Antibiotics are the first line of treatment against infections and have contributed immensely to reduce the morbidity and mortality rates. Recently, extensive use of antibiotics has led to alterations of the gut microbiome, predisposition to various diseases and most importantly, increase in the emergence of antibiotic-resistant bacteria, which poses a major threat to global public health. Another major issue faced worldwide due to unregulated use of antibiotics in children as well as in adults is the influence of metabolism and body weight homeostasis, leading to obesity. Apart from the involvement of biosocial causes influencing diet, physical activity, and antibiotic use, pathogenesis of obesity is linked to interconnected functional alterations in cells, tissues and organs due to biochemical, epigenetic and genetic factors. Mitochondrial dysfunction is one such factor, which is becoming the primary focus of various aspects of research on multifactorial complex diseases and is providing new perspectives on etiology, biomarker-based diagnosis, and drug sensitivity. Through this review, we have made an attempt to present the interplay between use of antibiotics, obesity, and associated mitochondrial dysfunction. This may provide insights into the molecular basis, genetic predisposition and environmental triggers, which in turn may have potential clinical applications in the management of antibiotic use.

Obesity is a major area of concern for most of the developed and developing countries as it is a well-known risk factor for several health conditions. The public health situation in developing countries is already facing the burden of undernutrition and infectious diseases and has worsened with the emergence of obesity and its associated adverse health consequences. Interestingly, undernutrition has been reported to predispose individuals to obesity through non-reversible epigenetic modifications [1]. This has implications for public health, as the efforts to address the problem of undernutrition in developing countries need to be balanced in order to avoid the emergence of obesity [2]. Obesity is found to predispose individuals to other age-related chronic morbidities such as increased risk of diabetes, hypertension, cancer, cardiovascular disease, sleep apnea, osteoarthritis, periodontitis, atherosclerosis, etc. [3,4], and thus, it is important to control the rapid worldwide upsurge of obesity.

According to the reports of the World Health Organization, the global prevalence of obesity among adults in 2014 was over 600 million, and it was estimated to be 13% of the world's adult population. Between 1980 and 2014, the obesity rate has doubled [5,6]. Reports also suggest that globally, the Pacific Islands have the highest rate of obesity, while the lowest rates have been observed in Asia. Although Europe and North America are found to consistently show significantly high rates of obesity, the rates in African and Middle Eastern countries are found to be highly variable [7]. Several reports have revealed that approximately one-third of the total world's population is overweight and is at high risk for obesity and other comorbidities [8].

The use of antibiotics has been shown to alter the gut microbiota, which, in turn, could affect the lipid metabolism leading to obesity [9,10,11]. The weight gain observed in farm animals after antibiotic treatment is a testimony to this very fact [12,13]. Further, early life exposure to antibiotics was found to have long-term effects on the gut microbiome, body composition, metabolism and predisposition to obesity as well as other age-related disorders [14,15,16,17,18]. Apart from the use of antibiotics, drastic changes in lifestyle for years, such as diet and activity patterns, are believed to be among the chief contributors in increasing incidence of obesity [19]. But, the association of obesity with physical activity and diet is just a small proportion of the more complex situation that remains to be resolved. Several findings have revealed that genes play a crucial role in determining the risk of susceptibility or resistance of an individual to obesity. The potential association of viral factors such as from adenovirus 36 with obesity and weight gain in humans has also been described [20]. The etiology of obesity is not yet completely known, but it is believed to be an outcome of the complex interplay of environmental, genetic, and behavioral factors [7].

Mitochondria play a crucial role in orchestrating lipid metabolism. Initially, as the fat content and its deposition in the liver increases, the rate of mitochondrial beta-oxidation increases. As a result, several metabolic adaptations occur, subsequently leading to mitochondrial dysfunction [21]. The maintenance of mitochondria in the cells is mainly regulated by the process of fusion and fission which repair the damaged mitochondria and remove those which are irreparable. Reports suggest that obesity is linked with an imbalance in the processes of fusion and fission which may adversely affect the mitochondrial morphology, size, number, and integrity [22,23].

Mitochondrial dysfunction is among the chief contributors in the pathogenesis of various metabolic disorders. Recent animal-based studies have suggested the effect of maternal obesity and postweaning high-fat diet on the key regulators of mitochondrial fusion and fission. Maternal obesity detrimentally changes mitochondrial targets which in turn, contribute to mitochondrial dysfunction and increased risk of obesity [24]. Potential modifications in mitochondrial bioenergetics may arise due to specific mutations that occur in the mitochondrial DNA. Owing to its endosymbiotic origins, mitochondria retain many catalytic subunits involved in the processes of electron transport and ATP synthesis for bioenergetics and signaling purposes [25]. It has been observed that the decreased number of mitochondria and impaired function may predispose individuals to obesity [26]. This concept was brought to light after a study on Finnish twins which revealed variations in the number and energy metabolism activity in fat cells of genetically identical twins with significant weight differences. Furthermore, differences were observed in the activities of mitochondrial enzymes in obese as well as non-obese children. The findings also correlated with the occurrence of decreased rate of oxidative phosphorylation which is normally seen in obese children [27]. Reports also suggest that obese individuals possess smaller-sized mitochondria with lower energy-generating ability as compared to their lean counterparts [28,29,30].

Another major characteristic of obesity includes insulin resistance, which may be a result of the alterations in the normal functioning of the mitochondria [31]. In children, studies have established that decreased skeletal muscle mitochondrial oxidative phosphorylation is strongly correlated with insulin resistance and altered metabolic phenotype. Although obesity has not yet been directly linked to mitochondrial dysfunction in children, its function is found to be a main contributor to altered metabolism [32]. In addition, increased fatty acid oxidation leads to increased reactive oxygen species (ROS) generation, which is likely to play a crucial role in developing insulin resistance and a subsequent decline in the electron transport chain (ETC) activity. In non-alcoholic fatty liver disease studies using human as well as rodent models, a reduced quinone pool and an overall reduced redox state in the mitochondrial matrix were found. This was suggested to be associated with increased ROS production which is known to impair the ETC, increase cytokine expression and cause mitochondrial DNA mutations [21]. Thus, caloric intake and ROS generation are involved in causing mitochondrial dysfunction.

Increased mitochondrial biogenesis and activity during adipocyte differentiation [33], as well as the role of mitochondrial dysfunction resulting in faulty fatty acid oxidation in mature adipocytes [34], confirm the importance of mitochondria in lipid metabolism subsequently linking it to diet-induced obesity [35]. Remarkably, mitochondrial dysfunction due to conditional knockout of mitochondrial transcription factor TFAM in adipose tissues was found to protect individuals against obesity [36]. Evidence from several studies in mice as well as humans supports the potential link between obesity and the levels of mitochondrial DNA in white adipose tissue. Lipid accumulation and insulin resistance due to the disruption of the normal functioning of mitochondria may have a crucial role in the etiology of obesity [37]. The relevance of mitochondrial function in a range of disorders such as obesity, type 2 diabetes, and lipodystrophies has shifted the focus to this previously unknown area, thus providing new insights into the pathogenesis of these diseases [38]. Obesity and subsequent mitochondrial dysfunction is also related to unregulated antibiotic use as well as induced variations as depicted in Figure 1.

Fig. 1

Diagrammatic representation of link between obesity and unregulated use of antibiotics, the two major public health challenges.

Fig. 1

Diagrammatic representation of link between obesity and unregulated use of antibiotics, the two major public health challenges.

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An important indicator of fat oxidation is the respiratory quotient (RQ), and higher RQs have been observed in pre-obese or reduced-obese individuals, signifying lower fat oxidation [39]. Also, it has been noted that deteriorated mitochondria are marked by a less distinct inner membrane and larger vacuoles. The mitochondrial DNA content assessment yielded considerable differences in obese and lean individuals, showing notable reduction in case of obesity [28]. Diminished ETC activity was also observed, but the underlying causes could not be completely explained. Obesity is associated with higher levels of phosphofructokinase and glyceraldehyde 3- phosphate dehydrogenase, while the activity levels for citrate synthase, cytochrome c oxidase and beta-hydroxyacyl CoA dehydrogenase was lower. Also, it has been reported that the mitochondrial enzymatic markers of energy metabolism in obese individuals differ significantly from those of non-obese individuals [39]. Recent findings have also pointed out the role of oxidative damage to cardiolipin in impaired insulin signaling and metabolic syndromes. Through knockout studies, it was seen that ALCAT1 (a lysocardiolipin acyltransferase), associated with mitochondrial biogenesis [40], as well as the synthesis of a form of cardiolipin, may be upregulated in the presence of oxidative stress. However, its knockout could maintain normal mitochondrial function, safeguard against diet-induced obesity and enhance the signaling [21]. Mitofusin 2 (MFN2) is another vital protein that is required for a range of mitochondrial functions, including maintenance of mitochondrial integrity, fusion, metabolism, and tethering with the endoplasmic reticulum. Any deficiency or mutation in this gene could, therefore, lead to various diseases, including obesity [40].

Although obesity is known to be related to mitochondrial dysfunction [41], the molecular mechanisms underlying obesity-related metabolic defects are not well established. Increasing evidence suggests that mitochondrial dysfunction arising from mutations in the mitochondrial genome may be implicated in common diseases such as obesity, diabetes, cancer, neurodegeneration, cardiomyopathy, as well as aging [42]. The mechanisms resulting in mitochondrial dysfunction are generally linked to the development of obesity and other associated metabolic complications. Hence, several studies have been conducted in a large number of populations, to identify the major DNA variations involved in obesity. It has been found in a Japanese population that a single nucleotide polymorphism 15497 G/A at 251 residue is linked to obesity [43]. This SNP results in the replacement of glycine to serine amino acid in cytochrome b, which is the fundamental redox catalytic subunit concerned with quinone substrate binding, transmembrane electron transfer and also inhibition of oxidoreductase. Another study indicated that a mutation in the mitochondrial DNA, encoding the nicotinamide adenine dinucleotide dehydrogenase subunit I (NDI) gene, which forms a crucial part of the process of electron transport and 12S ribosomal RNA, has been implicated in obesity in a Japanese population [44], whereas studies in a Caucasian population obtained data indicating varied results [38,45]. Further, polymorphisms in the gene coding for mitochondrial uncoupling protein 2 (UCP2) were recognized as a risk factor for childhood obesity [46]. Uncoupling proteins are a group of mitochondrial transporter proteins, responsible for protein leaks across the inner membrane and differentiating oxidative phosphorylation from ATP synthesis. Also, a number of mitochondrial DNA variants have been analyzed in various populations for inadequate energy expenditure as well as its association with obesity and related metabolic alterations to date [37]. Although altered gut microbiota is linked to obesity, and mitochondrial dysfunction is observed in conditions of obesity, currently there is no direct evidence for ascribing the role of mitochondrial DNA polymorphic forms in obesity.

Although the discovery of antibiotics is considered as one of the greatest discoveries of the 20th century, the increasing magnitude of antibiotic misuse and subsequent development of resistance have become a menace to the public health system [47]. Antimicrobial agents were initially developed with the intention to treat infections caused by a range of pathogenic microorganisms such as bacteria, viruses, parasites and fungi. However, over a period of time, these microorganisms have evolved to evade or resist several antimicrobial agents [48]. When the existence of antibiotic-resistant strains of microorganisms was first reported about 70 years ago [49], it may have been overlooked due to the presence of other drugs that could potentially treat these infections. But the widespread, unregulated use of antibiotics has led to the emergence of several drug-resistant microorganisms causing diseases such as typhoid [50], cholera [51], diarrheal illness [52], enterococcal infections [53], gonorrhea [54,55], urinary tract infections [56], malaria [57], HIV [58], tuberculosis [59], and other respiratory infections [60] including influenza [61].

The ability of microorganisms to develop resistance to antimicrobial agents can either be attributed to mutations [62] or the acquisition and horizontal transfer of resistant genes [63,64,65]. In addition, the probiotic microorganisms are not spared from developing antibiotic resistance and could possibly turn into a major threat [66]. The gut microbiota forms the major reservoir of antibiotic resistance genes, which are also found distributed in the environment [67]. Resistance to antibiotics is found to be transferred between humans, animals, birds, and plants through a vicious cycle as a result of overuse of antibiotics, as illustrated in Figure 2[68,69,70]. Currently, antibiotic resistance can be considered one of the most dangerous and rapidly spreading health problems throughout the world. Though the process of emergence of antibiotic resistance in microorganisms is a natural phenomenon, the pace at which it occurs and also the selective pressure posed by the inappropriate use of antibiotics has aggravated the urgency of the situation. The findings summarizing the resistance data of common bacteria from 114 countries were recently published by the World Health Organization and found to be alarming. It was reported that the standard means of treatment to most common bacteria causing infections has already been rendered ineffective in several parts of the world, owing to antibiotic resistance. Escherichia coli was found to be resistant to third-generation cephalosporins and fluoroquinolones, Klebsiella pneumoniae to third-generation cephalosporins and carbapenems, Staphylococcus aureus to methicillin and Streptococcus pneumoniae to penicillin [71]. Recently, the emerging resistance of Neisseria gonorrhoeae to third-generation cephalosporins and quinolones, and of Enterobacteriaceae to carbapenems and colistin was addressed in the updated report. In addition, the treatment guidelines for chlamydial infections, syphilis, tuberculosis, malaria, HIV, and influenza have been reformed due to multidrug resistance of these causative organisms [72]. Therefore, the resistance of microorganisms to last-line therapy, decline in research of new antibiotics in combination with the decrease in effectiveness of the existing ones further amplifies the intensity of this situation and could have catastrophic consequences [73].

Fig. 2

Figure illustrating the influence of antibiotics on the generation and transmission of antibiotic resistance, on cytokines, leading to mitochondrial dysfunction and obesity, and on MMPs, affecting mitochondrial function as well as involvement in several diseases.

Fig. 2

Figure illustrating the influence of antibiotics on the generation and transmission of antibiotic resistance, on cytokines, leading to mitochondrial dysfunction and obesity, and on MMPs, affecting mitochondrial function as well as involvement in several diseases.

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Primarily, it was thought that microbiota changes in children were attributed to infections. But based on phylogenetic, metagenomic as well as individual antibiotic purchase records, it was observed that macrolide use in Finnish children resulted in a long-lasting shift in the microbiota composition as well as function. Macrolide use was also found to be correlated with increased risk of asthma and weight gain. This study also showed that penicillin use was not linked with significant genome-wide compositional or functional changes [74]. Although both antibiotics were administered for respiratory infections, their effects on microbiota varied greatly, suggesting the strong correlation between antibiotic use and modified microbiota.

Furthermore, research-based evidence suggests that unregulated use of antibiotics in early childhood is associated with increased vulnerability to metabolic disorders. These results were backed up by similar mouse studies, which demonstrated that antibiotic use may disrupt the microbiome, which would subsequently lead to metabolic disease predisposition. The findings of mouse studies have previously linked early-life antibiotic exposure to alterations in intestinal microbiome and associated susceptibility to various immune or metabolic diseases [75,76,77,78]. Nevertheless, due to marked differences in diet, metabolism, and gut microbiome, mouse-related experimental data are not readily comparable with human. In human clinical trials, altered intestinal microbiota consisting of reduced diversity and varied composition was observed with oral intake of antibiotics [79,80]. Although antibiotics are important to curb infections, inappropriate use of antibiotics contributes to altered gut microbiome and metabolic disorders. Thus, antibiotic use in the present day is considered as a double-edged sword.

Several findings suggest that the unregulated use of antibiotics often results in problems associated with antibiotic resistance or side effects. Certain classes of antibiotics are known to inhibit mitochondrial biogenesis as an “off-target” effect [81]. Further on, the fact that various bactericidal antibiotics such as quinolones, aminoglycosides, and β-lactams are capable of inducing mitochondrial dysfunction and production of ROS, confirms the bacterial origin of the organelle [82]. Mitochondria share several metabolic pathways with bacteria [83]. Thus, the antibiotics targeted against pathogenic bacteria could potentially affect the function of the mitochondria. Earlier reports have confirmed that antibiotics, such as erythromycin and chloramphenicol, induce mitochondrial mutations and thus affect protein synthesis in yeast [84,85]. A recent study has used five classes of mitochondria-targeting antibiotics including erythromycins, tetracyclines, glycylcyclines, an antiparasitic drug, and chloramphenicol in order to demonstrate and exploit their side effects. The findings of the study summarized that these commonly used classes of antibiotics target either 39S large mitochondrial ribosome, or 28S small mitochondrial ribosome or mitochondrial OXPHOS [81], hence compromising the crucial mitochondrial functions.

Antibiotic use is often associated with several side effects in humans, especially during pregnancy, particularly targeting the ribosomal RNA, and impairing the mitochondrial physiology, which subsequently leads to interference in protein synthesis. With the emergence of antibiotic resistance in pathogenic bacteria, the identification of appropriate antimicrobials for microbial infections possessing least side effects has become essential. The constant exposure of mitochondrial DNA to the oxidative environment in the cells has made it more prone to mutations. These mitochondrial mutations and genetic variability may have implications in influencing antibiotic selectivity and sensitivity to the host cell [86].

Mitochondria plays a pivotal role in a number of cellular functions, including the generation of cellular energy for ATP synthesis, ion homeostasis, fatty acid biosynthesis, calcium storage, apoptosis, as well as production of reactive oxygen species [87]. The role of mDNA as a signaling molecule is also gaining attention with the discovery of biological pathways linking mitochondria to immunity [88]. Based on the energy requirement of different tissues, specific side effects as a result of antibiotic use may occur. Accumulating evidence has highlighted that the use of aminoglycosides such as streptomycin, gentamycin, neomycin, kanamycin, etc., either in high doses or for extended periods, potentially results in nephrotoxicity, ototoxicity, and hearing loss. The sensitivity of mutations associated with hearing loss and deafness in mitochondria, such as m. 1555A>G [89], m. 1494C>T [90,91], m. 1095T>C [92], m. 827A>G [93], m. 1645C>G, m. 3243A>G, and m. 961A>G, to aminoglycosides, indicates their role in inducing the phenotype in Chinese and Spanish populations [86,94].

Erythromycin is known to cause bilateral vision loss in Leber's hereditary optic neuropathy patients. It has also been observed that tetracycline use affects the activity of cytochrome oxidase, leading to several side effects. Other antibiotics, such as chloramphenicol and macrolides, are also associated with significant ototoxicity and toxic optic neuropathy. Chloramphenicol is also associated with the C2939A, T2991C mutations and side effects including myelosuppression, lactic acidosis, peripheral neuropathies, etc. It has been reported that the use of linezolid resulted in low levels of mitochondrial translational products and lactic acidosis associated with A2706G as well as G3010A mutations, in addition to other side effects [86]. Streptomycin administration linked with G1555A mutation results in ototoxicity and deafness [89]. Further, clozapine treatment may give rise to increased production of pro-inflammatory cytokines involved in inflammation, which in turn is associated with alterations in mitochondrial function and obesity [95] (Table 1, 2). The antidiabetic drug metformin was found to inhibit OXPHOS by directly targeting the ETC, thus acting as a mitochondrial inhibitor as well as inducing lactic acidosis [96,97]. It is also known that during the treatment of infections with antibiotics, the mitochondrial functions may be compromised. Therefore, mitochondrial mutations that may be the cause of side effects of antibiotics remain to be understood [86].

Table 1

Antibiotics used commonly with their mechanism of action, side effects, and sensitivity depending on the associated mitochondrial mutations

Antibiotics used commonly with their mechanism of action, side effects, and sensitivity depending on the associated mitochondrial mutations
Antibiotics used commonly with their mechanism of action, side effects, and sensitivity depending on the associated mitochondrial mutations
Table 2

Summary of the antibiotic-induced mtDNA variants and associated conditions (MITOMAP database)

Summary of the antibiotic-induced mtDNA variants and associated conditions (MITOMAP database)
Summary of the antibiotic-induced mtDNA variants and associated conditions (MITOMAP database)

Interestingly, reports have suggested that mitochondrial DNA mutations can also be induced by bacteria present in the microbiome [98] as well as other pathogenic bacteria [99]. Due to their involvement in facilitating major cellular functions, mitochondria have been an attractive target for pathogenic bacteria [100]. Several mitochondrial targeted toxins involved in sensitizing or inhibiting cells towards cell death have been reported. Although the exact mechanisms by which the virulence factors from these pathogens interact with different components of the mitochondria are not clearly elucidated, most of the toxins are predicted to form channels, thus affecting the ability of the host cell to survive. Reports have also emphasized that trafficking of the bacterial toxins to specific targets in the mitochondria plays a crucial role in the pathogenesis [101]. The toxins supposedly hijack the transport machineries in the mitochondria, which is made easier due to the bacterial origin of the mitochondria. Evidently, it has been shown that the N-termini of bacterial proteins involved in targeting share common characteristics with mitochondrial targeting signals [102]. The cross talk between the bacteria residing in the gut and host mitochondria are found to affect the signaling pathways within the host. The identification of the mode of action of colanic acid, which is synthesized in bulk under conditions of environmental stress, induces alterations in mitochondrial function and subsequent systemic signals to improve the host fitness [103]. Although not much is known about the bacterial impact on the mitochondrial function, involvement in causing obesity and other comorbidities would be thought-provoking. While the association of antibiotic use and obesity is being well explored over the years, there is a growing possibility that bacteria, both present in the gut microbiome as well as the pathogenic ones may target the mitochondria, influence the metabolic function of the cell ultimately leading to obesity and other metabolic disorders.

Matrix metalloproteinases (MMPs) are a family of proteinases, initially known for their cytosolic localization and ability to degrade extracellular matrix proteins, and form an important event in inflammation and tissue remodeling [104]. Recently, MMPs have been identified in various intracellular organelles including the nucleus and mitochondria. MMPs are also known to affect cellular behavior through the release of growth factors and cytokines, a fact that dramatically increases the magnitude of their effects [105].

MMP activity relies upon environmental influences from surrounding cells, extracellular matrix proteins, systemic hormones, and other growth factors [106,107,108]. A wide range of cytokines and growth factors such as TGF- β, HGF, EGF, FGF-2, PAF, and TNF-α are also found to control the activity of MMPs [109,110,111,112]. Reports suggest that cytokines such as IL-1β and TNF-α, stimulate MMPs production including MMP-2, MMP-3, and MMP-9 through the MAP kinase pathway [113,114]. It has also been reported that MMPs might be involved in altering the biological activity of cytokines, either by direct proteolytic processing or by shedding their receptors [115]. Interestingly, recent findings demonstrated the regulatory effect of antibiotics such as roxithromycin, which inactivates MMP-9 [116] and clarithromycin, which affects tissue inhibitor of metalloproteinases [104]. Similarly, doxycycline [117] and erythromycin [118] have also shown MMP-inhibitory activity.

Furthermore, activated MMP-9 and MMP-2 have been found to be associated with mitochondrial dysfunction, damaging the integrity of the mitochondria and activating apoptotic machinery [119]. MMPs have been reported to be involved in the development of various diseases such as cancer, atherosclerosis, and diabetes [120,121,122,123,124,125]. In addition, increased levels of MMP-2 and MMP-9 are observed in diabetic retinopathy patients as well as diabetic rodents [121,126,127]. Several studies have also reported the involvement of MMPs in obesity-mediated adipose tissue remodeling [128]. MMPs are mainly found to control the processes of proteolysis and adipogenesis during obesity-mediated fat mass development [129], and it has been reported that obese individuals, as well as rodents, expressed higher levels of MMPs in plasma [128,130].

The activated MMPs enter the mitochondrial membrane and damage the structure and integrity of mitochondria. The resulting leakage of cytochrome c into the cytosol leads to the activation of apoptosis and increased ROS levels. This leads to mtDNA damage, the accumulation of MMPs, affects the functionality of the ETC, and further contributes to mitochondrial dysfunction [119]. Animal studies have also confirmed the occurrence of mitochondrial damage due to superoxide-mediated activation of MMP-2, which is responsible for initiating apoptosis of retinal capillary cells in diabetic retinopathy conditions [131].

Antibiotics are reported to influence the activity of anti-inflammatory cytokines such as IL-3, IL-4, IL-10, etc. [132,133,134,135,136]. They are also found to exert modulatory effects on the functioning of several pro-inflammatory cytokines such as TNF-α, IL-1, IL-2, IL-6, IL-8, IL-12, IL-18, etc. [132,133,134,135], thereby impairing the mitochondrial biogenesis pathway and, hence, affecting the normal mitochondrial activity [137].

Non-sense mutations or frameshift mutations, resulting in the generation of premature termination codons (PTCs) are implicated in a range of genetic diseases such as cancers [138]. Cells are equipped with sophisticated surveillance mechanisms, such as non-sense-mediated mRNA decay to target and efficiently degrade such non-sense transcripts containing such mutations [139] in order to restore the normal functioning of the cell. In absence of non-sense-mediated decay (NMD), the transcripts possessing PTCs would accumulate, resulting in translation and stabilization of truncated proteins which may have damaging effects on the cell [140,141]. NMD could possibly be crucial in causing the disease phenotypes of these disorders [142,143]. However, the specific mechanisms by which NMD occurs are not clearly understood [144,145]. In addition, the mechanism of mRNA decay in prokaryotes is strikingly different from that of eukaryotes in terms of the proteins involved in mediating the process and internal versus terminal degradative events [146,147]. Although NMD generally prevents the function of aberrant truncated proteins, the truncated protein may sometimes retain normal functions, regardless of the mutations that may have occurred [148,149,150]. In such instances, if the expression of a mutant protein compensates for the missing cellular functions, selective inhibition of NMD is considered as a better option [151].

Currently, there are very few reports highlighting the role of premature termination of protein biosynthesis in obesity [152]. Studies on obese subjects confirmed the presence of premature stop codons in the genes encoding leptin receptor, melanocortin-4 receptor, pro-opiomelanocortin, and pro-hormone convertase 1. Those results are indicative of the effect of non-sense mutations as well as frameshift mutations on energy homeostasis [153,154,155,156].

Obesity, over a period of time, engenders significant increase in the levels of free fatty acids and their consequent accumulation in tissues other than the adipose tissue. This may further lead to consequences, such as apoptotic effects due to the presence of non-oxidized fatty acids, elevated rate of fatty acid oxidation outside mitochondria, releasing superoxides and hydrogen peroxide [157,158], which may be accompanied by enhanced mitochondrial dysfunction and ROS production [159]. Moreover, the vast deposits of fat and the constant release of fatty acids from them causes disruption of ATP synthesis and deficit of energy. Reports also suggest that increased free fatty acids in the inner mitochondrial membrane promote uncoupling of oxidation and phosphorylation leading to mitochondrial function impairment [160,161]. Thus, the role of NMD as a surveillance mechanism is crucial in selective degradation of the mutations resulting in premature stop-codons and subsequent mitochondrial dysfunction.

Interestingly, studies have also demonstrated that treatment with antibiotics such as aminoglycosides and negamycin can overcome the PTC-causing mutations resulting from the single base substitutions in order to allow the stop-codon read-through of the mRNA, thus allowing the synthesis of near-normal functional protein [162,163,164,165]. These findings point out the divergent role of antibiotics in causing non-sense or frameshift mutations and subsequent mitochondrial dysfunction as well as in rescuing from premature termination of translation, thus bypassing NMD and allowing for the production of proteins functionally similar to normal proteins. Antibiotics at low doses induce codon misreading while at high doses inhibit prokaryotic protein synthesis, cause severe side effects and may lead to emergence of drug-resistance in bacteria [138]. Thus, NMD could perhaps be an important link between obesity, impaired mitochondrial function, and inappropriate antibiotic use as portrayed in Figure 3.

Fig. 3

Non-sense-mediated decay as the potential link between antibiotic use, mitochondrial dysfunction, and obesity.

Fig. 3

Non-sense-mediated decay as the potential link between antibiotic use, mitochondrial dysfunction, and obesity.

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As mentioned previously, due to the bacterial origin of mitochondria, it is highly possible that antibiotics target the mitochondria and its components in the same way as they target bacteria. Bactericidal antibiotics are known to cause oxidative stress and subsequent damage through the disruption of normal mitochondrial functioning. Commonly used antibiotics such as aminoglycosides target both mitochondrial as well as bacterial ribosomes [166,167]. Quinolones are known to act on bacterial gyrases and mtDNA topoisomerases [168,169]. Similarly, β-lactams are found to inhibit cell wall synthesis in bacteria and carnitine/acylcarnitine transporters in mitochondria [170,171]. Thus, bactericidal antibiotics have proven to adversely affect the mitochondria. Several reports suggest that antibiotic exposure during early life was found to be associated with increased risk of overweight and obesity in a dose-dependent manner [14,15,16,17,18,172,173,174,175,176,177,178,179,180,181]. A recent meta-analysis also shows that antibiotic exposure is an independent risk factor for childhood obesity [182]. However, the pathogenesis of obesity is a complex process, and the precise mechanisms underlying antibiotic-induced obesity is yet to be completely elucidated. Accumulating evidence also indicates the role of gut microbiota in causing obesity [183,184,185]. It has been proposed that the intricate interactions between gut microbiota, host genetics, and diet could possibly result in obesity [186]. Experimental evidence confirmed that antibiotics have profound and lasting effects on the ecology of developing as well as mature microbiotas [80,187]. It has been observed that on discontinuation of antibiotics, the gut microbiota recovered and resembled that of normal-weight mice; however, the mice exposed to antibiotics still remained fat. Thus, early-life exposure to antibiotics may permanently direct host metabolism to the obese-prone phenotype [188,189].

In addition to the damaging effects of antibiotics on gut microbiota, the effects of antibiotics on mitochondria are of importance due to their role in processes including ATP production and energy expenditure. Certain classes of antibiotics are known to inhibit mitochondrial biogenesis in mammalian cells [81]. Further, the abundance, morphology, and organization of mitochondria dictate the adipocyte differentiation process [33]. Also, since mitochondria are the major producers as well as primary targets of ROS, they are thought to play a prominent role in antibiotic-induced obesity [190]. Antibiotics may either directly target ATP synthase and abrogate the ATP synthesis pathway [191], inhibit anaerobic glycolysis [192], or they may disturb the mitochondrial respiration by altering membrane ion permeability [193]. The resulting mitochondrial dysfunction may lead to defective fatty acid degradation and subsequent accumulation leading to metabolic disorders such as obesity. Although there appears to be a strong correlation between exposure to antibiotics and obesity through their detrimental effect on mitochondrial function, the specific mechanisms remain unexplored.

Undoubtedly, antibiotics have contributed immensely towards treatment of infections in humans, animals, birds, and plants. But, the constant use of antibiotics has led to the emergence and transmission of antibiotic-resistant pathogens. Misuse of antibiotics also contributes to the pathogenesis of obesity in humans as well as animals by disrupting the gut microbiome, affecting the metabolism and causing changes in body weight. In addition, intense antibiotic use causes mutations in the mitochondrial DNA, which could also lead to mitochondrial dysfunction and thereby, obesity. Antibiotics also exert their influence on cytokines, causing a decrease in energy production and increased ROS production, and alter the mitochondrial biogenesis pathways. Similarly, MMPs are affected by antibiotics such that they damage the structure and integrity of the mitochondria, activate the apoptotic machinery, and disturb ETC functionality. Moreover, MMPs are involved in adipose tissue remodeling, and control proteolysis and adipogenesis in obese individuals. These examples highlight the critical role of MMPs and cytokines in mitochondrial dysfunction as well as obesity. In order to circumvent PTCs, resulting from overuse of antibiotics, as well as obesity, the NMD pathway is activated. This may either lead to the production of (a) a functionally normal protein or (b) a truncated protein, which results in impairment of mitochondrial activity.

In summary, antibiotics seem to have multifaceted roles, wherein they cause mitochondrial dysfunction, influence obesity, and are involved in the modulation of NMD pathway, regulation of the activity of MMPs and cytokines, and they confer antibiotic resistance. Through this review, as seen in Figure 4, we have attempted to provide a coherent association for the intricate dynamics between antibiotic use and obesity, along with highlighting the critical roles played by NMD and mitochondrial dysfunction in bringing about the same.

Fig. 4

Summary of the complex association between antibiotic use and obesity, while highlighting the critical roles played by non-sense-mediated decay (NMD) and mitochondrial dysfunction.

Fig. 4

Summary of the complex association between antibiotic use and obesity, while highlighting the critical roles played by non-sense-mediated decay (NMD) and mitochondrial dysfunction.

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All the authors declare no conflict of interest.

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