Download Probiotics or antibiotics: future challenges in medicine

Journal of Medical Microbiology (2015), 64, 137–146
Review
DOI 10.1099/jmm.0.078923-0
Probiotics or antibiotics: future challenges in
medicine
Yousef Nami,13 Babak Haghshenas,1 Norhafizah Abdullah,2
Abolfazl Barzegari,3 Dayang Radiah,2 Rozita Rosli1
and Ahmad Yari Khosroushahi4,53
Correspondence
1
Ahmad Yari Khosroushahi
2
[email protected]
Norhafizah Abdullah
[email protected]
Institute of Biosciences, University Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
Chemical and Environmental Engineering Department, Faculty of Engineering,
University Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
3
Research Center for Pharmaceutical Nanotechnology, Faculty of Pharmacy,
Tabriz University of Medical Sciences, Tabriz, Iran
4
Drug Applied Research Center, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz,
Iran
5
Department of Pharmacognosy, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz,
Iran
Genetic and environmental factors can affect the intestinal microbiome and microbial
metabolome. Among these environmental factors, the consumption of antibiotics can significantly
change the intestinal microbiome of individuals and consequently affect the corresponding
metagenome. The term ‘probiotics’ is related to preventive medicine rather than therapeutic
procedures and is, thus, considered the opposite of antibiotics. This review discusses the
challenges between these opposing treatments in terms of the following points: (i) antibiotic
resistance, the relationship between antibiotic consumption and microbiome diversity reduction,
antibiotic effect on the metagenome, and disease associated with antibiotics; and (ii) probiotics as
living drugs, probiotic effect on epigenetic alterations, and gut microbiome relevance to hygiene
indulgence. The intestinal microbiome is more specific for individuals and may be affected by
environmental alterations and the occurrence of diseases.
Introduction
Antibiotics, as substances that either prevent the growth of
or kill a living organism, are considered miracle drugs.
The history of antibiotics started in 1932, when the first
sulfonamide was prepared by Selman Waksman. In the
1940s to the 1960s, the term ‘antibiotic’ was distinguished
from the term ‘chemotherapeutic drug’ in that the former
are natural drugs made by using fungi or bacteria (Castanon,
2007; Cheng et al., 2003; Prantera & Scribano, 2009).
Antibiotics can enhance human lives by treating or preventing diseases. However, a major public-health threat is
the resistance to antibiotics or the increased capability
of bacteria to stay alive in the presence of antibiotics.
Moreover, antibiotics only treat bacterial infections and
cannot be effectively used to treat virus-related infections,
such as colds (Cars et al., 2008; Costelloe et al., 2010).
Antibiotics have the greatest effect on human health among
all medical developments achieved since the beginning of the
20th century. Antibiotics are selective and specific in their
3These authors contributed equally to this work.
078923 G 2015 The Authors
target; thus, these drugs can eradicate invading bacteria
without inducing toxicity to the infected host (Guarner et al.,
2006). Antibiotics are frequently prescribed in most countries
(Quigley, 2011). Antibiotics are extensively used in farming,
veterinary medicine and medicine in Australia. Almost
400 000 kg of the total amount went into stock feed to stop
diseases in intensively raised animals or for use as a growth
promoter. In other words, over 20 g of antibiotics are used for
agricultural purposes per year for every man, woman and
child in Australia. However, other countries consume a
significantly higher amount. For example, the mean for
the USA is over 27 g per person each year (Ellison, 2006;
Friedman, 2012).
Meanwhile, probiotics are considered as living drugs that
can reduce antibiotic consumption and increase human
health development. The application of probiotics in preventing and managing gastrointestinal (GI) disorders has
gained considerable interest over the past two decades. The
consumption of these products is increasing worldwide
because probiotics are generally regarded as safe. Anticarcinogenic, anti-diabetic, anti-allergic and anti-inflammatory
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Y. Nami and others
genetically modified probiotics, as well as oral vaccine
development, are counted as new trends of probiotic usage
(Bouton et al., 2002). This review discusses the major future
challenges for antibiotics and probiotics, and the advantages
and disadvantages of their use during medical consumption.
Challenges faced by antibiotics (present and
future)
Antibiotic resistance
Antimicrobial resistance, which has been reported against
almost every antibiotic discovered, is one of the most
urgent public-health concerns that weaken in a global way
the usefulness of the antibiotic treatment of infectious
illness. The world of science, since penicillin led to the
antibiotic age in the mid-20th century, has been involved
in a conflict between bacterial resistance and the expansion
of antibacterial agents. Critical concern, throughout the
first decade of the 21st century, has been devoted to the
development of resistant enterococci, multi-drug resistant
staphylococci, and resistant mycobacteria, placing serious
public-health and clinical challenges for humans (Preidis &
Versalovic, 2009).
Our ability to treat contagious disease has been compromised by the growing levels of multi-drug resistance
in human pathogenic bacteria. The unchecked spread of
multiple-antibiotic resistance in clinically relevant pathogenic microbes has seemingly started to dull the hue of the
golden era of antibiotics considerably. Most clinically used
antibiotics are structural products of compounds isolated
from natural sources. The common consumption of antibiotics in human medicine and the broad-spectrum activities
of antibiotics has probably caused the human microbiome
to undertake considerable responsive changes to this
therapy. This phenomenon encourages the investigation of
the amount to which the human-associated microbiome
in the antibiotic era has developed to become a basin of
antibiotic-resistance genes (Carlet, 2012; Kazimierczak &
Scott, 2007).
Resistance is closely related to antibiotic consumption in
human, agricultural and veterinary practice. The use of
antibiotics for growth promotion and protection of crops
causes resistance elements to appear in saprophytic bacteria.
Resistance may be conveyed to human bacteria that are
sometimes pathogenic when these crops are eaten. The
possibility of finding resistant organisms in the gut is linked
to the tonnage of antibiotic consumption in the country
where the person lives. This possibility is also related to
the ease with which a resistance mechanism can increase.
Resistant organisms transferred from one person to another
remain resistant. Novel colonizing and infecting flora tend
to return to the sensitive phenotype when antibiotic pressure
is removed (Porsby et al., 2011; Prescott, 2008).
Resistance might be acquired by the means of genetic
elements resulting in three fundamental outcomes: (i)
inactivation of enzyme production, (ii) a change of the
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target site, and (iii) antibiotic exclusion from the natural
target site (e.g. vancomycin against Gram-negative organisms) (Scherer et al., 2013). However, the concern remains
significant because of the existence of many multipleresistant organisms, which are expensive to treat or cannot
be treated at all. Vancomycin-resistant enterococcal infections emerged as a new and potentially untreatable scourge
during the 1990s (Climo et al., 2009; Sievert et al., 2008;
Smith et al., 2009).
The appearance of vancomycin resistance among strains
of Staphylococcus aureus has been a main academic issue.
However, fully resistant clinical isolates have been identified. Although eight confirmed infections with S. aureus
with relatively reduced susceptibility to vancomycin have
been identified in the United States since 1997, the first
fully vancomycin-resistant S. aureus was not discovered
until June 2002. S. aureus is one of the hazardous bacterial
pathogens for which vancomycin has been the drug of
choice for several years; thus, the prospect of vancomycinresistant S. aureus development has become a great concern
(Lodise et al., 2008). Susceptibility reports on Escherichia
coli bacteraemia, the most common bacteraemia from 1990
to 1999, and ampicillin resistance have remained at a
high level at approximately 55 % of cases (Hammad &
Shimamoto, 2010). Gentamicin resistance increased from
1.7 % in 1990 to 3 % in 2000, and ciprofloxacin resistance
has been increasing from extremely low levels of less than
l % to 5 % in 2000. S. aureus is the second most commonly
reported bacteraemia (Ogunshe, 2008; Oudhuis et al.,
2011). Resistance to meticillin, which indicates flucloxacillin resistance, has been significantly growing since the
early 1990s (Dancer, 2008).
Strains of Salmonella that are resistant to antimicrobial
agents have become a worldwide health problem. A distinct strain of Salmonella enterica serotype Typhimurium,
known as definitive type 104 (DT104), is resistant to
ampicillin, chloramphenicol, streptomycin, sulfonamides
and tetracycline, and has become a major cause of illness in
humans and animals in Europe, especially in the UK
(Glynn et al., 1998). Orman et al. (2002) revealed that the
progressive acquisition and accumulation of plasmidmediated resistance determinants occurred from 1984
to 1998 in nontyphoid Salmonella isolates of the most
prevalent serovars from Argentina. It is suggested that
antimicrobial-resistance mechanisms in these bacteria may
have been the consequence of plasmid exchange between
Salmonella enterica serovar Typhimurium and E. coli or
Shigella flexneri and/or spreading of mobile elements from
the nosocomial environment. Fey et al. (2000) provided
additional evidence that antibiotic-resistant strains of
Salmonella in the United States evolve primarily in
livestock. Resistance to ceftriaxone, the drug of choice for
invasive Salmonella disease, is a public-health concern,
especially with respect to children, since fluoroquinolones,
which can also be used to treat this disease, are not
approved for use in children.
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Probiotics or antibiotics
Antibiotics and the reduction of microbiome diversity
Despite the wide consumption of antibiotics, few studies
have measured the effects of such drugs on the quantity or
variety of bacteria in the mammalian intestine. A microbiome is defined as an entirety of microbes that contains
genetic elements, as well as environmental interactions in a
specific environment. Micro-organisms that live within or
on the human body are called microbiota, and their
genomes that act together as a living system are known as
the human microbiome. The human intestine is inhabited
by 100 trillion micro-organisms that represent each of the
three domains of life (Nayak & Mukherjee, 2011). Several
intestinal bacteria are regarded as mutualistic; they help
maintain and improve regular mammalian physiology,
appropriate digestion, epithelial cell function, metabolism,
enteric nerve function, angiogenesis and the immune
system. Patients with inflammatory bowel disease or
allergies have altered intestinal bacteria, although bacterial
communities in the intestine promote normal immune
homeostasis, which indicates that microbial populations
may affect disease pathogenesis (Gueimonde & Collado,
2012; Peterson et al., 2008; Tuohy et al., 2009; Ventura
et al., 2009). The infant gut microbiota undergoes dramatic
alterations during the first 2 years of life. Antibiotic treatment is one of the most significant factors that influence
the development and acquisition of this population. Fouhy
et al. (2012) evaluated the short-term recovery of the infant
gut microbiota following antibiotic treatment. They compared the gut microbiota of nine infants who underwent
parenteral antibiotic treatment with ampicillin and gentamicin (within 48 h of birth) by using high-throughput
sequencing (employing both 16S rRNA- and rpoB-specific
primers) and quantitative PCR (Fouhy et al., 2012).
They revealed that the gut microbiota of the antibiotictreated infants had significantly lower proportions of
Actinobacteria (P50.00001) and the associated genus Bifidobacterium (P50.0132), as well as the genus Lactobacillus
(P50.0182), and significantly higher proportions of Proteobacteria (P50.0049), than the untreated controls 4 weeks
after the cessation of treatment. By week 8, the Proteobacteria levels remained significantly higher in the treated
infants (P50.0049), but the Actinobacteria, Bifidobacterium
and Lactobacillus levels had recovered and were similar to
those in the control samples. Despite this recovery of total
Bifidobacterium numbers, rpoB-targeted pyrosequencing
revealed that the number of different Bifidobacterium species
present in the antibiotic-treated infants was reduced. It
is, thus, obvious that the mutual use of ampicillin and
gentamicin in early life can significantly affect the evolution
of the infant gut microbiota.
The mammalian GI microbiota consists of various collections of bacteria in a native environment. For the host
health maintenance, these various GI microbes are considered important, since they have substantial metabolic
and defensive performances, for instance, assisting the
host in the immune system, epithelium development and
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nutrient extraction; and against pathogens, they are also
considered as a natural defence (Jia et al., 2008).
Most antibiotics are either administered orally or injected,
so that they circulate through the host system and affect the
whole microbiota. Next-generation sequencing technologies enabled the determination of the effects of antibiotics
on mammalian microbiota with the use of conserved phylogenetic markers (e.g. the 16S rRNA gene sequence) for
making taxonomic assignments. For example, 16S rRNA
gene sequence analysis of the entire community illustrated
that most bacterial taxa in the gut were influenced by
the administration of ciprofloxacin to humans, leading to
diversity, evenness and decreased richness (Dethlefsen et al.,
2008; Looft & Allen, 2012).
It is clear that agricultural and medical antibiotic consumption is beneficial. Nevertheless, the collateral consequences
are complex and numerous. It is noted that the prediction
of negative side effects, for instance, the promotion of
antibiotic resistance, is of importance, but other variations
in the host and its microbiota are difficult to predict. The
range of unpredicted effects of antibiotic therapy possibly
goes beyond the simple growth inhibition of susceptible
strains. Thus, these bioactive organic compounds should be
considered as multi-activity signalling molecules. After
birth, nearly every surface of the human body is occupied
by a various and rich commensal microbe community.
This microbiota has perpetual and significant impact on
physiological development and human health, involving
prevention of pathogen invasion, dietary and nutritional
processing, and the maturation of the immune system.
Consequently, both long-term and short-term influences on
the commensal microbiota and its encoded microbiome are
expected to be produced by antibiotic treatment to avoid or
remove a pathogenic infection at nearly any body site
(Collado et al., 2012).
Pervasive deviations in the microbial community structure
and persistent increases in antibiotic resistance among
sampled cultivatable species are caused by antibiotic treatment, which may be attributed to the rapid increase
of antibiotic-resistant strains in low basal levels in the
microbiota. This increase is also caused by the horizontal
transfer of antibiotic-resistance genes. The application of
meta-genomic functional selection, high-throughput sequencing on microbiota exposed to antibiotics and novel
cultivation methods ought to facilitate a complete comprehension of the processes that result in the association
between the resistant microbiome and antibiotics, and its
effect on clinical problems related to antibiotic resistance
(Engelbrektson et al., 2006; Mikelsaar, 2011). The main
causative agent of peptic ulcer disease and gastric cancer is
the bacterium Helicobacter pylori and antibiotic treatment is
the typical treatment for this bacterium. Jakobsson et al.
(2010) studied short- and long-term effects of metronidazole and clarithromycin treatment, the therapy regimen
usually used against H. pylori, on the indigenous microbiota
in the throat and in the lower intestine. They found that the
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microbial communities of untreated control subjects were
relatively stable over time, while dramatic shifts were
observed 1 week after antibiotic treatment, with reduced
bacterial diversity in all treated subjects in both locations.
Additionally, they revealed that high levels of the macrolide
resistance gene ermB were found after 4 years treatment.
This study highlights the importance of a restrictive antibiotic usage in order to prevent subsequent treatment failure
and the potential spread of antibiotic resistance (Jakobsson
et al., 2010). In addition, antibiotic usage strongly affects
microbial intestinal metabolism and thereby impacts human
health. Perez-Cobas et al. (2013) demonstrated that antibiotics targeting specific pathogenic infections and diseases
may change gut microbial ecology and interactions with host
metabolism at a much higher level than previously assumed.
Microbial ecology research studies have provided convincing data for the crosstalk between members of the autochthonous microbiota and the host immune system. The
tight interrelationship between microbiota and host mucosal
cells is mediated by microbial metabolites that are in charge
of bacterial cell-to-cell communication by quorum-sensing
mechanisms, and also through the activation of eukaryotic
cells following secretion of host defensins and modulation of
cytokine expression profiles. All these host functions can be
positively influenced by probiotic bacteria of human origin.
However, few requirements for evaluating these strains for use
in humans have been set according to their composition and
metabolic activity (Mikelsaar et al., 2011).
Antibiotic effects on the human metagenome
The study of the metagenome, the genetic material recovered
from environmental samples, is called metagenomics. This
broad field may also be considered as environmental genomics, community genomics or ecogenomics. The initial
environmental gene sequencing involved cloning specific
genes (often the 16S rRNA gene) to generate a variety of
profiles in a natural sample, whereas traditional microbiology and microbial genome sequencing and genomics
depend on cultivated clonal cultures. Such work showed
that most of microbial biodiversity has been missed by
cultivation-based methods (Belda-Ferre et al., 2012; Turpin
et al., 2011).
Recently conducted studies utilize ‘shotgun’ Sanger sequencing or massively parallel pyro-sequencing to obtain
balanced samples of all genes from all sampled community
members. Its capability to disclose the previously concealed
variety of microscopic life makes metagenomics a powerful
lens for seeing the microbial world that has the potential to
revolutionize our understanding of the whole living world
(Garcia-Mazcorro et al., 2011). Although the composition
and mechanisms of microbial communities remain mysterious, such communities still serve a key function in
preserving human health.
Most of the bacterial types forming part of the biosphere
have not been cultivated at all. Consequently, comprehensive research on bacterial communities involves the
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utilization of non-culture-based methods, which are
known as metagenomics. Nonetheless, the issue of which
antibiotics are regarded as pollutants, which might have
significant impact on the structure of natural bacterial
populations, has not been taken into account. Hence, the
use of non-culture-based techniques (metagenomics) is
essential for describing the alterations in bacterial populations confronted with antibiotic contamination in a more
precise manner (Gueimonde & Collado, 2012; Tuohy et al.,
2009; Ventura et al., 2009).
Metagenomics, since it is a more complete technique
compared to culture-based methods, is presently utilized
for describing the microbial population’s structure. The
describing of the microbiota, through two complementary
approaches, could be addressed as: the analysis of microbial
species distribution or the analysis of genes distribution
(Ventura et al., 2009).
Probiotics as living drugs (alternative medicine)
The concept of probiotics can be traced back to 1908 when
Eli Metchnikoff, a Nobel Prize winner, proposed that
‘ingested lactobacilli can displace toxin producing bacteria,
promoting health, prolonging life’. Lilly and Stillwell
introduced the term ‘probiotics’ in 1965. Probiotics are
considered as microbially derived factors that stimulate the
growth of other organisms. By emphasizing the requirement of viability for probiotics, Roy Fuller (Fuller, 1989)
highlighted the useful effect of probiotics on the host. As
non-digestible substances, probiotics have an important
physiological effect on the host by provoking the growth or
activity of the limited indigenous bacteria. Species of
Lactobacillus and Bifidobacterium are the most frequently
utilized probiotics. Probiotics have different types, the
health benefits of which are determined by their function
in the gut. Several major probiotics have been identified
through their genus, species and strain level, including
Lactobacillus, Bifidobacteria, Saccharomyces boulardii, Streptococcus thermophilus, Enterococcus faecium and Leuconostoc.
The lactic acid bacteria consisting of Lactobacillus species
that have been utilized for food preservation by fermentation for thousands of years can serve a twofold function by
acting as agents for food fermentation and can possibly
impart health benefits (Ogue-Bon et al., 2011; Siew-Wai
et al., 2010).
Various infections, particularly infections of mucosal
surfaces such as the gut and vagina, have been treated using
biological agents (biotherapeutic agents or probiotics). The
value of traditional treatments diminished after the
discovery and progress of antibiotics. However, alternatives
to antibiotics are required to fight the increasing number of
infections emerging because of the extreme consumption of
antibiotics (Butler et al., 2012).
Probiotics aid the naturally occurring gut microbiota.
Diarrhoea caused by antibiotics has been prevented by using
some probiotic preparations. Researchers have documented
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Probiotics or antibiotics
probiotic effects on various GI and extra-intestinal disorders,
such as irritable bowel syndrome (Hoveyda et al., 2009),
vaginal infections (Reid et al., 2009), inflammatory bowel
disease (Damaskos & Kolios, 2008) and immune enhancement (Gill & Prasad, 2008).
Dairy products and probiotic-fortified foods are the most
common forms of probiotics. Capsules, tablets and sachets,
including bacteria in freeze-dried form, are also available.
Depending on the strain and product, the dose of probiotics needed differs. A fixed dose that is required for
probiotics is impossible to consider. In fact, the dosage
should be in accordance to the human studies showing the
health benefit of the microbial ecosystems and mucosal
immunity. Through motivating both the non-immune
mechanisms and the mucosal immune mechanisms by
antagonism/competition with potential pathogens, the
probiotics influence the intestinal ecosystem. These phenomena mediate the most effective probiotic impacts, for
instance, decreasing the severity and incidence of diarrhoea.
By destroying the activity of particular bacterial enzymes
that may raise the levels of pro-carcinogens, probiotics
lessen the risk of colon cancer in animals. Different probiotic
strains, such as Lactobacillus reuteri ATCC 55730 (Cimperman
et al., 2011), Lactobacillus rhamnosus GG (Teran et al., 2009),
Lactobacillus casei DN-114 001 (Merenstein et al., 2010) and
Saccharomyces cerevisiae (Saccharomyces boulardii) (Dinleyici
et al., 2012), have been proven to be beneficial in decreasing
the severity and duration of acute infectious diarrhoea in
children. The duration of acute diarrhoeal illness in children
is shortened by nearly 1 day through the oral administration
of probiotics. In the prevention of child and adult diarrhoea,
Lactobacillus GG, L. casei DN-114 001 and Saccharomyces
boulardii are useful in particular settings.
Antibiotic-associated disease
As living organisms, probiotics, particularly L. rhamnosus
GG and the yeast Saccharomyces boulardii, have beneficial
therapeutic effects when ingested. The advantage of these
probiotics in the prevention of antibiotic-associated diarrhoea (AAD) has been proven through controlled trials.
The effectiveness of Saccharomyces boulardii (Goldin &
Gorbach, 2008) or L. rhamnosus GG (Snydman, 2008) in
adults or children undergoing antibiotic healing has been
reported.
Saccharomyces boulardii, as an assistant to antibiotics, has
revealed an advantage in controlled trials concerning the
difficult clinical problem of frequent Clostridium difficile
disease (Riddle & Dubberke, 2009). The normal gut flora
retains a quality called colonization resistance, which
hinders the overgrowth of pathogens. Volatile fatty acids
and a decrease in the pH of luminal contents may cause
some of these antibacterial effects. The most common
disruption of the flora is produced by antibiotics that can
cause diarrhoea (AAD). An appealing area for the utilization
of probiotics is in the avoidance of AAD (McFarland, 2008).
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AAD differs in frequency, but can occur in up to 39 % of
hospitalized patients given antibiotics because of an intense
change in the normal colonic flora. Alterations in the faecal
flora result in changes in colonic carbohydrate digestion,
reduce short-chain fatty acid absorption and induce
osmotic diarrhoea, although the pathophysiology underlying these changes remains poorly understood. The results
of AAD include a longer hospital stay (8 days on average), a
higher cost of care [£1280 to 2560 ($2000 to 4000) per stay],
a fivefold increase in the incidence of other nosocomial
infections, and a threefold increase in death (ranging from
0.7 to 38 %).
Probiotic impact in children has been the focus of many
studies (McFarland, 2008; Ruszczyński et al., 2008). The
control groups received placebo and antibiotics in all trials,
and probiotics were given together with antibiotics in the
test subjects. The meta-analysis is indicative that probiotics
can be implemented to stop AAD, and that Saccharomyces
boulardii and lactobacilli have the potential to be utilized in
this situation. Bacteria and yeast, including the bacteria
Lactobacillus spp. (Ruszczyński et al., 2008) (L. rhamnosus
GG), an Enterococcus (Al-Nassir et al., 2008) and the
non-pathogenic yeast Saccharomyces boulardii, have been
investigated in AAD prevention (Barc et al., 2008). A metaanalysis of probiotics in AAD prevention evaluated nine
controlled trials that showed that both lactobacilli and
Saccharomyces boulardii can stop AAD. However, the
mechanisms of action of probiotics are not evidently realized.
The probable mechanisms involve competition for nutrients, stimulation of immunity, production of antimicrobial
materials, and the inhibition of mucosal and epithelial
adherence of pathogens. More mechanisms might involve
immunomodulation of gut-associated lymphoid tissue, effects
on mucin secretion and receptor competition. Lactobacillus
GG has been discovered to adhere to mucosal cells; it may
strive for nutrients and yield a substance that avoids bacteria
and alters faecal glucuronidase, which might be an intestinal
bacterial metabolism marker. The efficiency of probiotics in
stopping AAD in children has been proven by the results of six
placebo-controlled randomized controlled trials involving
766 children. Compared with the placebo, treatment with
probiotics reduced the danger of AAD from 28.5 to 11.9 %.
So, probiotics decrease the danger of AAD in children. The
consumption of probiotics, which are live microbial food
ingredients and valuable to health, is a preventive measure.
The postulation that in several cases diarrhoea is connected
to the disturbance in the normal intestinal microflora is
regarded as the rationalization for the probiotics consumption in AAD.
No important dissimilarity in the duration of diarrhoea
between groups has been reported by Correa (P50.253).
However, administration of probiotics may pose some
danger, although adverse effects seem to be rare. The majority
of complications occur in severely immune-compromised
subjects or in patients with other life-threatening illnesses
managed in intensive-care areas. Although the utilization of
probiotics in immune-competent subjects seems to be safe,
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whether they can be utilized in the prevention of AAD in
immune-compromised patients still remains unclear (Botina
et al., 2011; Lonnermark et al., 2010).
Probiotic effects on epigenetic alterations
The study of the mechanisms or pathways that initiate and
retain heritable patterns of gene expression and gene
function without altering the DNA sequence is referred to
as epigenetics. This definition is parallel to that of genome,
which refers to the complete set of genetic information
enclosed in the DNA of an organism. Some epigenetic
pathways, for example, DNA methylation and histone
modifications, have been identified by researchers (Nakao,
2001; Bastow et al., 2004).
Alterations in the epigenetic pathways are implicated in
common human diseases. Cancer epigenetic changes have
been recorded in nearly every step of tumour development.
Less DNA methylation (hypo-methylation) results in
chromosome instability and initiates oncogenes. A malignant cell can have 20–60 % less genomic methylation than
its normal counterpart. By contrast, the silencing of tumour
suppressor genes may be initiated by excessive DNA
methylation (hyper-methylation) (Iacobuzio-Donahue, 2009).
Epigenetic markers have been evaluated by medical
researchers as a tool for primary cancer diagnosis and
clinical-outcome prediction. Therapeutics based on epigenetic strategies are also implemented for cancer prevention or treatment. Increasing evidence has shown that the
development of particular human diseases, such as neurodevelopmental disorders (Abel & Zukin, 2008), cardiovascular diseases (Ordovás & Smith, 2010), type 2 diabetes
(Park et al., 2008), obesity (Blaut & Bischoff, 2010;
Gluckman & Hanson, 2008) and infertility (Rajender
et al., 2011), is mainly caused by epigenetic changes.
Epigenetics includes genetic control by elements other
than an individual’s DNA sequence. To determine which
proteins are transcribed, epigenetic changes switch genes
on or off. Epigenetics is involved in several normal cellular
processes. One way to switch genes off, which can also
contribute to differential expression, is epigenetic silencing.
Epigenetic changes can be responsible for some disease
states despite being required for normal development and
health. Abnormal activation or silencing of genes can be
caused by the disruption of any of the three systems that
help the epigenetic changes. Disturbances of this kind have
been connected to cancer and disease syndromes, involving
mental retardation and chromosomal instabilities (Canani
et al., 2011).
Cancer was regarded to be connected to epigenetics.
Researchers discovered that diseased tissue from patients
with colorectal cancer had less DNA methylation than
normal tissue from the same patients. Abnormally high gene
activation by shifting the arrangement of chromatin can be
caused by the loss of DNA methylation, because methylated
genes are typically switched off (Kumar et al., 2013).
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The link between the gastric mucosa and allergy is becoming
progressively clearer. The permeation of antigens across the
gut lining has been the primary implicating factor in food
hypersensitivities, which manifest as allergies. Probiotics
positively affect the GI mucosa in a number of ways, many of
which are currently being clarified. Thus, probiotics affect
the host defence mechanisms in three important ways. First,
probiotics promote the structural integrity of the GI barrier
through its adhesive properties (Sengupta et al., 2013).
Second, probiotics bind antigens; thus, reducing their
immunogenicity (Delcenserie et al., 2010). Third, probiotics
reduce inflammation of the gut by the balancing of pro- and
anti-inflammatory cytokines (Shadnoush et al., 2013). Probiotics stop IgE-associated allergy until age 5 in Caesareandelivered children, but not in the total cohort over the past
decades (Kuitunen et al., 2009). Allergy is a major health
issue because the rate of children with allergies in the
westernized world has significantly increased. This increase
has been attributed to the so-called ‘hygiene hypothesis’.
Many farm studies have demonstrated that child exposure to
large numbers of microbes is linked to fewer allergic diseases
at school age. The use of farm milk may independently
protect against the development of allergies (Kuitunen et al.,
2012).
The gut microbiome and hygiene indulgence
The hygiene hypothesis has been an evolving concept in
immunology for more than 20 years. This hypothesis
highlights the assumption that experiencing an environment that is tremendously clean with a lesser microbial
problem than the environments we developed in and
dwelled in for a majority of human history upsets the
commonly regulated balance of the immune system and
tips it toward an allergy predilection (Kinross et al., 2011).
Based on observations showing that allergies are less
widespread amongst children who have older siblings, lived
on farms, attended day care or had pets, in comparison
with children expecting to have less exposure to bacterial
and viral diseases, soil organisms and commensal bacteria
early in life, the hypothesis was expanded. Children who
did not have such exposures are expected to develop
allergies as they age.
At birth, we all have the necessary blood cells that provide
our innate immunity; however, interaction with foreign
bodies (antigens) is required to provide antibodies, which
is our ‘learned immunity’. This assumption is consistent
with the idea that children with hygienic backgrounds and
a limited exposure to antigens from bacteria have a greater
predisposition to suffer from allergies, including asthma.
This correlation between hygiene and allergy has been
dubbed the hygiene hypothesis. Probiotics may offer the
primary-care physician a safe and efficacious method for
treating allergy (Yazdanbakhsh et al., 2002; Okada et al.,
2010). Based on the hygiene hypothesis, the decrease in
infections explains the greater occurrence of allergic and
autoimmune diseases in advanced countries. The occurrence
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Journal of Medical Microbiology 64
Probiotics or antibiotics
of autoimmune and allergic diseases is related to the level of
sanitary conditions at both the national and individual
levels. Collective hygiene is also essential. However, the
sanitary quality of drinking water and food (cold chain),
vaccination (as mentioned above), or the excessive use of
antibiotics that affect gut flora may be more important than
individual hygiene (Bach & Chatenoud, 2012). RibouletBisson et al. (2012) revealed that Lactobacillus salivarius
UCC118 administration had an effect on genus Firmicutes
members in pig and mice. This effect was not observed when
the mutant strain was administered, and was, thus, associated
with bacteriocin production. Surprisingly, they showed that
L. salivarius UCC118 administration and production of
Abp118 in both models had an effect on Gram-negative
micro-organisms, although Abp118 is usually not active in
vitro against this group of micro-organisms. Thus, L.
salivarius UCC118 administration has a significant but subtle
impact on mouse and pig microbiota, by a mechanism that
seems at least partially bacteriocin-dependent.
Culture of microbiome in newborn gut
Saliva is a complex fluid that serves a number of significant
functions. The antibacterial effect attributed to lysozyme
content is one of the initially recognized properties of
human saliva. According to many studies, saliva contains
various antibacterial substances, such as lactoperoxidase,
antibodies, lactoferrin, leukocytes and cationic proteins
(Hattori & Taylor, 2009; Kho et al., 2014). Periparturient
licking by females of their anogenital and mammary areas
and wound licking are considered as the two behavioural
patterns connected to licking where the antibacterial
impact of saliva might be crucial. Licking of the anogenital
and mammary areas before parturition is obvious in
dogs, rodents and cats. During late pregnancy, the shift of
grooming from other parts of the body to the anogenital
and mammary areas has similarly been quantitatively
recognized for rats. The intestinal bacterial flora that is
regarded as protective against opportunistic pathogens
does not exist in newborn mammals with a sterile gut. In
case of being exposed before colostrum ingestion, the
newborns are in an endangered state to some of the more
dangerous strains of E. coli regularly discovered in faeces.
Finally, licking their wounds instantly after being hurt or
during the curing process is a common observation among
carnivores and rodents that have constant cutaneous
injuries (Johnson & Versalovic, 2012).
Physically washing the wound of external material, such as
tissue debris and bacterial contaminants, using the tongue
is another obvious function. The licking of wounds would
be mainly adaptive in decreasing bacterial infection if the
saliva of the animals has antibacterial agents that are
effective against potential wound-tissue pathogens. The
hygienic function of maternal licking of the mammary and
anogenital areas in protecting newborns from these
diseases is facilitated by the bactericidal effects of saliva.
E. coli and Streptococcus canis, along with coagulase-positive
http://jmm.sgmjournals.org
Staphylococcus and Pseudomonas aeruginosa, are among the
common wound contaminants of dogs. Wound contamination by E. coli and Streptococcus canis can be reduced by
wound licking and the use of saliva (Gilchrist et al., 2010;
Guarner et al., 2006).
Conclusion
The intestinal microbiota of the host can be modulated
through the consumption or administration of probiotic
micro-organisms that establish an excellent means of
remediation and deterrence against a variety of intestinal
disorders and infections. Given the lack and hazards of
antibiotics, including reduction of microbiome diversity
and antibiotic resistance, the use of probiotics instead of
antibiotics is becoming increasingly acceptable.
Future perspective
The human body is a ‘supra-organism’ and the GI flora has
been referred to as ‘a virtual organ of the human body’.
The majority of probiotics in use have been designed for
the GI tract, while there is now an impetus to progress the
field to encompass other regions of the body.
Lactobacilli derived from the endogenous flora of normal
donors, as probiotics in functional foods or as vaccine
carriers, displayed similar properties in vitro but strainspecific effects under in vivo conditions.
Probiotics, in the future, will be expanded in order to
address microbiota-associated conditions that are outside
the limits of the micro-organisms utilized as probiotics
today. Micro-organisms, which have been genetically modified, may supply effective epitopes for improving natural
immune responses, restoring antigen-specific tolerance and
oral vaccine delivery. The components of the cell surface,
which supply a potential strategy for the treatment of
inflammatory intestinal disorders, can be changed by probiotic bacteria. The transplant of faecal microbiota into the
duodenum of diabetic patients with the metabolic syndrome
enhanced their sensitivity to insulin. A more adequate
approach in future studies will be provided by cocktails of
defined microbes with vital functionalities. Nevertheless,
particular valuable strains with outstandingly properties, for
instance, Faecalibacterium prausnitzii (chronic gut inflammation), Oxalobacter formigines (kidney stones), etc., in
well-designed clinical trials, ought to be more comprehensively investigated.
Efficient probiotic interventions in relation to microbiotaassociated situations require a broad comprehension of
the relationships between microbial, genetic and environmental effects within humans. This will contribute to the
identification of the subset of patients responsive to gut
microbiota manipulations and the optimal agents to apply
in a specific subject. Through probiotics, the future of
decreasing the risk of illness is bright and hopeful, but
validated biomarkers for numerous target diseases are
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143
Y. Nami and others
deficient. Therefore, in the field of probiotic investigation,
the defining of validated biomarkers needs to be advanced.
In addition, in healthy populations, the measurement of
meaningful physiological changes needs further investigation. The identification of subjects on the limits of a
normal physiological range might be considered as a
productive direction for research on healthy subjects. The
consequence of extensive utilization of probiotic products
regarding quality-of-life indicators and society-wide economics ought to be evaluated, in different communities,
through end points involving the reducing of prevalent
infectious diseases. Support for sustained research in the
probiotic field of study could be provided through such
information. Based on the effect of probiotics both locally
in the GI tract and distantly at other sites of the body,
studies regarding the immunomodulatory actions of
probiotic bacteria should be performed to evaluate both
their local and systemic effects on the upregulation of
immune responses against infection and the downregulation
of immune responses associated with allergic reactions.
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Trials of probiotic therapy must adequately address
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Trials of probiotic therapy should be well ordered,
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Some probiotics can improve clinical outcomes for
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Probiotics act by direct interaction with the host cells
through immune signalling mechanisms and/or changing the composition and activities of the colonizing
microbiota.
There is a clear association of microbiome alterations
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Acknowledgements
randomized, double-blind, placebo-controlled pilot study of Lactobacillus
reuteri ATCC 55730 for the prevention of antibiotic-associated diarrhea
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The financial support of the University Putra Malaysia and Tabriz
University of Medical Sciences, Tabriz, Iran, are gratefully acknowledged.
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