Impact of antibiotics on the human microbiome and consequences for host health

Abstract It is well established that the gut microbiota plays an important role in host health and is perturbed by several factors including antibiotics. Antibiotic‐induced changes in microbial composition can have a negative impact on host health including reduced microbial diversity, changes in functional attributes of the microbiota, formation, and selection of antibiotic‐resistant strains making hosts more susceptible to infection with pathogens such as Clostridioides difficile. Antibiotic resistance is a global crisis and the increased use of antibiotics over time warrants investigation into its effects on microbiota and health. In this review, we discuss the adverse effects of antibiotics on the gut microbiota and thus host health, and suggest alternative approaches to antibiotic use.


| INTRODUCTION
Since their discovery, antibiotics have revolutionized the treatment of infectious diseases on a global scale. They are recognized as one of the contributing factors to increased life expectancy in the 20th century owing to the decline in infectious disease mortality (Adedeji, 2016). However, their overuse and misuse in human and veterinary medicine and animal husbandry have resulted in the current global antibiotic resistance crisis (Llor & Bjerrum, 2014;Vidovic & Vidovic, 2020) which is exacerbated by the slow rate of new drug development (Simpkin et al., 2017). Despite this, antibiotics are still widely prescribed in disease treatment and studies have reported increased consumption of antibiotics in certain countries in the past number of years (Adriaenssens et al., 2011;Klein et al., 2018).
More recently, scientists have uncovered the detrimental impact of broad-spectrum antibiotics on the gut microbiota. Home to bacteria, archaea, microeukaryotes, and viruses, the gut microbiota plays a fundamental role in human health. It prevents pathogen colonization, regulates gut immunity, provides essential nutrients and bioactive metabolites, and is involved in energy homeostasis (Mills et al., 2019). In infants, the gut microbiota is acquired during birth and thereafter plays an essential role in the development of infant gut immunity. Evidence to date strongly suggests that balanced microbiota composition and rich species diversity are essential to its optimal functioning (Heiman & Greenway, 2016), which can be compromised in disease states (Mosca et al., 2016). Likewise, reduced diversity and imbalanced microbiota composition in the infant's gut are associated with intestinal illnesses and a predisposition to certain diseases later in life Volkova et al., 2021).
www.MicrobiologyOpen.com consequences for the host. Despite this, in Western countries, up to 35% of women are exposed to an antibiotic during pregnancy and delivery, and antibiotics comprise 80% of the drugs a woman is exposed to during pregnancy (Kuperman & Koren, 2016;Stokholm et al., 2013). Mothers are frequently prescribed intrapartum antibiotics prophylactically to prevent and treat infections (Verani et al., 2010).
Clostridioides difficile (formerly known as Clostridium difficile) infection is an example of a disease brought about directly through antibiotic disruption of the gut microbiota (Theriot et al., 2014). Illness ranges from mild diarrhea to death (Guh & Kutty, 2018).
Antibiotic eradication of beneficial bacteria in the gut enables C. difficile to flourish (Rea et al., 2011). A recent study also concluded that oral antibiotic use is associated with an increased risk of colon cancer (S. . These are just some of the examples of how antibiotic therapy can compromise health. This review thus focuses on the negative impacts of antibiotics on human health from pregnancy through to adulthood, most of which are microbiota-dependent, although we also provide evidence of nonmicrobiota-associated negative impacts. We discuss the changes to microbiota composition and functionality and the consequences for host health (Figure 1). We look at the impact of antibiotics at the single bacterial cell level, and how antibiotic use and misuse result in antibiotic resistance development. Further, we consider alternative approaches to antibiotic therapy and discuss therapeutics that can be used to maintain and improve host health and minimize the effects of antibiotics when used.

| INTRODUCTION TO MICROBIOTA COMPOSITION FROM INFANCY TO ADULTHOOD
It was previously believed that infants are protected in the mother's womb which is a sterile environment, but studies have now demonstrated that amniotic fluid samples, placenta from mothers, and meconium samples from infants contain bacterial DNA suggesting the early exposure of infants to bacteria (Aagaard et al., 2014;de Goffau et al., 2019;Moles et al., 2013;Stinson et al., 2019). However, this is much debated (Perez-Muñoz et al., 2017) due to issues with contamination and varying interpretations, thus we emphasize on microbiota development from infancy to adults in this review.
The gut microbiota in the early stages of life becomes more diverse until it reaches a stable adult-like composition by 2-4 years of age. Following birth, the gut is colonized by facultative anaerobes due to the partially aerobic or microaerophilic environment. These then F I G U R E 1 The negative impacts that can occur on host health due to overuse and misuse of antibiotics generate the appropriate atmosphere for the development of anaerobes by consuming the available oxygen. Thereafter, followed by early exposure to food (breast milk or infant formula), this composition changes, and facultative anaerobes such as Bifidobacterium, Bacteroides, and Clostridium dominate (Voreades et al., 2014). An initial decrease in Proteobacteria and Enterobacteriaceae accompanied by increases in Bacteroidetes and bifidobacteria have been reported in many studies (Bäckhed et al., 2015;Bokulich et al., 2017).
The establishment of the adult-like microbiota occurs at 2-4 years of age, which is represented by the high relative abundance of Bacteroidetes and Firmicutes (Fouhy et al., 2019).
Feeding habit is another crucial factor affecting the infant's gut microbiota composition. Because of the presence of oligosaccharides in human milk (human milk oligosaccharides) that are largely used by bifidobacteria, breastfed infants show higher levels of bifidobacteria compared to formula-fed infants, and the proportions remain high even postweaning (Bezirtzoglou et al., 2011;Fallani et al., 2011).
Bacteroides, Streptococcus, and Lactobacillus have also been reported in breastfed infants (Harmsen et al., 2000). Formula-fed infants present higher abundances of Escherichia coli, C. difficile, the Bacteroides fragilis group, and lactobacilli than their breastfed counterparts (Penders et al., 2006). Gestational age is another factor that affects the gut microbiota composition with preterm infants showing lower diversity, higher abundance of Proteobacteria and reduced levels of obligate anaerobes such as Bifidobacterium, Bacteroides, and Atopobium compared to full-term infants (Arboleya et al., 2012;Moles et al., 2013). Another factor is antibiotic administration, as shown in Figure 2, and is discussed below.
F I G U R E 2 Diagrammatic representation of the effect of various antibiotics on human gut bacteria. Green (left) denotes increasing levels, while red (right) indicates decreasing levels PATANGIA ET AL.
| 3 of 23 The gut microbial composition changes throughout pregnancy and a healthy pregnancy is characterized by an increase in the bacterial load and profound alterations in the composition of gut microbiota (Nuriel-Ohayon et al., 2016). During the first to the third trimester of pregnancy, major changes such as an overall increase in Proteobacteria and Actinobacteria and reduced richness have been reported owing to the major physiological changes (Koren et al., 2012). Also, the vaginal microbiota during pregnancy has been reported to changerepresented by the high bacterial load with high Lactobacillus abundance, low richness, and diversity compared to the vaginal microbiota of nonpregnant females (Aagaard et al., 2012;Freitas et al., 2017).
The gut microbiota of healthy adults is predominantly composed of the phyla Firmicutes and Bacteroidetes, representing the majority, followed by Actinobacteria, Proteobacteria, and Verrucomicrobia (Arumugam et al., 2011). Indeed, the gut microbiome can be perturbed by short-term use or even low-doses of antibiotics that can have long-term effects on health , this cautions against the misuse and overuse of antibiotics, particularly in pregnant women and young children.

| ANTIBIOTIC TYPES COMMONLY ADMINISTERED
The use of antibiotic therapy during pregnancy and lactation varies depending on the underlying condition, country, and medical guidelines, but some of the most commonly prescribed antibiotics during pregnancy are β-lactam antibacterials (Petersen et al., 2010). Some of the other antibiotic classes prescribed include sulfonamides/trimethoprim and macrolides/lincosamides/streptogramins (de Jonge et al., 2014). Common infections for which antibiotics are prescribed during pregnancy include urinary tract infections, respiratory tract infections, skin or ear infections, bacterial vaginosis, and fever of unknown origin (Heikkila, 1993;Petersen et al., 2010). Antibiotics are frequently administered to mothers during labor to prevent Group B Streptococcus transmission, to reduce and prevent infections in the endometrium, and to prevent wound infections (Braye et al., 2019); though the WHO advises against the prophylactic use of antibiotics post uncomplicated delivery. This is of concern as infant antibiotic exposure through intrapartum antibiotic prophylaxis (IAP) has been shown to alter infant gut microbial diversity (Tapiainen et al., 2019).
Further, antibiotics are commonly prescribed to newborns, owing to their high susceptibility to infections and lowered immunity, particularly in premature infants (Clark, 2006;Vergnano et al., 2005).
The most commonly used antibiotics for infants include amoxicillin, co-amoxiclav, benzylpenicillin, cephalosporins, gentamycin, vancomycin, clindamycin, and azithromycin. These antibiotics are indicated in respiratory and ear infections, bronchitis, pharyngitis, and high temperature (CDC, 2017). Table 1 summarizes the commonly used antibiotics and their indication for use.

| Impact of antibiotics during pregnancy and lactation
Perinatal and peripartum antibiotic use can impact gut microbial colonization and the resistome profile in infants Zhou et al., 2020). To understand the potential impact of antibiotic administration on offspring during pregnancy, scientists examined the temporal impact of cefoperazone, on both maternal and offspring microbiota when administered during the peripartum period in an interleukin 10 (IL-10)-deficient murine model of colitis (Miyoshi et al., 2017). Offspring from cefoperazone-exposed dams developed altered gut microbial communities into adulthood and had increased susceptibility to spontaneous and chemically induced colitis (Miyoshi et al., 2017 antibiotic-altered microbial community. They observed that the altered microbial community was transmitted to the IL-10-deficient offspring which resulted in the development of markedly increased colitis (Schulfer et al., 2018). Another study demonstrated that uptake of antibiotics during pregnancy can lead to alterations in the vaginal microbial composition before birth (Stokholm et al., 2014); this can impact the microbial composition infants receive at birth (Dobbler et al., 2019). Maternal antibiotic uptake during pregnancy has been reported to be associated with altered microbial composition depending on the antibiotic type (Azad et al., 2016;Coker et al., 2020). It is also associated with increased risk of asthma and allergy in the infant (Stokholm et al., 2014) although there is some controversy around this (Kim et al., 2019), as well as with functional impairment in development and cognition (Kenyon et al., 2008), obesity (Mueller et al., 2015),

| Impact of antibiotic administration directly to infants on the infant gut microbiota
Premature infants are very often treated with antibiotics owing to their health conditions, and antibiotics are one of the most commonly prescribed drugs in the NICU (Clark, 2006  reported that the effect of ciprofloxacin on the gut microbiota was profound and rapid with a decrease in richness and diversity of microbiota accompanied by shifts in levels of Bacteroidetes, Lachnospiraceae, and the Ruminococcaceae. By 1 week after the end of each course, communities began to return to their initial state, but the return was incomplete and variable from the initial stage (Dethlefsen & Relman, 2011). Many studies have investigated the long-term impact on gut microbiota following a course of antibiotics. A short term course of clindamycin (7 days) resulted in significant disturbances in the bacterial community such as a sharp decline in Bacteroides (Jernberg et al., 2007;Löfmark et al., 2006) and enterococcal colonies (Lindgren et al., 2009) that remained for up to 2 years post-treatment and was accompanied by increased levels of ARGs and strains (Jernberg et al., 2007;Lindgren et al., 2009;Löfmark et al., 2006). Another study (n = 10) that can persist for years after treatment (Jakobsson et al., 2010;Sjölund et al., 2003).
Furthermore many antibiotics are used for dentistry procedures routinely. These antibiotics can increase the number of resistant strains present orally, can increase the minimum inhibitory concentrations, and can also eliminate the nonpathogenic strains (Harrison et al., 1985;Ready et al., 2004), which can lead to systemic infections and inflammation.

| In adults
Due to the role of the microbiota in host metabolism and physiology, many studies postulate that microbial imbalances can be related to obesity (Riley et al., 2013;Scott et al., 2016), diabetes (Boursi et al., 2015;, and asthma (Arrieta et al., 2015;Kozyrskyj et al., 2007). Blaser and Falkow (2009)  Studies have reported a link between antibiotic usage and obesity (Del Fiol et al., 2018). Some studies suggest that an increased ratio of Firmicutes to Bacteroidetes rather than specific levels is associated with obesity (Kasai et al., 2015), though results are conflicting (Duncan et al., 2008;Schwiertz et al., 2010). While the microbial component of obesity is debated, studies have reported a common change at functional microbial levels. Indeed, obese individuals have higher short-chain fatty acid (SCFA) content compared to lean individuals (Schwiertz et al., 2010;Turnbaugh et al., 2006).
Furthermore, obesity is associated with metabolic alterations related to glucose homeostasis and insulin resistance and linked to the development of diabetes (Cani et al., 2012). In a study in 96 humans (48 each antibiotic group and controls), researchers reported significant and persistent weight gain after an episode of infectious endocarditis in patients who had been treated with vancomycin and gentamycin (Thuny et al., 2010).
An association between antibiotic-induced changes in microbial colonization and type 1 diabetes in male mice was reported (Candon et al., 2015). A combination of broad-spectrum antibiotics or vancomycin alone was given to neonatal nonobese diabetic mice that spontaneously developed autoimmune type 1 diabetes. The microbiota was significantly altered with an increase in Escherichia and Lactobacillus species and a decrease of the Clostridiales order compared to controls. A major reduction of IL-17-producing cells was also observed in the lamina propria of the ileum and the colon of vancomycin-treated mice (Candon et al., 2015), which can affect host defense mechanisms. Some studies in human populations also suggest a link between repeated use of broad-spectrum antibiotics and diabetes (Boursi et al., 2015;, while some suggest a protective and preventative role of antibiotics and diet in diabetes development in diabetes-prone animals partly due to lowering of specific antigenic load or development of tolerogenic APCs (Brugman et al., 2006;Hu et al., 2015). Antibiotics can lead to antibiotic-associated diarrhea (AAD) and studies have demonstrated that clindamycin can result in alteration of the microbial community which can promote the colonization of potential pathogens such as C. difficile which can lead to diarrhea and colitis (Buffie et al., 2012;McDonald, 2017). Another study in a mouse model reported that antibiotic treatment resulted in decreased alpha and beta diversity, which potentially caused a decrease in levels of serotonin, tryptophan hydrolase, and secondary bile acids which can further affect gut motility and metabolism (Ge et al., 2017).

| During pregnancy and infancy
Extrinsic factors such as antibiotics can alter the diversity of the maternal microbiota that can affect the infant's gut microbiota diversity, immunity, and disease development in later life, both directly and indirectly (Azad et al., 2016;Nyangahu et al., 2018;Tapiainen et al., 2019;Tormo-Badia et al., 2014). According to the hygiene hypothesis, if the host is not exposed to a diverse range of microbiota early in childhood or in the developing stages, immune-related disorders may develop such as asthma and allergic sensitization. Antibiotics can have a similar effect when administered during infancy.

| Changes in immune response
The immune system is trained to fight pathogens during infancy, and this is the time when microbial colonization takes place. Any disturbance to microbial colonization has been shown to affect immune maturation due to this co-developmental process. Studies in germfree mice have confirmed that the absence of microbes in the gut results in both physiological and immunological changes to the gut environment. These changes include alterations in mucus thickness and composition (Szentkuti et al., 1990), reduced gastric motility (Abrams & Bishop, 1967), and bile acid metabolism (Rodrigues et al., 2017). This was reported to be accompanied by reduced levels of SCFAs and secondary bile acid pools (Zarrinpar et al., 2018). Similar results were reported following vancomycin treatment (Vrieze et al., 2014). This can lead to impairment of barrier function (Kelly et al., 2015); act as a causative factor in the development of ulcerative colitis (Machiels et al., 2013), and Salmonella infection (Gillis et al., 2018).
Studies have also reported that antibiotic uptake can result in changes in protein expression, energy metabolism in the microbiota, with a slight increase following antibiotic therapy, which may be as a coping mechanism to antibiotic stress but decreased at later stages

| Accumulation of metabolites/xenobiotics
Xenobiotics (including antibiotics, heavy metals, and environmental chemicals) have an impact on gut microbial composition. The effect here is cyclical in that the microbiota is necessary for xenobiotic biotransformation ( Figure 3). The metabolism of xenobiotics before it reaches its target organ site is largely dependent on the microbiota.
The gut microbiota can affect the xenobiotic half-life in the host, the extent to which they reach the target receptor, and may also influence the host's capacity to metabolize xenobiotics (Koppel et al., 2017).

Both in vivo and in vitro studies have shown that the gut microbiota is
involved in the biotransformation of xenobiotics (Lu et al., 2013).  (Lynch & Price, 2007).
Another study speculated that increased levels of hepatic lipid accumulation and TG levels in mice were due to antibiotic treatment and the altered gut microbial composition (Jin et al., 2016). Studies have shown that antibiotic treatment in mice increases the levels of sialic acid and succinate which increase the susceptibility of the host to Salmonella and C. difficile infections (Ferreyra et al., 2014;K. M. Ng et al., 2013). In the same manner, an antibiotic-altered microbial composition can result in deficiencies of certain metabolites or vitamins that are solely produced by bacteria. For example, one study reported that antibiotic-induced changes in the gut microbiota of mice resulted in shifts in copper (Cu) metabolism. This can have consequences for immunity and the intestinal barrier due to the role of Cu in these functions (Miller et al., 2019).
Furthermore, cross-feeding is a significant feature of the gut microbiota. For example, B. adolescentis produces lactate and acetate by utilizing fructo-oligosaccharides and starch. Butyrate-producing anaerobes cannot utilize fructo-oligosaccharides and starch but rely on lactate and acetate as growth substrates. Therefore, B. adolescentis indirectly facilitate the proliferation and expansion of butyrate-producing species through cross-feeding. This type of dependency is also seen in many other bacterial groups (Heinken & Thiele, 2015;Rowland et al., 2018). This codependency can be disturbed by antibiotic use leading to increased accumulation or deficiency of some metabolites/compounds. For example, a study reported a decrease in abundance of Gram-negative bacteria in the gut by vancomycin which is a Gram positive-targeting antibiotic (Ubeda et al., 2010). This can be due to the interdependency of bacteria in their community.

| Changes in bacterial signaling pattern
Antibiotics can alter the transcription of several major functional genes such as those encoding transport proteins, genes involved in the metabolism of carbohydrates, and protein synthesis (Goh et al., 2002;J. T. Lin et al., 2005). A study demonstrated induced expression of virulence-associated genes in Pseudomonas aeruginosa leading to higher secretion of rhamnolipids and phenazines on exposure to subinhibitory concentrations of antibiotics (Shen et al., 2008). Many studies have reported that aminoglycosides (Hoffman et al., 2005), β-lactams (

| ARG reservoir
ARGs are now reported to be found in the environment including oceans and freshwater bodies (Hatosy & Martiny, 2015), soil | 9 of 23 (Cycoń et al., 2019), glaciers (Segawa et al., 2013), the food chain, and also within humans. Apart from bacteria, viruses have also been reported to be carriers of ARGs (Debroas & Siguret, 2019).
Some of this spread of ARGs is historical such as in some untouched/uncontaminated environments (Van Goethem, 2018) but much of it is because of the wide use of antibiotics by humans.
For instance, apart from their use in treating infections in humans, antibiotics have been widely used as growth promoters for weight gain in animals (Butaye et al., 2003) and to treat and control infections (Ding et al., 2014;Mcmanus et al., 2002). They have also been used in aquaculture for similar reasons (Cabello, 2006;Lulijwa et al., 2019). Some of these antibiotics are the same as, or are structurally similar to the ones used to treat human infections such as erythromycin, gentamycin, enrofloxacin, neomycin, streptomycin (Marshall & Levy, 2011). The development of antibiotic-resistant bacteria in agriculture and aquaculture is a serious concern as such bacteria can enter humans through the food chain promoting crossresistance and also reducing the susceptibility of infectious bacteria to antibiotic treatment.
Intriguingly, some studies have reported the presence of ARGs in humans from remote communities who have had very limited exposure to antibiotic therapy. They reported high levels of acquired resistance to antibiotics such as tetracycline, ampicillin, trimethoprim/sulfamethoxazole, streptomycin, and chloramphenicol (Bartoloni et al., 2009). Similarly, ARGs in healthy humans have been reported despite the absence of antibiotic use (Bengtsson-Palme et al., 2015;Sommer et al., 2009;de Vries et al., 2011). Studies in healthy infants and children who have never been exposed to antibiotics report the presence of genes that confer resistance to β-lactams, fluoroquinolones, tetracycline, macrolide, sulfonamide, or multiple drug classes. The major ARG carriers were found to be Enterococcus spp., Staphylococcus spp., Klebsiella spp., Streptococcus spp., and Escherichia/ Shigella spp. (Casaburi et al., 2019;Karami et al., 2006;Moore et al., 2013;L. Zhang et al., 2011).
In the gut, bacteria can horizontally and vertically transmit genes to other related or unrelated bacteria due to their proximity via mobile genetic elements (  (Källén & Danielsson, 2014;Kenyon et al., 2008;Meeraus et al., 2015). Similarly, amoxicillin use during the first trimester was linked to cleft lip and cleft palate development, and though reported in only a small number of cases, it exemplifies the adverse effects of antibiotic use during pregnancy (Lin et al., 2012). Birth defects such as microphthalmia, hypoplastic left heart syndrome, atrial septal defects, and cleft lip with cleft palate have also been associated with the use of sulfonamides and nitrofurantoin during the first trimester of pregnancy (Crider et al., 2009). Similarly, trimethoprim-sulfonamide use during pregnancy is associated with a higher risk of cardiovascular malformations (Czeizel et al., 2001). The evidence in all cases is mixed (Muanda & Sheehy, 2017), and is usually linked with consumption during the early months of pregnancy. This could be due to the antibacterial impacting the neonate during the organogenesis and early devel-  (Morgun et al., 2015), and oxidative tissue damage in mammalian cells (Kalghatgi et al., 2013). Though controversial, some studies suggest that antibiotic use can be related to increased risk of breast cancer (Tamim et al., 2007;Velicer et al., 2004) and increased risk of miscarriage .
Sometimes, antibiotics can worsen the condition they are meant to treat. The bactericidal action of many β-lactam antibiotics has been reported to increase toxin production such as Shiga toxin which is released from entero-hemorrhagic E. coli, predisposing the host to a higher risk of a hemolytic uremic syndrome (Kimmitt et al., 1999;Wong, 2000). Antibiotics can also affect host metabolism directly without microbes as a mediator while making the targeted pa- FMT can be more beneficial for regaining microbial balance in the gut (Suez et al., 2018). FMT has been widely used therapeutically for rebalancing the microbiota of C. difficile-infected patients; restoring F I G U R E 4 Various alternatives to antibiotics that can be used alone or in some cases in combination with antibiotic treatment PATANGIA ET AL.
| 11 of 23 their microbial and metabolic activity (Weingarden et al., 2014). FMT can also utilize donor fecal material from the patient itself before antibiotic therapy, known as autologous FMT. Many factors such as efficacy, cost, and suitability make FMT an attractive option but detailed studies are needed to optimize the process and understand other probable therapeutic applications beyond gut disorders (Allegretti et al., 2019;Ramai et al., 2019).
One wounds and ulcers healed post phage therapy; healing was associated with a reduction in pathogens (Markoishvili et al., 2002).
The use of engineered bacteriophages to treat drug-resistant Mycobacterium abscessus was reported to show clinical improvement in a patient with cystic fibrosis (Dedrick et al., 2019). Another promising approach is the use of phage lytic proteins as antimicrobial compounds (Mondal et al., 2020), making phages a strong antibacterial contender of antibiotics.
Bacteriocins represent another category of potential antibiotic alternative. Bacteriocins are ribosomally produced antibacterial peptides produced by bacteria which themselves are immune to the killing peptide due to specific immunity mechanisms. To date, bacteriocins have been mainly used in the food industry as food safety and preservative agents (Silva et al., 2018). Bacteriocins have shown promising results as antimicrobials in animal studies. For example, mouse model studies have reported the successful use of pyocin to treat P. aeruginosa lung infections with high efficacy and without any adverse effects (McCaughey et al., 2016;Merrikin & Terry, 1972). Another study in mice reported that administration of nisin-and pediocinproducing Lactococcus lactis and P. acidilactici strains helped reduce intestinal vancomycin-resistant enterococci colonization (Millette et al., 2008). Bacteriocins have been successfully used to treat and prevent bovine mastitis with comparable efficacy to antibiotics (L. T. Cao et al., 2007;Crispie et al., 2004;Kitching et al., 2019). Furthermore, nisin has proven to be effective in treating mastitis caused by Staphylococcus in eight lactating females (Fernández et al., 2008).
Another effective way of addressing the problem of antibiotic resistance is with the use of monoclonal antibodies as alternatives or in conjunction with antibiotics. Monoclonal antibodies bypass the complications of toxicity, resistance development, and early clearance by the immune system which is seen in the case of antibiotics.
The use of monoclonal antibodies for treating bacterial infections is emerging in the past few years, before which monoclonal antibodies were mostly used for treating cancer, autoimmune diseases, or viral infections (Zurawski & McLendon, 2020). A recent study in rabbits demonstrated the success of the use of monoclonal antibody obiltoxaximab against anthrax protective antigen. The authors reported that the use of obiltoxaximab improved the survival of rabbits that received a lethal dose of B. anthracis spores (Henning et al., 2018). In a recent clinical trial of 2655 participants, authors reported that the use of bezlotoxumab (monoclonal antibody against C. difficile toxin) for treating C. difficile infection resulted in a lower recurrence of infection (Wilcox et al., 2017). In another recent study, Watson et al.
(2021) generated a monoclonal antibody from B cells of a patient to be used against Mycobacterium tuberculosis infection in mice.
Monoclonal antibodies are costlier than producing antibiotics but have many benefits and more studies in this direction will help can help transform medicine.
One of the major advantages of bacteriocins, phages and their endolysins, and monoclonal antibodies is that they can be highly target-specific thus rendering minimal if any, collateral damage to the microbiota.

| CONCLUSION
This review has summarized the importance of the gut microbiota in host metabolism and immune functions such as immunity development, colonization resistance, cell signaling, and with the help of advanced omics technologies, the complex interactions between host and microbiota are now becoming clear. Antibiotics disrupt the microbial balance and hence the networking within the bacterial community, and that with the host. The resulting resistant bacteria make clinical treatment difficult. Due to this complex link between the host and microbiota, the current usage of antibiotics requires careful stewardship, with an emphasis on the application of antibiotic alternatives, while limiting collateral damage. To this end, we need to design, develop, and translate new antibiotic alternatives from bench to bedside, in addition to methodologies that are efficient in conserving and restoring the microbial community after antibioticassociated perturbations.

ACKNOWLEDGMENTS
The authors were funded in part by Science Foundation Ireland and APC Microbiome Ireland.

CONFLICT OF INTERESTS
None declared.

ETHICS STATEMENT
None required.

DATA AVAILABILITY STATEMENT
Not applicable.