on the molten agar. This method is con- modern techniques – such as fluorescent labeling of biofilms in com-
sidered more sensitive and allows an independent variation of time and bination with mathematical predictive modeling, such as COMSTAT
incubation conditions of test and indicator cultures (Tagg et al., 1976). (Wilson et al., 2017). The studies screening for the antibiofilm activity
After incubation, the antimicrobial activity is expressed either as in- of probiotics are even more limited than those testing planktonic cul-
hibition zone (mm) or as arbitrary units (AU/mL). tures. However, some studies have evaluated this biological activity of
The Agar Well Diffusion assay can be used to determine the an- probiotics by different methods and with different ways of analyzing
tagonistic effects of cell-free supernatants. Different nutrients, selective the results (Missaoui, Saidane, Mzoughi, & Minervini, 2019; Manna,
or differential media, are prepared. The plates are inoculated with the Ghosh, & Mandal, 2019; Hager et al., 2019; Mahdhi et al., 2018;
indicator microorganism. Subsequently, 6-mm or 7-mm wells are pre- Abdelhamid, Esaam, & Hazaa, 2018; Aarti et al., 2018; Cui, Yan et al.,
pared in each plate. The supernatant of the probiotic microorganism is 2018; Cui, Shi et al., 2018). There is no consensus on what the most
centrifuged and diluted in aliquots at different concentrations and then cost-effective method is to determine the antibiofilm activity of pro-
pipetted into the wells. After incubation, the antimicrobial activity is biotic microorganisms.
expressed as an inhibition zone or as arbitrary units (AU/mL) (Tagg Another challenge for the alternative antimicrobial therapy or any
et al., 1976; Parente, Brienza, Moles, & Ricciardi, 1995). We do not other therapy is that in vitro results can be reproducible in in vivo
recommend using the disk diffusion method for this purpose because of models and, subsequently, in the human body. In vivo testing should be
standardization issues due to variations between the viscosity of the test very well designed to avoid bias. To establish the efficacy of the pro-
substance and the physical differences of the discs (Hoelzer et al., 2011; biotic product, randomized, double-blind, placebo-controlled clinical
Balouiri et al., 2016). trials should be performed (Fijan, 2016). To determine if a probiotic can
A study tested 104 strains of Lactobacillus acidophilus to compare prevent or treat a specific pathogen infection, two types of study can be
broth microdilution, disc diffusion and Etest methods in determining performed: a preventive study (clinical study to check if exposure to
the antimicrobial activity of probiotics. Except for some specific agent- that pathogen is prevented after probiotic use) or an interventional
related effects, there was a good agreement between Minimum study (prior exposure to the pathogen and subsequent treatment with
Inhibitory Concentration (MIC) values in the broth microdilution the probiotic or its supernatant) (Fijan, 2016). In many cases, animal
method and the Etest. Another study demonstrated a higher capacity of model results are not reproducible in humans. To prevent this problem,
cell-free supernatants of Lactobacillus plantarum strains against patho- it is possible to use alternative methods, such as 3D cell cultures and
genic bacteria in liquid medium than on agar plates (Mayrhofer et al., human tissues.
2008). However, given the importance of obtaining a MIC value for Although clinical trials in humans are considered mandatory for
determining possible dosages in in vivo tests (Turnidge, 1990; Mouton establishing the health benefits of probiotics, a few strains that showed
et al., 2018), we recoomend the broth microdilution method when the positive results have been employed after legal authorities were con-
objective of the analysis is to screen biomolecules for their potential vinced about these health claims. This may dramatically impact the
antimicrobial drug. validity of workflows currently used to characterize probiotics
Microdilution is one of the simplest and most reproducible methods (Papadimitriou et al., 2015). Thus, in order to optimize and standardize
for antimicrobial susceptibility screening. The procedure involves the the selection and use of probiotics for antimicrobial therapy, we re-
preparation of 1:2 dilutions of the antimicrobial agent (cell-free su- commend conducting research in the form of a bioguided study. Bio-
pernatant), (e.g., 32, 64, 138, 256, 512 µg/m) in a liquid growth guided studies aim to monitor the biological activity of interest, in-
medium dispensed into a 96-well microplate. Subsequently, each well is creasing the chances of isolating a compound with high biological
inoculated with a standard inoculum of the pathogenic strain (0.5 potential; this type of study has been indicated for the discovery and
McFarland) and the plate is incubated after mixing under conditions establishment of new therapies (Pieters & Vlietinck, 2005; Porte et al.,
appropriate for each microorganism. The broth microdilution method 2014). Fig. 2 summarizes our proposed bioguided study for monitoring
provides the MIC value, which is the lowest concentration of the anti- the antimicrobial properties of probiotic microorganisms.
microbial agent that completely inhibits microbial growth (Balouiri
et al., 2016). For details on broth microdilution testing and its specific 4. Antimicrobial activity of probiotics against human pathogens
conditions for each microorganism, we suggest consulting the Clinical
Laboratory Standards Institute (CLSI) guidelines. According to the United Nations Food and Agriculture Organization
The antimicrobial activity proven by agar susceptibility or broth and the World Health Organization, probiotics are living microorgan-
microdilution methods unfortunately does not characterize a probiotic isms that confer a benefit to the health of the host when administered in
microorganism as promising, as there are other factors to consider. In adequate amounts (FAO/WHO, 2019).
the microbiological viewpoint, an extremely important factor is the Currently, the main probiotic microorganisms used by humans are
ability of microorganisms to develop as biofilms (Flemming et al., Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus plantarum, L.
2016). Bacterial biofilms are formed by communities embedded in a acidophilus, L. casei, L. casei Shirota, L. paracasei, L. reuteri, L. johnsonii, L.
self-produced matrix of extracellular polymeric substances. Organized plantarum e L. rhamnosus L. reuteri, L. rhamnosus, L. paracasei,
as a biofilm, microorganisms exhibit different living conditions than Bifidobacterium bifidum, B. infantis, B. lactis, Saccharomyces bourlardii,
when in planktonic growth. Biofilms also serve as a physical barrier and and Propionibacterium freudenreichii (Morais & Jacob, 2006; Lesbros-
exhibit a genotype that provides increased virulence, which makes Pantoflickova, Corthesy-Theulaz, & Blum, 2007; Reddy & Narendera,
them up to 1000 times more resistant to antimicrobials than planktonic 2010; Sikorska & Smoragiewicz, 2013; Markowiak Slizewska, 2017a,b).
bacteria (Donlan & Costerton, 2002; Marsh, 2004; Flemming et al., In recent years, several studies have revealed benefits in the ad-
2016). ministration of probiotics, ranging from direct inhibition of pathogenic
A standardized assay to assess the activity of antibiofilm agents has microorganisms to improvements in host immune system functions
not been established yet. However, there are different methods avail- (Sajedinejad et al., 2017; Lopes, Moreira et al., 2017; Rossoni et al.,
able for studying biofilms as well as for evaluating the antibiofilm 2017; Markowiak Slizewska, 2017a,b; Goderska, Agudo Pena, &
3
Fig. 2. Proposed bioguided study for monitoring

the antimicrobial activity of probiotic micro-
organisms. (A) Probiotic microorganism isolated
from any source. (B) Biomonitoring (B1- de-
termination of in vitro antimicrobial activity and
B2 - probiotic resistance to hostile conditions.
Upon confirming promising results in
Biomonitoring 1, start Biomonitoring 2 (C),
which is the in vivo analysis of antimicrobial
properties. After obtaining promising results in
an animal model, move forward to
Biomonitoring 3 (D) to evaluate biological
properties and safety in alternative models of 3D
cell cultures and human tissues. At this point,
two approaches are possible, namely: clinical
trials in humans (E) to determine an alternative
antimicrobial therapy, or the analysis and iso-
lation of probiotic-derived molecules (F) to de-
velop a new antibiotic (monodrug). After de-
tection of supernatant components of the
antibiotics and their isolation, these molecules
should again pass through the three biomoni-
toring phases (F, G, H and I) added of toxicity
assays. Finally, the most promising molecule is
submitted to human clinical testing for the de-
velopment of the new antibiotic.
Table 1 Alarcon, 2018; Moraes, Costa, Segundo, & Peruzzo, 2019). Table 1
Most studied probiotic microorganisms with antimicrobial activity. Adapted shows the main probiotic microorganisms with antimicrobial effects.
from (Marco et al., 2006; Lesbros-Pantoflickova et al., 2007; Reddy & The use of probiotics has intensified, but the vast majority of studies
Narendera, 2010; Sikorska & Smoragiewicz, 2013; Ouwehand et al., 2016; relate them to intestinal health (Underwood, 2019).
Markowiak Slizewska, 2017a,b; Wong et al., 2019). The use of probiotic microorganisms is intended to support the
Lactobacillus Bifidobacterium Other bacteria health of the host. The literature shows a large number of studies using
probiotics, but most of them explain only how probiotics can maintain
L. acidophilus B. bifidum Saccharomyces bourlardii
the intestinal health of the host. The mechanisms of action of probiotics
L. amylovorus B. infantis Propionibacterium freudenreichii
L. casei B. lactis Enterococcus faecalis are various, such as the production of inhibitory substances, such as
L. crispatus B. adolescentis Enterococcus faecium bacteriocins and hydrogen peroxide, which inhibit Gram negative and
L. plantarum B. animalis subsp. lactis Lactococcus lactis Gram positive pathogenic bacteria; blockage of adhesion sites; compe-
L. casei Shirota B. longum R0175 Leuconstoc mesenteroides tition for nutrients; among others (Kanmani et al., 2013; Neal-
L. paracasei B. breve Pediococcus acidilacticiei
L. rhamnosus Sporolactobacillus inulinus
McKinney et al., 2012; Sikorska & Smoragiewicz, 2013; Markowiak
L. reuteri Streptococcus thermophilus Slizewska, 2017a,b; Moraes, Costa, Segundo, & Peruzzo, 2019). Pro-
L. johnssonii Escherichia coli biotics participate in immune response modulation in several ways,
L. helveticus R0052 Saccharomyces cerevisiae var. namely: by increasing nonspecific phagocytic activity through macro-
boulardi
phage activation (Jain et al., 2008) and altering the release of pro and
L. fermentum Bacillus coagulans
anti-inflammatory cytokines (Dong, Rowland, & Yaqoob, 2012; Zhao
et al., 2012; Ganguli et al., 2013; Plaza-Díaz et al., 2017).
Several probiotic species are widely used in research (Villena et al.,
4
Table 2
In vivo and ex vivo studies reporting the antimicrobial activity of probiotics.
Probiotic Objective Conclusion Reference
Lactobacillus casei In vivo study, comparing the therapeutic effectiveness Oral administration of the probiotic L. casei Shukla et al., 2013
of the probiotic L. casei alone and together with associated with albendazole reduced Giardia
antiprotozoal drugs against giardiasis in a murine infection, as evidenced by the normal recovered
model. intestinal morphology.
Lactobacillus rhamnosus HS111, Randomized double-blind study with 59 denture Decrease in Candida spp. in individuals who used Ishikawa et al., 2015
Lactobacillus acidophillus HS101 and wearers who had Candida spp. in the oral cavity the probiotic formulation.
Bifidobacterium bifidum
Bifidobacterium animalis subsp. Lactis Randomized controlled trial with 51 patients using The use of yogurt supplemented with B. animalis Eren, Laleman,
yogurt for four weeks supplemented with B. animalis can have a positive effect against the accumulation Yalnizoglu, Kuru, &
for periodontal health of bacterial plaque and gingival inflammatory Teughels, 2017
parameters.
Lactobacillus salivarius Randomized double-blind study with development of The results suggest that the mouthwash containing Sajedinejad et al., 2017
an experimental mouthwash for the treatment of probiotics was healthy for daily use as an
periodontitis. alternative to maintain dental and periodontal
health.
Lactobacilus paracasei In vivo study. Lactobacilus paracasei was used to treat L. paracasei was able to modulate the immune Rossoni et al., 2017
Candida albicans infection in Galleria mellonella larvae. system of G. mellonella and protect against
The number of hemocytes and gene expression of candidiasis.
antifungal peptides were further assessed.
Lactobacillus reuteri DSM 17938 Use of L. reunteri to ameliorate inflammation in an ex The probiotic decreased the inflammatory process Khmaladze et al., 2019
vivo skin model, and in vitro antimicrobial activity and presented antimicrobial action against S.
against skin pathogens. aureus, S. pyogenes, Cutibacterium acnes, and P.
aeruginosa.
2016; Yang et al., 2014; Yun, Oh, & Griffiths, 2014). Among these as decreased production of pyocyanin, decreased production of pro-
benefits are antimutagenic (Yu & Li, 2016; So, Wan, & El-Nezami, teases and rhamnolipid, and decreased biofilm formation on the surface
2017), anticarcinogenic (Wollowski, Rechkemmer, & Pool-Zobel, 2001; of stainless steel. Another study conducted by Moraes, Costa, Segundo,
Casas-Solís et al., 2019; Devaraj et al., 2019) and antidiarrheal prop- and Peruzzo (2019) showed that Lactobacillus brevis and Bifidobacterium
erties (Liu et al., 2017; Devaraj et al., 2019), immune system stimula- bifidum were effective against S. aureus biofilms grown on titanium
tion (Casas-Solís et al., 2019), prevention of atopic dermatitis (Rather discs. The results showed reduction of S. aureus growth on titanium
et al., 2016; Huang et al., 2017; Lise, Mayer, & Silveira, 2018) and discs when both probiotics were used, but the greatest inhibitory effect
reduced blood cholesterol (Shimizu et al., 2015; Nath et al., 2018). on biofilm formation was observed for L. brevis strains.
Thus, the use of probiotics has been considered a promising strategy Other study performed by Sikorska and Smoragiewicz (2013) de-
for the prevention and control of various infectious diseases monstrated that the probiotics Lactobacillus reuteri, L. rhamnosus GG,
Tahmourespour, Salehi, Kermanshahi, & Eslami, 2011; Ishikawa et al., Propionibacterium freudenreichii, P. acnes, L. paracasei, L. casei, L. plan-
2015; Matsubara et al., 2016; Eren, Laleman, Yalnizoglu, Kuru, & tarum, L. bulgarocus, and L. fermentus inhibited methicillin-resistant S.
Teughels, 2017; Sajedinejad et al., 2017; Lopes et al., 2017; Rossoni aureus (MRSA) biofilm formation, possibly by competition and pro-
et al., 2017; Goderska, Agudo Pena, & Alarcon, 2018; Moraes, Costa, duction of acids and/or bacteriocin inhibitors.
Segundo, & Peruzzo, 2019). Table 2 shows in vivo/ex vivo studies that A review performed by Goderska et al. (2018) showed that Helico-
validated the antimicrobial activity of probiotics. bacter pylori (H. pylori) has been regarded as a difficult-to-treat infection
There are a multitude of probiotic formulations that are supposed to mainly because of acquired resistance to commonly used antibiotics.
benefit human health, including immunostimulatory effects or inter- There is a growing interest in using probiotics in combination with
bacterial competition between beneficial and pathogenic bacteria antibiotic regimens to eradicate H. pylori. Probiotics have been proven
(Piewngam et al., 2019). In this context, the use of probiotics has been to be useful in the treatment of several intestinal diseases such as
considered a promising strategy for the prevention and control of var- diarrhea, in addition to the benefits of probiotic bacteria to the in-
ious infectious diseases. testines; some beneficial effects on the stomach have also been re-
A study performed by (Lahtinen et al., 2007) showed that three of ported, including anti-Helicobacter pylori activity (Aiba et al., 2017).
38 Bifidobacterium strains were able to inhibit the growth of Staphylo- The benefits of probiotic therapy in H. pylori cases are decreased mi-
coccus aureus, which is commonly found in systemic and peri-implant crobial load and improved host tolerability. Several studies have shown
infections. Lazarenko (2012) investigated the antibacterial activity of favorable effects of different probiotics against H. pylori by strength-
several probiotic Lactobacilli strains. The authors reported that Bifido- ening the mucosal barrier, while promoting competition for adhesion
bacterium bifidum (B. bifidum) was mostly effective against S. aureus in and immunomodulation.
an intravaginal infection model in mice, with a significant reduction in Klebsiella pneumoniae (K. pneumoniae) is a multi-resistant opportu-
the number of S. aureus cells from vaginal smears. B. bifidum showed the nistic pathogen able to colonize the human gut, with a high ability to
best anti-staphylococcal activity when compared to other probiotic form biofilm. In a study conducted by Lagrafeuille et al. (2018), the
strains of different genera. anti-biofilm activity of 140 species of Lactobacillus (supernatant cul-
Piewngam et al. (2018) identified an inverse correlation between tures) was evaluated against K. pneumoniae. Of this total, the super-
human colonization with Bacillus species and S. aureus. The authors natant of 13 strains significantly impaired biofilm formation, including
further discovered a primary mechanism by which Bacillus species can that of Lactobacillus plantarum (L. plantarum) CIRM653 – which was also
kill S. aureus through the inhibition of quorum sensing. Fengycins are a able to disrupt K. pneumoniae preformed biofilms. The association of K.
specific classes of lipopeptides secreted by Bacillus species – identified pneumoniae with L. plantarum CIRM653 showed reduced three-dimen-
by chromatography and mass spectrometry – that also present anti- sional structures associated with a decrease in K. pneumoniae biomass.
fungal activity (Chung & Raffatellu, 2019). Lee et al. (2019) studied the Research has shown that L. plantarum CIRM653 supernatant induced
probiotic Pediococcus acidilactici HW01 against Pseudomonas aeruginosa transcriptional modifications of K. pneumoniae biofilm-related genes,
(P. aeruginosa) and observed decreased motility of P. aeruginosa as well including down-regulation of quorum detection-related lsr operons and
5
overexpression of the type 3 pili structure genes. Another in vivo study biofilms.
by Vieira et al. (2016) demonstrated that Bifidobacterium longum 5 can Liao et al. (2019) analyzed the effects of L. casei administration for
reduce K. pneumoniae infection in mice. This probiotic protected mice vaginal candidiasis in an experimental model of C. albicans-infected
from K. pnemoniae lung infection, specifically by inducing secretion of mice. For the prophylactic test, the animals were submitted to vaginal
pro-inflammatory cytokines and neutrophil recruitment, and decreasing inoculation of L. casei for 7 days. Next, the animals were infected with
bacterial load in the lung, thereby reducing lethality rates by 50%. C. albicans into the vaginal cavity, and two days after the infection, all
Recent studies by Xu et al. (2020) suggested that patients affected mice were euthanized, and the number of CFU/mL was determined. In
by COVID 19 should use probiotics to avoid secondary infections. Some the therapeutic assays, the animals were infected with C. albicans, and
patients with COVID-19 had intestinal microbial dysbiosis. The nutri- after 2 days, they received L. casei for five days. Next, the number of
tional and gastrointestinal functions must be assessed in all patients. CFU/mL in the vaginal samples were determined. The results showed
Nutritional support and application of probiotics are suggested to reg- that prophylactic administration of L. casei was able to improve the
ulate the balance of the intestinal microbiota and reduce the risk of immunity of vaginal mucosa, increasing the production of IL‐17 during
secondary infection due to bacterial translocation. the infection. IL‐23 levels were lower than those in the control group,
Annual mortality rates from infectious diarrhea are about 2.2 mil- showing that L. casei also had anti‐inflammatory properties. Regarding
lion. Children are more vulnerable to severe gastroenteritis, and group to the therapeutic group, L. casei reduced the fungal vaginal burden
A rotavirus is the main cause of the disease. Studies by Gonzalez-Ochoa after a 5-day treatment.
et al. (2017) demonstrated that the association of probiotics, such as Krzyściak et al. (2017) studied L. salivarius as a possible probiotic
Bifidobacterium and Lactobacillus species, in combination with pre- candidate against mixed biofilm cultures of C. albicans and Streptococcus
biotics, showed an improved anti-rotavirus response by reducing in- mutans (S. mutans), since this microbial association has been implicated
fectiousness and increasing rotavirus-specific anti-IgA levels. In addi- in the progression of early childhood caries. The probiotic treatment
tion, these probiotics have been linked to a shorter duration and reduced the biofilm mass and the number of S. mutans and C. albicans
severity of diarrhea due to rotavirus infection, not only preventing the cells. Moreover, C. albicans cells treated with L. salivarius had their
infectious process, but also contributing to a lower incidence of re- ability to form hyphae or germ tubes significantly impacted.
infections. Poor skin conditions can affect the patient's quality of life because of
Evidence indicates that the pathogenic potential of Candida spp. discomfort. Human skin is composed of numerous fungi and bacteria
also depends on their ability to produce biofilms on abiotic and biotic that live in symbiosis (Mottin & Suyenaga, 2018). Acne and Atopic
surfaces (Ribeiro et al., 2019). Nyanzi et al. (2014) investigated the Dermatitis (AD) are chronic skin conditions which require long periods
anti-Candida activity of the crude extract of 13 different Lactobacillus of treatment and maintenance. Studies have shown that the use of
strains. The authors found MIC values ranging from 1.25 to 10 mg/mL. probiotics in these cases has shown good results without adverse ef-
Wannun et al. (2016) studied the antimicrobial activity of supernatant fects. In vitro studies have shown the capacity of probiotics, such as
cultures of L. paracasei and identified a protein with a molecular weight Streptococcus salivarius and Enterococcus faecalis, to directly inhibit P.
of approximately 25.000 Da, which showed antimicrobial activity acnes growth through the production of antibacterial proteins (bacter-
against Gram-positive, Gram-negative bacteria and yeast in in vitro iocins) and immunomodulatory effects. Probiotics have been shown to
microdilution tests. have direct benefits (by inhibiting P. acnes) and indirect benefits (by
Orsi et al. (2014) verified that the crude filtrate supernatants from L. decreasing the inflammatory response) (Kober et al., 2015; Bowe et al.,
acidophilus ATCC 314, L. rhamnosus ATCC 7469, L. plantarum ATCC 2006).
8014 and L. reuteri ATCC 55730 were able to affect both Candida albi- In a clinical study using Lactobacillus plantarum (L. plantarum) ex-
cans (C. albicans) hyphae formation and preformed and mature biofilm tract, Muizzuddin et al. (2012) observed a reduction in mild acne le-
development. The inhibitory effects were Lactobacilli strain-dependent. sions, with amelioration of erythema and skin barrier reconstruction.
L. plantarum, L. acidophilus and L. reuteri impaired biofilm formation A study performed by Oh et al. (2006) reported an inhibitory effect
and only L. plantarum and L. reuteri disrupted biofilm cells. Recent of a bacteriocin produced by Lactococcus sp. HY 499 against S. epi-
studies have also confirmed that Lactobacillus spp. can reduce C. albi- dermidis, S. aureus and P. acnes, in a patch test. The authors suggested
cans hyphae formation (Ribeiro et al., 2017; Santos et al., 2019) by the use of this bacteriocin produced by Lactococcus sp. HY 449 as an
releasing antimicrobial compounds. antimicrobial agent in cosmetic formulations. A lack of normal micro-
Chew et al. (2015) used L. rhamnosus GR-1 and L. reuteri RC-14 to bial skin diversity combined with an abundance of staphylococcal
treat Candida glabrata (C. glabrata). Biofilm formation was evaluated by species in patients with atopic dermatitis further leads to disruption of
scanning electron microscopy (SEM) and genes related to biofilm for- skin‐barrier homeostasis (Knackstedt, Knackstedt, & Gatherwright,
mation were also analyzed. The SEM analysis revealed disrupted mixed 2020). The absence of allergic reactions and irritation consists of a great
biofilm cultures of C. glabrata and probiotic lactobacilli. In addition, the advantage for the use of probiotics compared to current treatments
biofilm-related C. glabrata genes EPA6 and YAK1 were downregulated (Powers et al., 2015). The inhibitory effects on P acnes, S. epidermidis
in response to the probiotic lactobacilli challenges. and S. aureus are relevant, as the same probiotic can be potentially used
Rossoni et al. (2017) evaluated the protective action of probiotics to treat different skin conditions.
against C. albicans infection. Exposure to a dose of L. paracasei 28.4 Studies indicate that individuals with atopic dermatitis have an
activated the immune system of Galleria mellonella larvae, which may abundance of Staphylococcus aureus, when compared with individuals
allow the larvae to modulate C. albicans infection. These results show without the disease. Such an imbalance may be related to the break-
that probiotics can affect the immune response of larvae. Other study down of the skin barrier (D’Auria et al., 2016), which results in an in-
performed by Rossoni et al. (2018) evaluated the inhibitory effects of effective protection from allergens and microorganisms.
probiotic microorganisms on three C. albicans strains. Thirty lactobacilli A group of researchers led by Kawahara (Kawahara, Hanzawa, &
strains were isolated and tested for their antimicrobial activity against Sugiyama, 2018) evaluated the topical application of homogenized
C. albicans biofilms in vitro. L. paracasei 28.4, L. rhamnosus 5.2 and L. Lactobacillus reuteri in water and showed that there was significant
fermentum 20.4 isolates exhibited the most significant inhibitory ac- suppression in the development of atopic skin lesions induced by mites
tivity against C. albicans, disrupting biofilm development and retarding and other pathogens.
hyphal formation. qPCR analysis showed that the ALS3, HWP1, EFG1 In another study, Rosignoli et al. (2018) tested whether the topical
and CPH1 genes were downregulated after treatment with the probiotic application of Lactobacillus johnsonii could inhibit S. aureus adhesion to
microorganisms. L. paracasei 28.4, L. rhamnosus 5.2 and L. fermentum the skin and increase innate skin immunity. The authors demonstrated
20.4 demonstrated antifungal activity through inhibition of C. albicans that application of this suspension reduced S. aureus adhesion by up to
6
Fig. 3. Schematic representation of the encapsulation of probiotic microorganisms using a biocompatible matrix for delivery of therapeutic substances to the site of
action.
74% and modulated endogenous expression of antimicrobial peptides 5. Probiotic encapsulation for delivery to the action site
(AMPs).
A study conducted by Navarro Lopes et al. (2018) determined the The benefits of probiotics to human health are unequivocal.
effectiveness of a mixture of oral probiotics. The authors showed a However, for these beneficial bacteria to exercise their biological ac-
significant decrease in the SCORAD index [Scoring of Atopic Dermatitis tivities effectively, the number of viable organisms must be greater than
(SCORAD) index] in the experimental group when compared to the or equal to 107 CFU/mL or gram of product in use (Rossier-Miranda
control. In addition, they demonstrated that the probiotic mixture re- et al., 2010; Serna-Cock & Vallejo-Castillo, 2013). In addition, the
duced the use of topical steroids in individuals with moderate atopic survival of probiotic microorganisms can be affected by different factors
dermatitis (AD). This study corroborates the data found by Huang et al. (e.g., pH, temperature, peroxide production etc.), which makes deli-
(2017), who demonstrated that a mixture of Lactobacillus fermentuns vering viable cells to the place where they should exercise their action a
and Lactobacillus salivaris reduced the SCORAD scores in individuals challenging task. Thus, the study and investment in technologies for
aged 1 to 18 years. probiotic encapsulation is much needed (Gbassi & Vandamme, 2012).
As for atopic dermatitis and seborrheic dermatitis, topical probiotics Drug encapsulation technologies have been studied over time and
have demonstrated the ability to increase skin ceramides, improve er- shown significant benefits, such as increased therapeutic efficacy and
ythema, flaking and itching and reduced S. aureus microbial load. reduced dose-dependent toxicity (Singh, Hemant, Ram, & Shivakumar,
However, studies have used different probiotics, vehicles and dosage 2010). To date, nanotechnology provides different viable nanocarrier
and investigated several parameters. The most used probiotics were S. options for preserving and delivering drugs, such as liposomes, mi-
thermophiles, V. filiformis, S. hominis, S. epidermidies and L. johnsonii (Di celles, carbon nanotubes and dendrimers (Kumari, Singla, Guliani, &
Marzio et al., 2003; Blanchet-Réthoré et al., 2017; Knackstedt et al., Yadav, 2014).
2020). In addition to drugs, living cells (e.g., probiotic microorganisms) can
Thus far, several studies have evaluated the action of probiotics also be encapsulated. Common nanocarriers used for drug delivery may
against fungal and bacterial. Although the results are quite surprising, not serve for cell encapsulation. Instead, a biocompatible matrix should
the exact molecular mechanisms by which probiotics can inhibit pa- be employed to encapsulate and immobilize viable cells protecting
thogenic strains remain largely unknown and speculative. Thus, for them from a hostile environment, such as chemical and physical stress
future studies, new approaches should be developed to improve pro- and the host's immune response (Orive, Santos, Pedraz, & Hernández,
biotic research. Even though probiotics are considered safe, additional 2013). The biocompatible matrix should act as a semipermeable
studies are needed to improve the exact composition and routes of membrane, allowing bi-directional transport of nutrients (Griffith &
administration. Naughton, 2002, Gurruchaga et al., 2015). Thus, the cells can remain
viable and produce therapeutic substances that will be delivered more
than once to the site of action by permeating through the polymer
matrix (Fig. 3).
7
The effectiveness of cell encapsulation depends on the matrix

polymers, which can be obtained from natural sources (poly-
saccharides, polypeptides and polynucleotides) or manufactured.
Different biocompatible materials have been used to immobilize cells in
a matrix, such as hyaluronic acid, fibrin, agarose and collagen (Vrana
et al., 2009). Table 3 shows a selection of recent studies that carried out
the encapsulation of probiotic microorganisms in order to assess their
antimicrobial potential. Alginate was considered the most studied and
appropriate biomaterial due to its biocompatibility and ease of handling
(Vrana et al., 2009). It has been shown that alginate can pass through
stomach acids without any degradation, with the spheres formed by this
gel reaching the intestine satisfactorily (Rayment et al., 2009). Pro-
biotic encapsulation with alginate was compared to the formation of a Fig. 4. Global production of probiotic research in the last 20 years
“beneficial” biofilm by these bacteria (Li et al., 2018). (2000–2020). Data obtained from bibliographic searches in Pubmed using
Although probiotics have been extensively studied in recent dec- general descriptors (Probiotics, antimicrobial probiotics and probiotic en-
ades, their biological activity remains little explored (Fig. 4). In addi- capsulation) and the Boolean operator “NOT” to limit the total number of
tion, the number of probiotic encapsulation studies is well below the productions with probiotics that did not address their antimicrobial activity.
total number of studies on encapsulation systems. Fig. 4 shows the
number of published articles reporting encapsulation systems (red line) conventional therapy alone. Consistent with this, the probiotics-con-
as compared to antimicrobial activity of probiotics (green line) and ventional drugs synergism promoted reduction in H. pylori therapy-as-
other biological activities of probiotics (blue line). sociated side effects (23% vs 47%, synergism vs conventional therapy
Encapsulation of probiotic microorganisms to treat infectious con- alone) (Lesbros-Pantoflickova et al., 2007).
ditions other than intestinal infections may open new avenues for al- As shown in Table 4, some studies have validated the beneficial
ternative antimicrobial therapies as well as adjuvant and/or synergistic effect of synergism between probiotics and conventional therapies for
approaches with conventional antibiotic therapy. the treatment of fungal and bacterial infections. A report by Russo et al.
(2018) evaluated the effectiveness of an oral formulation containing
6. Probiotics-conventional drugs synergism for antimicrobial probiotics with lactoferrin glycoprotein as an adjuvant therapy to to-
therapy pical clotrimazole for vulvovaginal candidiasis (VVC) episodes. Key
findings showed that the investigated probiotics (Lactobacillus acid-
While the antimicrobial drugs currently used in clinical practice are ophilus GLA- 14 and Lactobacillus rhamnosus HN001) and the lactoferrin
effective, they have a high cost, side effects and therapeutic resistance mixture administered simultaneously with the antifungal drug (clo-
(Graham & Fischbach, 2010; Vítor & Vale, 2011). For this reason, the trimazole) was able to reduce the symptoms and recurrence of VVC.
combination between probiotic microorganisms and conventional The authors highlighted the administration of probiotics and lactoferrin
drugs has been considered. The advantages of this synergism include: after conventional therapy with topical clotrimazole as a potential
(i) faster healing; (ii) half dose of conventional drug needed; (iii) re- maintenance treatment that reduced candidiasis relapse at a 3- and 6-
duction of side effects caused by classical therapy; and (iv) increasing month follow-up. Similarly, Martinez et al. (2009) evaluated whether
eradication rates of some microbial infections (Wolvers et al., 2010; lactobacilli improved the efficacy of fluconazole in patients with VVC.
Kosgey et al., 2019). The results evidenced the importance of adjuvant treatment with pro-
Lesbros-Pantoflickova, Corthesy-Theulaz, and Blum (2007) re- biotics (L. rhamnosus GR-1 and Lactobacillus reuteri RC-14) that were
viewed nine studies addressing the benefits of co-administration of added to a single dose of 150 mg fluconazole during a 4-week therapy
probiotics with antibiotics for the treatment of H. pylori infections, for VVC. The effectiveness of the combination between probiotics and
particularly in the prevention of side effects and improvement of era- an antifungal drug was validated based on the rate of culture-free
dication rates. Probiotics administered together with standard therapy women (38.5%) as compared to that of women who received only
(two antibiotics and a proton pump inhibitor) for H. pylori infection fluconazole (10.3%). Evidence shows that probiotics represent an al-
achieved an eradication rate of 81%, as compared to 71% of ternative and effective approach for the treatment of VVC, in view of
Table 3
Recent studies that carried out the encapsulation of probiotic microorganisms to assess their antimicrobial potential.
Probiotic microorganism Material Results Reference
Bifidobacterium animalis subsp. Poly(vinyl alcohol) Probiotic 1 showed an encapsulation efficiency of 84.07% and Akbar et al., 2018
Lactis Bb12 (probiotic 1) and a combination of 85.73% before and after 1 week, respectively. Probitic 2 showed
Streptococcus thermophilus (TH-4®), Lactobacillus 90.09% and 93.59% encapsulation efficiency before and after
paracasei 431® and Bb-12 (probiotic 2) 1 week, respectively .
Pediocucus acidilactici, Lactobacillus reuteri and Alginate with inulin The bacterial protection against acidity was increased by the Atia et al., 2016
Lactobacillus salivarius addition of inulin. Samples with 5% w/v inulin were the most
effective in protecting the probiotics against bile salts.
Two Lactobacillus plantarum strains ando ne Lactobacillus Gum arabic (30%) and The three isolates had a survival rate greater than 80% in Cui, Yan et al., 2018;
paraplantarum strain isolated from pig’s stool. gelatine (15%), Alginate lyophilized and microsphere forms. Cui, Shi et al., 2018
Lactobacillus acidophilus Ovalbumin matrix with L. acidophilus probiotic was protected from the bactericidal Govender et al., 2016
glyceryl monostereate effects of amoxicillin in the double formulation.
Lactobacillus curvatus CRL705, CRL1532 e CRL1533 and Calcium alginate solution Alginate encapsulation improved gastrointestinal tolerance. Castellano et al., 2018
Lactobacillus sakei CRL1613 and skim milk Henc, these strains should be considered as potential probiotic
candidate against intestinal pathogenic bacteria.
Lactobacillus plantarum ST-III Sodium alginate The correlation analysis showed that the viability of Qu et al., 2016.
encapsulated bacteria after exposure to gastric sulcus and bile
salts was positively correlated with the mechanical strength of
the microspheres.
8
their ability to resist Candida spp. and maintain or recover the normal
vaginal microbiota (Matsubara et al., 2016). Additionally, the co-ag-
Improved eradication rates and reduced therapy-
Increased treatment effectiveness (according to

gregation between lactobacilli and Candida spp. prevents the binding of
Improved clinical periodontal outcomes and

yeast cells to receptors on the vaginal epithelium, thereby blocking an
important virulence factor of Candida species – host-yeast adhesion
ameliorated periodontal inflammation

(Reid et al., 2003; Reid & Hammond, 2005).
Reduced symptoms and relapse
Some studies have investigated the synergistic effect of probiotics
with conventional antifungal drugs for the treatment of Candida spp.
infections. However, the potential of probiotics as an adjuvant to con-
associated side effects
ventional antifungal therapy for other highly prevalent invasive fungal

Synergism impact
infections remains to be determined in future research.

culture method)
The administration of beneficial microrganisms in the form of pro-

biotics as an adjuvant treatment has been also a valuable approach for
the therapy of chronic periodontitis (CP). Ikram et al. (2019) reported
an evaluation and comparison of the clinical efficacy of administration
of probiotics containing L. reuteri as an adjuvant to scaling and root
Chronic periodontitis
planing (SRP) for the treatment of CP. Research findings demonstrated

Helicobacter pylori
Clinical condition
that the adjunctive use of L. reuteri was effective in resolving in-

flammation and improving periodontal outcomes through improvement
Vulvovaginal
Vulvovaginal
candidiasis
candidiasis
of the clinical periodontal parameters, including plaque index, bleeding

gastritis
on probing, periodontal pocket depth, and clinical attachment level

gain.
Collectively, it is possible to affirm that the use of probiotics are
presently being investigated as an adjuvant innovative treatment to
patients
current antimicrobial agents, but these novel therapeutic strategies

No. of
remain to be further tested and validated.

160
55
48
30
Amoxicillin + clarithromycin + lansoprazole
7. Final considerations
The human body is the target of several pathogenic microorganisms,

such as S. aureus, MRSA, P. aeruginosa and C. albicans. This review
provided unequivocal evidence on the antimicrobial activity of pro-
biotics against clinically relevant pathogens. Nonetheless, while some
Scaling and root planing
molecules have been considered responsible for the antimicrobial ac-

Conventional therapy
tivity of probiotics (e.g., biosurfactants, hydrogen peroxide, lactic acid,

acetic acid and bacteriocins), further studies should characterizate new
Clotrimazole
Fluconazole
molecules and elucidate their inhibitory mechanisms against patho-

genic fungal and bacterial strains. Probiotic research needs to be bio-
guided during the whole process until they enter the clinical phase.
Currently, there is no consensus or standardization for the clinical use
Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-
of probiotics as an antimicrobial therapy, and the definition of dosage,

mechanism of action and clinical efficacy remain to be determine.
Lactobacillus + Bifidobacterium containing yogurt
Lastly, the use of nanotechnologies to encapsulate molecules from

Lactobacillus acidophilus GLA-14 and Lactobacillus
probiotic extacts should be encouraged for the development of more

effective therapeutic approaches.
Synergism between probiotics and conventional antibiotic therapies.
Funding
This work was supported by the National Council for Scientific and
Technological Development (Brazil) under Grant No 141129/2017-4.
Lactobacillus reuteri
This study was financed in part by the Coordenação de

rhamnosus HN001
Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) -

88887.476194/2020-00.
Probiotic
14
Ethical statement
Russo, Superti, Karadja, and De
The authors declare that this is a literature review work. Thus, it

does not imply human or animal experimentation.
Martinez et al. (2009)
Ikram et al. (2019)

Sheu et al. (2002)
Declaration of Competing Interest

Seta (2018)
Author (ref.)
The authors declare that they have no known competing financial

Table 4
interests or personal relationships that could have appeared to influ-

ence the work reported in this paper.
9
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Journal of Functional Foods 73 (2020) 104080

Contents lists available at ScienceDirect

Journal of Functional Foods

Probiotics as an alternative antimicrobial therapy: Current reality and future T

ARTICLE INFO ABSTRACT

1. Introdution Lactobacillus and Bifidobacterium) (Marco, Pavan, & Kleerebezem,

Fig. 2. Proposed bioguided study for monitoring

The effectiveness of cell encapsulation depends on the matrix

Improved eradication rates and reduced therapy-

Increased treatment effectiveness (according to

Improved clinical periodontal outcomes and

ameliorated periodontal inflammation

ventional antifungal therapy for other highly prevalent invasive fungal

infections remains to be determined in future research.

The administration of beneficial microrganisms in the form of pro-

planing (SRP) for the treatment of CP. Research findings demonstrated

that the adjunctive use of L. reuteri was effective in resolving in-

of the clinical periodontal parameters, including plaque index, bleeding

on probing, periodontal pocket depth, and clinical attachment level

current antimicrobial agents, but these novel therapeutic strategies

remain to be further tested and validated.

The human body is the target of several pathogenic microorganisms,

molecules have been considered responsible for the antimicrobial ac-

tivity of probiotics (e.g., biosurfactants, hydrogen peroxide, lactic acid,

molecules and elucidate their inhibitory mechanisms against patho-

of probiotics as an antimicrobial therapy, and the definition of dosage,

Lastly, the use of nanotechnologies to encapsulate molecules from

probiotic extacts should be encouraged for the development of more

This study was financed in part by the Coordenação de

Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) -

The authors declare that this is a literature review work. Thus, it

Ikram et al. (2019)

Declaration of Competing Interest

The authors declare that they have no known competing financial

interests or personal relationships that could have appeared to influ-

Investigation of alginate beads for gastro-intestinal functionality, Part 1: In vitro 5, 65–77.

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