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Effects of Antibiotics upon the Gut Microbiome: A Review of the Literature

  • Democritus University of Thrace-Medical School


The human gastrointestinal tract carries a large number of microorganisms associated with complex metabolic processes and interactions. Although antibiotic treatment is crucial for combating infections, its negative effects on the intestinal microbiota and host immunity have been shown to be of the utmost importance. Multiple studies have recognized the adverse consequences of antibiotic use upon the gut microbiome in adults and neonates, causing dysbiosis of the microbiota. Repeated antibiotic treatments in clinical care or low-dosage intake from food could be contributing factors in this issue. Researchers in both human and animal studies have strived to explain this multifaceted relationship. The present review intends to elucidate the axis of the gastrointestinal microbiota and antibiotics resistance and to highlight the main aspects of the issue.
Eects of Antibiotics upon the Gut Microbiome:
A Review of the Literature
Theocharis Konstantinidis 1, Christina Tsigalou 1, Alexandros Karvelas 1,
Elisavet Stavropoulou 2, Chrissoula Voidarou 3and Eugenia Bezirtzoglou 4, *
1Laboratory of Microbiology, Medical School, Democritus University of Thrace, Dragana,
68100 Alexandroupolis, Greece; (T.K.); or (C.T.); (A.K.)
Centre Hospitalier Universitaire Vaudois (CHUV), Rue du Bugnon, Vaud, CH-1011 Lausanne, Switzerland;
3Public Health Laboratory, Arta Prefecture, 47100 Arta, Greece;
4Laboratory of Hygiene and Environmental Protection, Medical School, Democritus University of Thrace,
68100 Alexandroupolis, Greece
*Correspondence: or
Received: 19 September 2020; Accepted: 13 November 2020; Published: 16 November 2020
The human gastrointestinal tract carries a large number of microorganisms associated with
complex metabolic processes and interactions. Although antibiotic treatment is crucial for combating
infections, its negative eects on the intestinal microbiota and host immunity have been shown to be
of the utmost importance. Multiple studies have recognized the adverse consequences of antibiotic
use upon the gut microbiome in adults and neonates, causing dysbiosis of the microbiota. Repeated
antibiotic treatments in clinical care or low-dosage intake from food could be contributing factors in
this issue. Researchers in both human and animal studies have strived to explain this multifaceted
relationship. The present review intends to elucidate the axis of the gastrointestinal microbiota and
antibiotics resistance and to highlight the main aspects of the issue.
Keywords: antibiotics; resistance; gut microbiome; microbiota
1. Introduction
Undoubtedly, since the discovery of penicillin by Alexander Fleming in 1928 and thereafter,
antibiotics used in the management of infectious diseases have saved millions of lives [
]. Over the
past two decades, antibiotic misuse and overuse has come to be considered a serious public health
issue, imperiling the great achievements of medicine. Antimicrobial resistance (AR) is a developing
concern that threatens to harm the eective treatment of infectious diseases, especially in high-income
countries [
]. Even though the irrational use of antibiotics was once considered a problem only in
developed countries, a striking rise in low and middle-income countries has occurred [
]. It is of
interest to note that de Jong et al., in their observational study, revealed that antibiotic-resistant
bacteria from animal farms could be the reason for therapeutic failure in adults living in rural areas,
an assumption that of course needs further investigation [
]. However, another study described that
higher prevalence rates of 8-fold were observed in urban settings when compared to rural settings, as
antibiotic prescription was more frequent in towns with hospitals. The antibiotic prescription rate
in urban areas was 46.8% where people receive more qualified hospital care [
]. AR occurs more
frequently in hospitals due to the increasing number of patients, surgical procedures, and interventions,
which are linked to the increasing use of antibiotics in the health care setting.
Antibiotics resistance percentages are rising daily, not only concerning the hospital community,
but also various other territories. Antibiotics are given to animals for treating infections, but mostly to
Biomedicines 2020,8, 502; doi:10.3390/biomedicines8110502
Biomedicines 2020,8, 502 2 of 15
achieve faster growth for commercial purposes. Moreover, AR is also present in plant pathogens [
Antibiotics used for therapy and animal feeding contribute to the spreading of antibiotics resistance in
food and environment [
]. Moreover, ESKAPE (Enterococcus,S. aureus,K. pneumoniae,A. baumannii,
P. aeruginosa, and E. coli) pathogens are a major cause of hospital-acquired resistant infections worldwide,
as they are associated usually with more serious morbidity and mortality rates and consequently to an
important economic loss due to various complications, prolonged hospitalization, expensive drugs,
and absenteeism in workplaces [5].
It is well known that antibiotics can produce alterations in the host’s indigenous microbiota by
selecting resistant bacteria that can appear as opportunistic pathogens [
]. Additionally, a low-dosage
intake of antibiotics or sub-therapeutic antibiotic treatment (STAT) from food and the environment have
also been associated with gut dysbiosis. Gut dysbiosis promotes negative eects in plenty of systems
and functions of the host. Since the gut microbiome could be “at the intersection of everything”,
its alterations have been linked to multiple pathological conditions, and scientists have focused on
the relationship between antibiotics and the gut microbiota [
]. Accumulating evidence mainly from
animal studies has underscored the contribution of antibiotics to gut microbiome disruptions [
Although morbidity and mortality, due to infectious diseases, were remarkably reduced, antibiotic
treatment has been implicated in gut microbiota disruptions.
Nowadays, resistance represents a common trait for almost all developed antibiotics.
Unfortunately, at the end of 20th century the development of new antibiotics was dramatically
decreased due to economic and regulatory obstacles [11].
In this review, we summarize current evidence regarding the gut microbiome and its alterations
in relation to antibiotics, analyzing the reasons associated with their inappropriate use.
2. Insights to the Gut Microbiome
Until now, the usage of classic microbiological techniques has limited the amount of information
found about the human microbiome. However, the introduction of new molecular methods such
as next-generation sequencing (NGS) and methodologies such as 16S ribosomal RNA (rRNA) gene
sequencing and metagenomic shotgun sequencing have revolutionized scientists’ knowledge about
these microorganisms.
The abundance, diversity, and features of microorganisms’ genes are collectively known as
the human microbiome, a seemingly “new actor on stage” due to its numerous roles in health
and disease [
]. Several publications have demonstrated the relationship between dysbiosis and
inflammatory and metabolic diseases, such as inflammatory bowel disease (IBD), obesity, cancer,
asthma, autism, autoimmune diseases, etc. [
]. Until now, these studies have failed to establish a
causative role for the microbiome but have mainly focused upon the relationship between pathogenesis,
clinical manifestations, and disease prognosis with microbiome alterations.
The human microbiome is comprised of almost 40 trillion bacterial cells and about 30 trillion
human ones, revising the notion of the ratio closer to 1:1 [
]. Most microbes belong to five major
phyla: Firmicutes,Bacteroidetes,Actinobacteria,Proteobacteria, and Verrucomicrobia [
]. The gut holds
the majority of species—around 2000, with Bacteroidetes and Firmicutes representing more than 90%
of its microbes [
]. The gut microbiome contributes to human body functions such as digestion,
metabolism, protection from pathogenic microbes, the production of vitamins, as well as the regulation
of the immune system and inflammatory reactions. These functions represent those of an “active
organ” [7] or a microbial “endocrine organ” [18,19].
The human gut microbiome has been categorized into three enterotypes according to the variation
in gut microbes [
]. A person’s enterotype could change due to dierent factors such as gender,
age, food intake, vaccinations, infections, smoking, etc., resulting in dierences in the composition
and diversity of the gut microbiota from newborns to elders [
]. The gut is massively colonized
after birth, excluding the possibility that the fetal gut is sterile [
]. Moreover, it was shown that
the composition of the human microbiome is aected by age and comorbidities [
]. A “healthy” gut
Biomedicines 2020,8, 502 3 of 15
microbiome has a high diversity; any kind of disruption may lead to dysbiosis, a critical condition
of imbalance between commensal and pathogenic microbes [
]. Eubiosis due to beneficial bacteria
maintains an important homeostatic niche by preventing any disequilibrium that might cause dysbiosis
and, consequently, metabolic and inflammatory conditions, including asthma, obesity, cancer, autism,
and autoimmune diseases [10].
As mentioned, a specific diet may shape the profiles of gastrointestinal bacteria in humans.
Dierences in food intake create a dierent community structure of the gut microbiota [
]. For example,
comparing the microbiota of European children (EU) to children coming from a rural African village
in Burkina Faso (BF), an environment that resembles that of Neolithic farmers, by high-throughput
16S r DNA sequencing and biochemical analysis [
] one could see that BF children presented a
higher proportion of Bacteroidetes numbers than Firmicutes. Moreover, Prevotella spp. and Xylanibacter
spp. were prevalent in these children; both are involved in cellulose and xylan hydrolysis. However,
these bacteria were absent from the intestinal microbiota of the EU children. Additionally, the BF
children showed a higher ability to produce metabolites such as short-chain fatty acids (SCFAs).
The microbiota of BF and EU children has co-evolved with diet since ancient times, and the high
amounts of SCFA seemed to provide the host with an important amount of energy [
]. In both
populations, Actinobacteria with a predominance of the genus Bifidobacterium were present in younger
infants who were breast-feeding [7,26].
The characteristic profile of the newborn gastrointestinal microbiota depends on age, race,
and the subject’s diet [
]. Several hours after birth, the newborn develops its normal microbiota.
Colonization by Bifidobacterium happens within four days after birth. Breast-fed infants carry a typical
gut flora featuring an increased concentration of Bifidobacterium. However, infants receiving artificial
alimentation do not usually carry Bifidobacterium or demonstrate low concentration numbers, showing
a generally lower microbial diversity. Moreover, male newborns show a higher count of Bifidobacterium
than females. Nevertheless, in both sexes its preponderance is manifested after maternal alimentation.
Positive eects of Bifidobacterium sp. on infant growth and health status have been reported [
]. A fierce
competition has been exhibited between B. bifidum and C. perfringens in the gut of newborns delivered
by caesarean section [
]. Multiple authors have stated the beneficial action of several bacteria on the
intestinal ecosystem, amongst them Bifidobacterium spp. [3538].
By the time the child reaches the age of three or four years, two dominant phyla exist:
Firmicutes and Bacteroidetes. The Firmicutes phylum includes Lactobacillus,Bacillus,Clostridium,
Enterococcus, and Ruminicoccus genera, which may exhibit diametrically opposite actions. For example,
Faecalibacterium prausnitzii is more abundant in the gut of obese children than in non-obese
children, whereas Clostridia in human feces are associated with s lower body mass index. Moreover
E. feacalis escaping from the gut might cause a deleterious blood infection, while Bacteroidetes are
protective [
]. However, the dierences were related to the presence of the Firmicutes
phylum’s class, the Mollicutes class, as obtained by animal studies with diet-induced obesity [
From this point forward, the gut microbiota tends to maintain a well-balanced condition, with few
changes across the adult life, ending in a dierent state in the elderly [
], who show a decrease in
Bifidobacterium spp. [
]. Diet and drugs correspond to critical microbiome alterations, when other
factors, such as genetics, have less impact on the microbial population [42].
In the human intestine, bacterial levels rise along the intestinal lumen. For example, the bacterial
numbers can be as high as 10 million bacteria/mL in fecal fluid. Qualitative and quantitative
dierentiation is registered in bacterial populations colonizing dierent parts of the gastrointestinal
ecosystem [
]. Lactobacillus, which are facultative anaerobic or aerobic rods, are permanent residents
of the ecosystem of the human gut [
]. Dierent studies suggest that the advantageous eects of
Lactobacillus are strain-dependent. Agerholm-Larsen L et al. reported weight gain with the use of L.
rhamnosus and also with L. acidophilus [
]. On the other hand, L. gasseri BRN17 and L. gasseri SBT2055
in dierent studies are associated with weight loss [
]. Lactobacillus show a selective adherence to
the intestinal epithelial cells [
]. Enterobacteriaceae are associated with gastrointestinal infections
Biomedicines 2020,8, 502 4 of 15
and carry specific adhesins, which mediate their adhesion to the intestinal mucosa [
]. Therefore,
non-pathogenic anaerobic bacteria, such as Lactobacillus and Bifidobacterium, could impede the ability
of the adhesion and invasion of several enteropathogenic enterobacterial strains [49].
In addition to food-induced eects on the gut microbiome, a significant contribution to its
development is derived from the administration of probiotics, prebiotics, and antibiotics [
]. Probiotics
and prebiotics might oer a more balanced protection in the gut, but antibiotics might decrease diversity
and promote dysbiosis [
]. Another factor that might decrease diversity and promote dysbiosis is
alcohol abuse [
]. Nevertheless, the explicit factors defining the development of beneficial lactic acid
microbiota are not perfectly clarified, but research focusing on the distributions of dierent strains
in the various human organs, during states of health and disease, may elucidate them. Adequate
knowledge of the intestinal microbiota and its probiotic profile in health and disease could provide
therapeutical advancements. Therefore, the probiotic approach will assist the investigation of the role
of bacterial species, as well as those components promoting their growth in the human intestine.
3. Antibiotic-Associated Shifts in the Gut Microbiota
As soon as antibiotics were introduced, they were acknowledged as the most eective and
life-saving drugs to combat infectious diseases, and they resulted in a substantial decrease in morbidity
and mortality. However, humanity soon realized that the irresponsible and thoughtless use, misuse,
and overuse of antibiotics led to the emergence of antimicrobial resistance (AR). AR poses a global threat
to modern medicine and its achievements and is a major health problem [
]. Additionally, recent
studies have illuminated the potential impact of antibiotic intake on the intestinal microbiome.
Antibiotics can negatively aect the required diversity of the gut microbiota in adults [
and children [
]. The short-term eects of antibiotic use include diarrhea, Clostridium dicile
infection, and AR [
], whereas the long-term consequences include the development of allergic
conditions—namely, asthma or food allergies and obesity [65,66].
Antibiotic administration for therapeutical purposes aects the bacterial microbiota both
quantitatively and qualitatively by reducing or eliminating bacterial species and allowing other
species to obtain more space and nutrients in the intestine. This microbial imbalance influences the
state of health and disease. However, these studies have faced limitations, such as drug composition
and route of administration, as well as the age of the patient, the deleterious impact of antibiotics
in early life [
], and other factors such as diet and functional foods [
]. In particular, Cox et al.
introduced the concept of the “critical developmental window” in the early life of mice when low-dose
antibiotics had the greatest impact on the gut microbiome, leading to metabolic eects [71].
The impact of antimicrobial agents used therapeutically or as a prophylaxis on normal
gastrointestinal microbiota causes disturbances in the ecosystem’s equilibrium. In all cases,
disequilibrium and alterations in the microbiota ecology depend on the involved drug and its
pharmacokinetic profile [
]. The human intestine has the capacity to metabolize drugs due to the
possession of an enormous carriage of Cytochrome P450 (CYP) enzymes, which are responsible for
the catalyzation reactions in phase I and phase II of drug metabolism [
]. Korpela et al. have
demonstrated that oral antibiotic therapy with macrolides led to changes in the intestinal microbiota
by creating a shift in the relative abundance of Bacteroides and Bifidobacterium [
]. In the same vein,
antibiotic treatment breaks the intestinal equilibrium, leading to a niche perfect for C. dicile growth
and spore germination [
]. However, other authors have stated an antibiotic-induced rise in toxin
production by C. dicile as a stress-induced response that may vary following the bacterial strain [
Likewise, antibiotic abuse lead to negative eect on the levels of proliferation or apoptosis of
intestinal cells, to enterocytes (sucrase) and endocrine cells. Therefore, lots of intracellular proteins
are released. Except for the local functional activity of releasing proteins, they may be useful as
markers of gut microbiome dysregulation. Zhernakova et al., in their study of the gut microbiota
of 1135 participants from a Dutch population-based cohort, demonstrated a connection between the
Biomedicines 2020,8, 502 5 of 15
microbiome and the dierent host factors. Authors reported that fecal chromogranin A (CgA) was
exclusively associated with the presence of particular microbial species [77].
Immunomodulatory and Indirect Eect of Antibiotics on the Gut Microbiota
The eect of antibiotic drugs to the human microbiome is complex and bi-directional. Except
for direct eect, antibiotics can also indirectly aect human microbiota. The gut microbiota dysbiosis
following exposure to antimicrobial agents may cause the dysregulation of immune responses [
Indeed, it was demonstrated with
in vitro
and ex vivo studies how a short-term treatment with
broad-spectrum antibiotics deeply aected both cellular and humoral immune response [
Some antibiotics have been reported to display immunomodulatory eect in addition to their
antimicrobial activity [
]. Konstantinidis et al. demonstrated that macrolides such as clarithromycin
can induce Neutrophils Extracellular Trap (NET) generation both
in vitro
in vivo
. Moreover,
in this study the authors showed that clarithromycin-induced NETs are decorated with functional
antimicrobial peptide LL-37, which is able to inhibit the growth of multidrug resistant strains [
In addition, LL-37 plays a critical role in the protection of the colon microbiota balance [
]. Di Fan et
al. found that hypoxia-inducible factor-1
), a transcription factor for human cathelicidin (LL
37), is important for activating innate immune eectors and is the key determinant of Candida albicans
colonization resistance [
]. Moreover, LL-37 plays multiple roles in innate immune responses and
wound healing [
]. Yoshimura et al., in their ex vivo model of CRAMP
mice, showed that
mice developed more severe colitis and succumbed rapidly [
]. Furthermore, Inomata et
al. reported than the antimicrobial peptide LL-37 upregulates the expression of several immune-related
genes [
]. The authors investigated the eect of LL-37 on the gene regulation of human gingival
fibroblasts (HGFs). During this study, it was proven that LL-37 alters the expression of 29 genes
that encode TLR-associated proteins. Moreover, LL-37 increased the LPS-upregulated expression of
]. Apart from the well-documented mechanisms related to LL-37 eects on neutrophils and
monocytes, T-cells also respond to LL-37 stimulation via T-cell proliferation, T-cell activation, as well
as the generation of regulatory T-cells (Tregs) [
]. Human antimicrobial peptides are abundantly
secreted by colonic epithelial cells and are critical components of innate immune response against
enteropathogenic bacteria such as Shigella spp., Salmonella spp., and C. dicile. The antibiotics-induced
synthesis of AMPs is the cornerstone mechanism of the indirect action of this group of drugs on the
human microbiome.
By the same token, antibiotics’ influence on intestinal bacterial diversity and long-term abuse has
been identified as an independent risk factor for metabolic disorder, such as atherosclerosis-driven
events. Kappel et al., in their experimental animal model, showed that the augmented atherosclerosis
induced by antibiotics was correlated to a loss of gut microbiome’s diversity by a reduction in
Bacteroidetes and Clostridia [
]. Moreover, antibiotics as gut microbiome modulators alter the immune
response to various non-infectious diseases and drugs, such as immune checkpoint inhibitors (ICI) in
patients with solid neoplasms. Kapoor et al. reports that the median overall survival of the patients
who received antibiotics in this window was 2.8 months (95% CI: 1.2–4.5) as compared to 9.2 months
(95% CI: 5.2–13.1) in those who did not receive antibiotics p=0.008 [92].
Antimicrobial agents induce autophagy and the inhibition of the immune response. In this
context, antibiotics may alleviate the progression of the autoimmune and neuroinflammatory
diseases [
]. Studies show that antibiotics may influence the pathogenesis of neurodegenerative
diseases, such as multiple sclerosis and Amyotrophic Lateral Sclerosis (ALS), through gut microbiome
dysfunction [
]. Some antibiotics, such as beta-lactam, except for direct antimicrobial eects also
act as neuromodulators due to the upregulation of the glutamate transporter 1 (GLT-1) expression [
Previous studies have shown that the microbiome plays a critical role in chemotherapy-induced
peripheral neuropathy (CIPN) [
]. Ramakrishna et al. report that chemotherapeutic agents cause
barrier dysfunction, resulting in increased systemic exposure to bacterial products and metabolites,
which promote both local and systemic inflammation, which drive pain sensitivity. The authors
Biomedicines 2020,8, 502 6 of 15
believe that microorganisms Porphyromonadaceae are associated with both bacteria and pain as well as
between microglia and pain, and that gut bacteria modification by antibiotics has a positive eect on
this phenotype [100].
Another pathway of the indirect eect of antibiotics on the human microbiome is the regulation of
radical nitric oxide (NO) synthesis by the activation of the inducible nitric oxide synthase. NO increases
mucosal blood flow and mucus thickness and prevents microbial infections [
]. However, the impact
of NO on the gut microbiota remains elusive. Studies indicate that the NO plays a vital role in host
defense against bacterial infections [102].
Immune cells play a significant role in the maintenance of tissue homeostasis by exhibiting the
plasticity of their phenotypes, such as M1 or M2 for macrophages or N1 and N2 for neutrophils.
Microbiota-derived metabolites, short-chain fatty acids (SCFAs), bacterial lipopolysaccharides (LPS),
and antimicrobial peptides wield anti-inflammatory or pro-inflammatory eects by acting on immune
cells [
]. Maekawa et al. demonstrated that the anti-inflammatory action of erythromycin is
mediated through the upregulation of the secreted homeostatic protein DEL-1 [
]. Through this
study, it was shown that erythromycin regulates neutrophil function in the tissues, such as lungs or the
periodontium, in a DEL-1-dependent manner (Figure 1).
Biomedicines 2020, 8, x FOR PEER REVIEW 6 of 16
Another pathway of the indirect effect of antibiotics on the human microbiome is the regulation
of radical nitric oxide (NO) synthesis by the activation of the inducible nitric oxide synthase. NO
increases mucosal blood flow and mucus thickness and prevents microbial infections [101]. However,
the impact of NO on the gut microbiota remains elusive. Studies indicate that the NO plays a vital
role in host defense against bacterial infections [102].
Immune cells play a significant role in the maintenance of tissue homeostasis by exhibiting the
plasticity of their phenotypes, such as M1 or M2 for macrophages or N1 and N2 for neutrophils.
Microbiota-derived metabolites, short-chain fatty acids (SCFAs), bacterial lipopolysaccharides (LPS),
and antimicrobial peptides wield anti-inflammatory or pro-inflammatory effects by acting on
immune cells [103,104]. Maekawa et al. demonstrated that the anti-inflammatory action of
erythromycin is mediated through the upregulation of the secreted homeostatic protein DEL-1 [105].
Through this study, it was shown that erythromycin regulates neutrophil function in the tissues, such
as lungs or the periodontium, in a DEL-1-dependent manner (Figure 1)
A high-fat diet (HFD) exhibited impaired neutrophil migration to the intestinal mucosa and
reduced the gene expression of the CXCL-1 chemokine and CXCR-2 receptor in the ileum [106]. In
this context, it was previously shown that the depletion of neutrophil migration is also correlated
with the proliferation of tumor cells and tumor-cell DNA damage in an interleukin-17-dependant
manner [107]. Moreover, a high-fat diet induced neutrophil activation by enhancing neutrophil
elastase activity [108]. The high levels of active neutrophil elastase are associated with a low
microbiome diversity and the downregulation of microbiome characteristics [109]. In addition,
neutrophil extracellular traps (NETs), as cornerstone mechanisms of neutrophil action, are involved
in several disease exacerbations. Dicker et al. report that NETs are associated with disease severity in
patients with Chronic Obstructive Pulmonary disease (COPD), a loss of microbiota diversity (p =
0.009), and the dominance of Haemophilus species’ operational taxonomic units (p = 0.01) [110]. Besides
this, it was previously reported than neutrophil ageing is regulated by the microbiome. This
mechanism is driven by the microbiota via the TLR receptor and myeloid differentiation factor 88-
mediated signaling pathways [111].
Figure 1. Effects of antibiotics upon the gut microbiome. Antibiotic treatment is crucial for combating
infections. On the other hand, antibiotic exposure can alter many basic equilibria in terms of intestinal
Figure 1.
Eects of antibiotics upon the gut microbiome. Antibiotic treatment is crucial for
combating infections. On the other hand, antibiotic exposure can alter many basic equilibria
in terms of intestinal microbiota and host immunity, promoting long-term disease. DC: dendritic
cells; DAMP: damage-associated molecular patterns; PMNs: polymorphonuclear leukocytes; PAMP:
pathogen-associated molecular patterns; Th: T helper cells.
A high-fat diet (HFD) exhibited impaired neutrophil migration to the intestinal mucosa and
reduced the gene expression of the CXCL-1 chemokine and CXCR-2 receptor in the ileum [
]. In this
context, it was previously shown that the depletion of neutrophil migration is also correlated with the
proliferation of tumor cells and tumor-cell DNA damage in an interleukin-17-dependant manner [
Moreover, a high-fat diet induced neutrophil activation by enhancing neutrophil elastase activity [
Biomedicines 2020,8, 502 7 of 15
The high levels of active neutrophil elastase are associated with a low microbiome diversity and the
downregulation of microbiome characteristics [
]. In addition, neutrophil extracellular traps (NETs),
as cornerstone mechanisms of neutrophil action, are involved in several disease exacerbations. Dicker
et al. report that NETs are associated with disease severity in patients with Chronic Obstructive
Pulmonary disease (COPD), a loss of microbiota diversity (p=0.009), and the dominance of Haemophilus
species’ operational taxonomic units (p=0.01) [
]. Besides this, it was previously reported than
neutrophil ageing is regulated by the microbiome. This mechanism is driven by the microbiota via the
TLR receptor and myeloid dierentiation factor 88-mediated signaling pathways [111].
4. The Reservoir of Antibiotics in Animal Feed and the Emerging Resistome
4.1. AR in the Food Chain
Due to the increased development of animal production in industrial plants, antibiotics are added
to feed for the ecient feeding of animals and poultry and for improving their growth. From the
total amount of produced antibiotics, 40% are used for this purpose [
]. In Europe, their use has
been registered since 1953. Penicillin and tetracyclines for low-level feeding (5 to 10 g/ton) are used
in premixes or feed supplements as growth promotions, specifically in poultry. A plethora of other
antibiotics, such as swine and ruminants, is used for producing meat. In addition to animal growth,
these antibiotics aid in the reduction in enterotoxaemia symptoms. The use of antibiotics for growth
promotion purposes was banned in the European Union in 2006 (European Commission, Brussels
(December 2005): “Ban on antibiotics as growth promoters in animal feed enters into eect”). Similar
actions were taken as of 2017 in the U.S.A. for drugs that are important to human health [113].
Antibiotics are purchased from the feed industry or from veterinary supply centers and are given
to animals, usually by being placed in their drinking water. In the United States, farmers use more
than 17 antibiotics in animal husbandry [
]. The amount of antibiotics used for infections is four
times less than the quantities used for breeding livestock, as the Food and Drug Administration (FDA)
stated in 2011 [
]. On 18 December 2018, the FDA reported that “domestic sales and distribution
of all medically important antimicrobials intended for use in food-producing animals decreased by
33 percent between the years 2016 and 2017”, probably due to eective antibiotic stewardship [116].
Antibiotics use also provides a clear benefit for the producer, as less feed is needed for the animal
to achieve the desired weight development; therefore, the cost of purchasing food for the animal is
reduced. Nevertheless, the mechanism of antibiotic use as a growth promoter is not yet clarified.
Animals are believed to develop latent infections following the production of catabolic products and
cytokines that interfere with the growth of animal flesh due to unhygienic conditions during breeding.
Antibiotics can prevent this situation by suppressing pathogens [
]. Alternatively, animal feed
is never sterile. In this vein, bacteria grow by consuming nutrients found in feed and producing
toxic substances that have adverse outcomes on animal health. Therefore, antibiotics overcome these
harmful bacteria in animal feed [
]. However, the use of antibiotics in this way must be banned due
to the increasing problem of AR. The administration of antibiotics leads to the development of AR,
which seems to be associated with the extended use of antibiotics rather than their short-term use [
Therefore, low-level antibiotic feeding causes bacterial resistance [
]. Antibiotics misuse in both
animals and humans leads to a significant increase in antibiotic-developed resistance [
], and this
resistance can be transferred through plasmids from resistant bacteria to sensitive ones [
]. Moreover,
hazards associated with animal health from using low-level antibiotics include the development
of resistant pathogenic strains, as well as increasing susceptibility to several infections due to the
disturbance of the microbiota or to immunosuppression [
]. Promising antimicrobial agents have
been developed and could be used in the animal industry, whilst eective vaccines are available for
enterotoxaemia and other infectious diseases. Should an animal vaccination program be introduced,
the constant demand for disease surveillance through antibiotics could wane, as long as research is
progressing constantly in this direction.
Biomedicines 2020,8, 502 8 of 15
Microbial communities survive in highly antagonistic environments where the nutritional sources
available can define their growth and genetic persistence. Human activities select resistant strains and
strengthen the transfer of genetic information from unlinked bacterial species by creating environmental
niches [
]. Antibiotic resistance is also developed in plant pathogens [
]. Furthermore, domestic,
hospital, and industrial waste contributes to the selection of resistant strains. Thus, resistant bacteria
can be passed onto other hosts in dierent ways, or their mutations can be passed to subsequent
bacterial generations. As stated, environmental niches (pathogenicity islands) that carry multiple
drug-resistant genes can be formed.
Researchers have performed studies in humans under clinical treatment or experimental exposure
(volunteers) to antibiotics [
]. Additionally, other researchers have investigated the dierent functions
of the intestinal microbiota subsequent to antibiotic administration in germ-free animals [
The importance of the ecological equilibrium of the intestine, called “colonization resistance”, as
antibiotic resistance is spreading between humans, should be limited [
]. Apparently, antimicrobials
entered the food chain a long time ago, and human existence has already been continuously influenced
for a significant amount of time. The use of antibiotics as growth promoters is suspected to be
a contributing factor in the emergence of resistant microbial strains responsible for detrimental
infectious diseases.
4.2. AR Genes in the Intestinal Microbiome
Although the gut microbiome may be considered as the basis of the host’s wellbeing, at the
same time it creates potential threats due to the presence of ARgenes (antibiotic resistance genes).
It could be a “reservoir” of Multi Drug Resistant Bacteria (MDR) or Pan Drug Resistant Bacteria
(PDR) and their antibiotics resistance genes [
]. Taken together, the ARgenes and their ancestors
of pathogenic and non-pathogenic gut bacteria comprise the “resistome”, as proposed by Gerard D.
Wright in 2006 and 2007 [
]. Scattering ARgenes by dierent methods—namely, horizontal gene
transfer, toxin–antitoxin systems, and Mobile Genetic Elements (MGEs)—creates a huge reservoir
of AR determinants in the intestinal microbiome. However, it seems that the majority of these
determinants are considered innate and are not shared with opportunistic pathogens [
]. Furthermore,
the “mobilome”, which consists of MGEs, serves as a path for transferring ARgenes among intestinal
bacteria [
]. Metagenomic research revealed that, after extended antibiotic treatment, especially with
aminoglycosides, an augmentation in the relative abundance of ARgenes emerged [
]. Clostridium
dicile is a well-known factor causing nosocomial diarrhea because of prolonged broad-spectrum
antibiotic treatment, and it is worth stating that probiotics (beneficial microbes for the gut) together with
antibiotics might prevent clinical infections [
]. Probiotic bacteria as well as dietary interventions
could be very promising, either preventing undesired shifts in the gut microbiome due to antibiotics or
restoring the harmed balance after detrimental antibiotic use [127,134,135].
5. Conclusions
Antimicrobial resistance poses an immense threat to global health. There is a considerable amount
of evidence from animal models regarding the involvement of disrupted intestinal microbiota under
antibiotic treatment. The role of antibiotics as a catalyst in this interaction, either as therapy or through
low-dosage intake through the food-chain, has not yet been fully clarified. New cutting-edge techniques
and more sophisticated and randomized control trials are required to elucidate the relationship and
examine the potentials and challenges for combating the new epidemic of AR. The World Health
Organization (WHO), following an extended surveillance study of antimicrobial resistance, evinces
the severity of the problem and emphasizes the necessity of concerted action among all states and
involved bodies in order for society to mitigate antimicrobial resistance’s colossal threat. Besides this,
the economic losses linked to antimicrobial resistance should be noted. In this vein, global collaboration
between scientists will permit us to explore and establish the best policy and the most eective process
and strategy in the community and the environment.
Biomedicines 2020,8, 502 9 of 15
Author Contributions:
Conceptualization, C.T. and E.S.; formal analysis, T.K. and A.K.; investigation, E.S.;
resources, C.V.; writing—original draft preparation, T.K.; writing—review and editing, C.T.; supervision, E.B.
All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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... They concluded that individuals with obesity showed gut microbiota profiles different from lean individuals (86). Houssain et al. conducted a metagenomic study of a syngeneic mouse model of triple-negative breast cancer (87). They found that obesity significantly lowers the alpha diversity of the gut microbiome in this mouse model and that tumor progression was significantly accelerated in obese mice compared to controls, suggesting a relationship between obesity-associated gut dysbiosis and breast cancer progression (87). ...
... Houssain et al. conducted a metagenomic study of a syngeneic mouse model of triple-negative breast cancer (87). They found that obesity significantly lowers the alpha diversity of the gut microbiome in this mouse model and that tumor progression was significantly accelerated in obese mice compared to controls, suggesting a relationship between obesity-associated gut dysbiosis and breast cancer progression (87). However, more comprehensive studies are needed to establish a mechanistic relationship between breast cancer and obesity itself. ...
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The mammary microbiome is a newly characterized bacterial niche that might offer biological insight into the development of breast cancer. Together with in-depth analysis of the gut microbiome in breast cancer, current evidence using next-generation sequencing and metabolic profiling suggests compositional and functional shifts in microbial consortia are associated with breast cancer. In this review, we discuss the fundamental studies that have progressed this important area of research, focusing on the roles of both the mammary tissue microbiome and the gut microbiome. From the literature, we identified the following major conclusions, (I) There are unique breast and gut microbial signatures (both compositional and functional) that are associated with breast cancer, (II) breast and gut microbiome compositional and breast functional dysbiosis represent potential early events of breast tumor development, (III) specific breast and gut microbes confer host immune responses that can combat breast tumor development and progression, and (IV) chemotherapies alter the microbiome and thus maintenance of a eubiotic microbiome may be key in breast cancer treatment. As the field expectantly advances, it is necessary for the role of the microbiome to continue to be elucidated using multi-omic approaches and translational animal models in order to improve predictive, preventive, and therapeutic strategies for breast cancer.
... Modern lifestyle has also had an impact on the gut microbiota. The gut's beneficial microbiome can be eliminated by excessive use of antibiotics, which can change the ecological relationships and disease patterns of a community [28]. Because the microbiome, particularly gut microbiome, influences human health and is related to variety of illness that includes cancer as it boosts chemo-drug's effectiveness via immunomodulation, enzymatic disintegration, ecological variations, and metabolism [29]. ...
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Purpose of Review Breast cancer (BC) is the most prevalent malignant disease occurring in women globally. The most common treatment options include chemotherapy, surgery, hormone therapy, radiation therapy, and biological therapy. The main problem with chemotherapy and radiotherapy is that they have side effects and are quite costly for patients in developing nations. This raises the need to discover and develop better therapeutic alternatives that are less harmful and more cost-effective. Identification of phytochemicals with potent anticancer activity and formulation of plant-based anticancer drugs could be an important step in this direction. This review is intended to provide detailed information about potent anticancer phytochemicals, their sources, and molecular mechanism of their action that have been identified till now. Recent Findings Phytochemicals play an important role for treatment and prevention of various types of diseases. Examples of the phytochemicals that possess anti-tumor activities are flavonoids, phenolics, alkaloids, carotenoids, etc. Every medicinal plant has a different level of anti-cancerous potential, and not all of them cure the disease completely. These natural compounds can be used in combination with chemotherapeutic drugs to enhance their effectiveness and minimize their side effects as well as toxicity. Several recent findings have identified molecules involved in various signaling pathways as specific targets of these active phytochemicals exhibiting anticancer activity. Summary There are ample studies available claiming the phytochemicals as potential candidates for the development of anticancer drugs. But the clinical studies involving phytochemicals are still very limited. Further investigations are needed to elucidate the mechanistic role of these bioactive compounds coupled with drug development processes and to test their potential at clinical levels.
... For instance, the reintroduction of a diverse microbiota through FMT could outcompete resistant pathogens for resources and space, limit their proliferation, and reduce the likelihood of resistant infections [16,20]. Furthermore, certain members of a healthy microbiota could potentially degrade antibiotics or sequester them [21,22], reducing the selective pressure that drives the evolution of resistance. Therefore, harnessing the microbiome's protective power through FMT may represent promising strategy in the global fight against AMR. ...
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The escalating crisis of antimicrobial resistance (AMR) warrants innovative therapeutic strategies. Fecal microbiota transplantation (FMT) and maggot debridement therapy (MDT) represent paradigm-shifting approaches, leveraging biological systems to mitigate AMR. FMT restores a healthy gut microbiome, providing a biotherapeutic counter to pathogenic bacteria, thereby reducing reliance on traditional antibiotics. Conversely, MDT, a form of bio-debridement, utilizes the antimicrobial secretions of maggots to cleanse wounds and eliminate resistant bacteria. Despite the promise these therapies hold, their broader clinical adoption faces multifaceted challenges including the need for rigorous scientific substantiation, standardized protocols, deepened understanding of mechanisms of action, and surmounting regulatory and public acceptance barriers. However, their potential integration with precision medicine could revolutionize disease management, particularly with antibiotic-resistant infections.
... Combined administration of different broad-spectrum antibiotics and antimycotics is a common experimental method to induce gut microbiome dysbiosis. While the detailed effects vary with drug choice, treatment duration and pre-interventional status, all drug concepts share a loss of α-diversity and distinct shifts in microbial population (Cryan et al., 2019;Konstantinidis et al., 2020;Rice et al., 2019). In agreement with the concept to use an antibiotic cocktail for gut microbiome depletion (Simon et al., 2020;Tirelle et al., 2020;Zarrinpar et al., 2018), administration of vancomycin, amoxicillin/clavulanic acid and nystatin for 14 days caused massive reduction in faecal bacterial species along with macroscopically expanded caeca. ...
The connection between dysbiosis of the gut microbiome and diseases and injuries of the brain has attracted considerable interest in recent years. Interestingly, antibiotic-induced microbial dysbiosis has been implicated in the pathogenesis of traumatic brain injury (TBI), while early administration of antibiotics associates with improved survival in TBI patients. In animal models of TBI, short- or long-term administration of antibiotics, both peri- or post-operatively, were shown to induce gut microbiome dysbiosis but also anti-inflammatory and neuroprotective effects. However, the acute consequences of microbial dysbiosis on TBI pathogenesis after discontinuation of antibiotic treatment are elusive. In this study, we tested whether pre-traumatic antibiotic-induced microbial depletion by vancomycin, amoxicillin, and clavulanic acid affects pathogenesis during the acute phase of TBI in adult male C57BL/6 mice. Pre-traumatic microbiome depletion did not affect neurological deficits over 72 h post injury (hpi) and brain histopathology, including numbers of activated astrocytes and microglia, at 72 hpi. However, astrocytes and microglia were smaller after pre-traumatic microbiome depletion compared to vehicle treatment at 72hpi, indicating less inflammatory activation. Accordingly, TBI-induced gene expression of the inflammation markers Interleukin-1β, complement component C3, translocator protein TSPO and the major histocompatibility complex MHC2 was attenuated in microbiome-depleted mice along with reduced Immunoglobulin G extravasation as a proxy of blood-brain barrier (BBB) impairment. These results suggest that the gut microbiome contributes to early neuroinflammatory responses to TBI but does not have a significant impact on brain histopathology and neurological deficits.
... The continued and irrational use of antibiotics has led to microbiota dysbiosis and antibiotic resistance, even caused other diseases. 19 The CAKUT in neonates or young infants often develop UTI easily. Obstructive uropathy allows for the prolongation of bacteriuria due to poor drainage, decreasing the clearance of invading pathogens. ...
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Purpose: The study was to detect the pathogenic bacterial profile and antibiogram among children with congenital anomalies of the kidney and urinary tract (CAKUT). Patients and methods: A retrospective analysis was performed using medical records of urine culture results and antibiotic susceptibility results in patients with UTIs from March 2017 to March 2022. Antimicrobial susceptibility pattern was determined by a standard agar disc diffusion method. Results: A total of 568 children were included. The proportion of culture-positive UTI was 59.15% (336/568). More than nine types of bacteria were isolated with most pathogens being Gram-negative species. Among Gram-negative isolates, the predominant bacteria were Escherichia coli (30.95%, 104/336) followed by Klebsiella pneumoniae (9.23%). Escherichia coli isolates were highly sensitive to amikacin (95.19%), ertapenem (94.23%), nitrofurantoin (93.27%), imipenem (91.35%), and piperacillin-tazobactam (90.38%) and high rate of resistant were also detected to ampicillin (92.31%), cephazolin (73.08%), ceftriaxone (70.19%), trimethoprim-sulfamethoxazole (61.54%) and ampicillin-sulbactam (57.69%). Klebsiella pneumoniae isolates showed sensitive to ertapenem (96.77%), amikacin (96.77%), imipenem (93.55%), piperacillin-tazobactam (90.32%) and gentamicin (83.87%), while highly resistant were observed to ampicillin (96.77%), cephazolin (74.19%), ceftazidime (61.29%), ceftriaxone (61.29%), and aztreonam (61.29%). The isolated Gram-positive bacteria mainly contained Enterococcus faecalis and Enterococcus faecium (each 15.77%). Enterococcus faecalis were sensitive to vancomycin, penicillin-G, tigecycline, nitrofurantoin and linezolid (100%, 94.34%, 88.68%, 88.68%, 86.79, respectively) and resistant to tetracycline (86.79%), quinupristi (83.02%), erythromycin (73.58%). Enterococcus faecium also showed a similar result. Multiple drug resistance (MDR) was observed in 264 (80.00%) of the 360 bacterial isolates. Only age was significantly associated with a culture-positive UTI. Conclusion: A higher prevalence of culture-positive UTI was detected. Escherichia coli was the most prevalent uropathogen followed by Enterococcus faecalis and Enterococcus faecium. These uropathogens showed highly resistant to the commonly used antibiotics. Moreover, MDR was commonly observed. Thus, empiric therapy is unsatisfactory as drug sensitivity always varies over time.
... Multiple reports have indicated that the prolonged consumption of antibiotics contributes to a heightened occurrence of breast carcinoma and one plausible factor underlying this is the reduction of gut microbial diversity 27 . Disturbances to the gut microbial homeostasis via treatment with antibiotics have been associated with enhanced tissue inflammation, severe fibrosis, and dissemination of tumor cells in hormone-receptor positive breast cancer models 28 . In agreement, a dysbiotic gut microbiota leads to an aggravated tumor growth in breast cancer models. ...
Full-text available
Regardless of the global progress in early diagnosis and novel therapeutic regimens, breast carcinoma poses a devastating threat, and the advances are somewhat marred by high mortality rates. Breast cancer risk prediction models based on the known risk factors are extremely useful, but a large number of breast cancers develop in women with no/low known risk. The gut microbiome exerts a profound impact on the host health and physiology and has emerged as a pivotal frontier in breast cancer pathogenesis. Progress in metagenomic analysis has enabled the identification of specific changes in the host microbial signature. In this review, we discuss the microbial and metabolomic changes associated with breast cancer initiation and metastatic progression. We summarize the bidirectional impact of various breast cancer-related therapies on gut microbiota and vice-versa. Finally, we discuss the strategies to modulate the gut microbiota toward a more favorable state that confers anticancer effects.
Background To determine the potential risk factor of COVID-19 severity and length of hospitalization, the association between multiple antibiotics administration and the risk of severe COVID-19. Methods A case-control study of 58 hospitalized COVID-19 patients (the case group) and 120 non-hospitalized home isolated COVID-19 patients (the control group) was conducted. Data were collected using hospital medical records and verbal questionnaires for the participants. Results Totally 89.2% of non-hospitalized mild COVID-19 patients received ⩽2 courses of antibiotics/year, while 36.0% of hospitalized patients received ⩾4 courses of antibiotics, 56.9% received 2-3 courses of antibiotics/year and only 6.9% of them were exposed to ⩽2 courses of antibiotics/year. our study emphasizes that the usage of 4 courses or higher per year was a significant risk factor for hospitalization [ OR : 17.5; 95% CI (2.596-118.263); P =0.003], while the usage of ⩽2 courses was a preventive predictor for severity and hospitalization [ OR : 0.072; 95% CI (0.006-0.900); P =0.041]. Furthermore, age was associated with 8.4% increase in the odds of severe COVID-19 [ OR : 1.084; 95% CI (1.024-1.148), P =0.005], and females were 89.1% less likely to hospitalized than males [ OR : 0.109; 95% CI (0.024-0.498); P = 0.004]. Our study shows that 70.4% of cases misused antibiotics and administered the antibiotics themselves without a physician's prescription. Around 50.0% of cases never completed the ideal duration of the course in contrast to controls, of which only 23.2% did not complete the ideal duration. Conclusions Our study shows that antibiotics misuse and overuse may be a potential risk factor for COVID-19 severity and hospitalization.
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Gut microbiota, an integral part of the human body, comprise bacteria, fungi, archaea, and protozoa. There is consensus that the disruption of the gut microbiota (termed “gut dysbiosis”) is influenced by host genetics, diet, antibiotics, and inflammation, and it is closely linked to the pathogenesis of inflammatory diseases, such as obesity and inflammatory bowel disease (IBD). Macrophages are the key players in the maintenance of tissue homeostasis by eliminating invading pathogens and exhibit extreme plasticity of their phenotypes, such as M1 or M2, which have been demonstrated to exert pro- and anti-inflammatory functions. Microbiota-derived metabolites, short-chain fatty acids (SCFAs) and Gram-negative bacterial lipopolysaccharides (LPS), exert anti-inflammatory or pro-inflammatory effects by acting on macrophages. Understanding the role of macrophages in gut microbiota-inflammation interactions might provide us a novel method for preventing and treating inflammatory diseases. In this review, we summarize the recent research on the relationship between gut microbiota and inflammation and discuss the important role of macrophages in this context.
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The human gut hosts a wide and diverse ecosystem of microorganisms termed the microbiota, which line the walls of the digestive tract and colon where they co-metabolize digestible and indigestible food to contribute a plethora of biochemical compounds with diverse biological functions. The influence gut microbes have on neurological processes is largely yet unexplored. However, recent data regarding the so-called leaky gut, leaky brain syndrome suggests a potential link between the gut microbiota, inflammation and host co-metabolism that may affect neuropathology both locally and distally from sites where microorganisms are found. The focus of this manuscript is to draw connection between the microbiota-gut-brain (MGB) axis, antibiotics and the use of "BUGS AS DRUGS" for neurodegenerative diseases, their treatment, diagnoses and management and to compare the effect of current and past pharmaceuticals and antibiotics for alternative mechanisms of action for brain and neuronal disorders, such as Alzheimer disease (AD), Amyotrophic Lateral Sclerosis (ALS), mood disorders, schizophrenia, autism spectrum disorders and others. It is a paradigm shift to suggest these diseases can be largely affected by unknown aspects of the microbiota. Therefore, a future exists for applying microbial, chemobiotic and chemotherapeutic approaches to enhance translational and personalized medical outcomes. Microbial modifying applications, such as CRISPR technology and recombinant DNA technology, among others, echo a theme in shifting paradigms, which involve the gut microbiota (GM) and mycobiota and will lead to potential gut-driven treatments for refractory neurologic diseases.
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Alterations of the gut microbiota may cause dysregulated mucosal immune responses leading to the onset of inflammatory bowel diseases (IBD) in genetically susceptible hosts. Restoring immune homeostasis through the normalization of the gut microbiota is now considered a valuable therapeutic approach to treat IBD patients. The customization of microbe-targeted therapies, including antibiotics, prebiotics, live biotherapeutics and faecal microbiota transplantation, is therefore considered to support current therapies in IBD management. In this review, we will discuss recent advancements in the understanding of host−microbe interactions in IBD and the basis to promote homeostatic immune responses through microbe-targeted therapies. By considering gut microbiota dysbiosis as a key feature for the establishment of chronic inflammatory events, in the near future it will be suitable to design new cost-effective, physiologic, and patient-oriented therapeutic strategies for the treatment of IBD that can be applied in a personalized manner.
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Background: The use of antibiotics is known to alter the gut microbiome and it is hypothesised that the use of antibiotics may also alter the response to immune checkpoint inhibitors (ICI). As data is limited from real-world settings, we performed a retrospective audit of patients who received ICI along with concomitant antibiotics. Patients and methods: This study is a retrospective audit of a prospectively collected the database of patients who received ICI for advanced solid tumours in any line between August 2015 and November 2018 at Tata Memorial Hospital, Mumbai, India. Antibiotic use was recorded from 2 weeks before the start of ICI and concomitantly with ICI. All statistical calculations were performed using Statistical Package for the Social Sciences (SPSS) statistical software for windows version 20.0. Results: A total of 155 patients were identified as having received ICI during the study period, out of which 70 (44%) patients received antibiotics. Median PFS in patients who received antibiotics was 1.7 months (95% CI: 1.1-2.3) as against 3.6 months (95% CI: 2.3-4.8) for patients who did not receive antibiotics (p = 0.912). Median OS in the patients who received antibiotics was 3.9 months (95% CI: 1.8-11.4) as compared to 9.2 months (95% CI: 4.2-12.3) who did not receive antibiotics p = 0.053 (HR = 1.023; 95% CI: 1.00-1.04). Among the patients who received antibiotics, median OS for patients who received ≤10 days of antibiotics was 8.8 months (95% CI: 4.2-11.2) while for patients receiving >10 days of antibiotics, it was 2.8 months (95% CI: 1.2-4.4), p = 0.025 (HR = 2.0, 95% CI: 1.1-3.7). Thirty-three (21.2% of total) patients received antibiotics during the window of 2 weeks before the start of ICI to 2 months of starting ICI. Median OS in the patients who received antibiotics in this window was 2.8 months (95% CI: 1.2-4.5) as compared to 9.2 months (95% CI: 5.2-13.1) who did not receive antibiotics p = 0.008 (HR = 1.8; 95%CI: 1.2-3.0). Conclusions: This study shows that the judicious use of antibiotics is required in patients on ICI or scheduled to be started on ICI.
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Antibiotics are widely used in the treatment of bacterial infections. Although known for their microbicidal activity, antibiotics may also interfere with the host’s immune system. Here, we analyzed the effects of bedaquiline (BDQ), an inhibitor of the mycobacterial ATP synthase, on human macrophages. Genome-wide gene expression analysis revealed that BDQ reprogramed cells into potent bactericidal phagocytes. We found that 579 and 1,495 genes were respectively differentially expressed in naive-and M. tuberculosis-infected macrophages incubated with the drug, with an over-representation of lysosome-associated genes. BDQ treatment triggered a variety of antimicrobial defense mechanisms, including phagosome-lysosome fusion, and autophagy. These effects were associated with activation of transcription factor EB, involved in the transcription of lysosomal genes, resulting in enhanced intracellular killing of different bacterial species that were naturally insensitive to BDQ. Thus, BDQ could be used as a host-directed therapy against a wide range of bacterial infections.
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Social stress (SS) has been linked to the development of cardiovascular disease (CVD), which is closely associated with insulin resistance (IR); however, the causal effect of SS on IR remains unclear. The 8-week-old male C57BL/6 mice were exposed to SS by housing with a larger CD-1 mouse in a shared home cage without physical contact for 10 consecutive days followed by high-fat diet (HFD) feeding. Control mice were housed in the same cage without a CD-1 mouse. After 6 weeks of HFD, insulin sensitivity was significantly impaired in stressed mice. While the percentage of classically activated macrophages in epididymal white adipose tissue (eWAT) was equivalent between the two groups, the percentage of lymphocyte antigen 6 complex locus G6D (Ly-6G)/neutrophil elastase (NE)-double positive cells markedly increased in stressed mice, accompanied by augmented NE activity assessed by ex vivo eWAT fluorescent imaging. Treatment with an NE inhibitor completely abrogated the insulin sensitivity impairment of stressed mice. In vitro NE release upon stimulation with a formyl peptide receptor 1 agonist was significantly higher in bone marrow neutrophils of stressed mice. Our findings show that SS-exposed mice are susceptible to the development of HFD-induced IR accompanied by augmented NE activity. Modulation of neutrophil function may represent a potential therapeutic target for SS-associated IR.
The Human Microbiome Initiative of NIH, begun in 2007, has opened the door to the power of the intestinal microbiome in health and disease. The 100 trillion gut microbes influence body function through three pathways: (1) via the neural route where 500 million neurons of the enteric nervous system (the body's second brain) connect to the brain and spinal cord, (2) via the immune route where the gut-immune capacity prevents infection and elicits immune response to vaccines, and (3) by the hormonal route wherein biologically active chemicals are released from enteroendocrine cells to control mood and body functions. Through research, the identification of diseases and disorders associated with abnormal microbiome ("dysbiosis") has increased in number with potential for reversibility. Our team has developed an orally administered fecal microbiota transplantation product that is effective in reversing dysbiosis in recurrent Clostridioides difficile (C. difficile) and is being used to reverse abnormal microbiomes in chronic dysbiotic disorders.
Macrolide antibiotics exert anti-inflammatory effects; however, little is known regarding their immunomodulatory mechanisms. In this study, using two distinct mouse models of mucosal inflammatory disease (LPS-induced acute lung injury and ligature-induced periodontitis), we demonstrated that the anti-inflammatory action of erythromycin (ERM) is mediated through upregulation of the secreted homeostatic protein DEL-1. Consistent with the anti-neutrophil recruitment action of endothelial cell-derived DEL-1, ERM inhibited neutrophil infiltration in the lungs and the periodontium in a DEL-1-dependent manner. Whereas ERM (but not other antibiotics such as josamycin and penicillin) protected against lethal pulmonary inflammation and inflammatory periodontal bone loss, these protective effects of ERM were abolished in Del1-deficient mice. By interacting with the growth hormone secretagogue receptor (GHSR) and activating JAK2 in human lung microvascular endothelial cells, ERM induced C/EBPβ-dependent DEL-1 transcription, which was mediated by MAPK p38. Moreover, ERM reversed IL-17-induced inhibition of DEL-1 transcription, in a manner that was not only dependent on JAK2 but also on PI3K/AKT signaling. As DEL-1 levels are severely reduced in inflammatory conditions and with aging, the ability of ERM to upregulate DEL-1 may be a novel approach for the treatment of inflammatory and aging-related diseases.
Introduction Neutrophilic inflammation is a major driver of bronchiectasis pathophysiology, and neutrophil elastase activity is the most promising biomarker evaluated in sputum to date. How active neutrophil elastase correlates with lung microbiome in bronchiectasis is still unexplored. We aimed at understanding if active neutrophil elastase is associated with low microbial diversity and distinct microbiome characteristics. Methods An observational, cross-sectional study was conducted at the Bronchiectasis Program of the Policlinico Hospital in Milan, Italy, where adults with bronchiectasis were enrolled between March 2017 and March 2019. Active neutrophil elastase was measured on sputum collected during stable state, microbiota analysed through 16S rRNA gene sequencing, molecular assessment of respiratory pathogens through real time PCR and clinical data collected. Measurements and Main Results Among 185 patients enrolled, decreasing alpha diversity, evaluated through the Shannon entropy (rho: −0.37; p-value <0.00001), Pielou’ evenness (rho: −0.36, p<0.00001) and richness (rho: −0.33; p<0.00001), was significantly correlated with increasing elastase. A significant difference in median levels of Shannon was detected between patients with neutrophil elastase ≥20 µg·mL ⁻¹ [3.82 (2.20–4.96)] versus neutrophil elastase <20 µg·mL ⁻¹ [4.88 (3.68–5.80)], p<0.0001. A distinct microbiome was found in these two groups, mainly characterised by enrichment with Pseudomonas in the high and with Streptococcus in the low elastase group. Further confirmation of the association of P. aeruginosa with elevated active neutrophil elastase was found based on standard culture and targeted real-time PCR. Conclusions High levels of active neutrophil elastase are associated to low microbiome diversity and specifically to P. aeruginosa infection.
Aims Multiple sclerosis (MS) whose pathogenesis is still unclear is a chronic progressive disease in the central nervous system. Gut microbiota can directly or indirectly affect the immune system through the brain gut axis to engage in the occurrence and development of the disease. Materials and methods C57BL/6 mice which were immunized by MOG35–55 to prepare experimental autoimmune encephalomyelitis (EAE) animal models were treated with rapamycin and MCC950 (CP-456773) in combination or separately. After sequencing the 16S rRNA V4 region of gut microbiota, the species, abundance and composition of gut microbiota were analyzed by Alpha diversity, Bata diversity and LEfSe analysis. The pathological changes and the expression of CD4 and CD8 of brain, large intestine and spleen were detected. Key findings The results showed that rapamycin and MCC950 could alleviate the progression of the disease by inducing autophagy and inhibiting the immune response. The Alpha diversity of EAE model group was no significant difference compering to control group while the number of OTUs was decreased. After the treatment by rapamycin and MCC950, the abundance and composition of gut microbiota was relatively recovered, which was close to that of normal mice. Significance Inhibiting immune cell-mediated inflammation and restoring the composition of gut microbiota may help to alleviate the clinical symptoms of multiple sclerosis. Furthermore, to research the regulatory effect between immune response and gut microbiota may be a new strategy for the prevention and treatment of multiple sclerosis.