**4. The obese and asthmatic children treated with antibiotics**

The children of the youngest age predominantly suffer from viral and atypical respiratory infection, which is, often, mistakenly treated with antibiotics, actually, very often with mac‐ rolides. This applies, furthermore, in the children suffering from asthma with accompanying obesity because their asthma exacerbation, very often, triggered with virus and followed by the fever, is often considered to be a respiratory infection with bronchial obstruction and is hitherto mistakenly treated with antibiotics.

The overweight cases, the asthmatics, and the children treated with penicillin or macrolide (one or more times) have the microbiota with the abundance of side bacteria and long‐term reduction in microbial richness [4] (**Figure 1**). For example, one of the macrolides, the azithro‐ mycin, reduces biomarkers of not only environmental enteropathy and pathogenic intestinal bacteria [32, 33], but also commensal and advantage bacteria, which makes restricted (poor) flora. The gut microbiota with restricted flora is mediated by cytolytic CD8+ T cells with depleted iNKT cells that contribute to epigenetically modulating of specific host immune traits (defense and immunoregulation) [6]. It is known that CD8+ T cell responses are elicited by certain microbiota, including Listeria and Salmonella and followed by the local enteric mucosal stress response, which is associated with striking increases in certain chronic inflam‐ matory and autoimmune diseases [6]. Besides that azithromycin inhibits ribosomal translo‐ cation, leading to the inhibition of bacterial protein synthesis, acts bacteriostatic but may be bactericidal at high concentrations, modulates differentiation and lipopolysaccharide (LPS) induces maturation in dendritic cells but decreases transcription and activity of histone deacetylation‐2 promoter, which results in gene repression [32]. After macrolide [3, 4, 32, 33], the microbiota slowly recovers so that it establishes persistence of the antibiotic‐associated microbiota composition, which contributes to the persistence of metabolic changes and com‐ promises the development of a healthy immune system, so that the consequences are early manifestations of asthma and obesity. The mentioned effect of macrolides is not dependent on the age of the child [4].

The impression is that use of antibiotics during early life, linked with poor gut microbial diversity, drive to "preponderance" of side over advantage effects of antibiotics (macrolides and penicillin) [3, 4, 32, 33]. Pronouncedly, in the case of irrational use of antibiotics during early life, the restricted gut flora is followed by a decreased microbial stimulation, which leads to the delayed immune maturation (Th2 and T regulatory) and the impaired immune regulation with Th2‐skrewing early in life, which precedes asthma at school age [3, 4, 8] and obesity early in life [10, 11, 14]. This consideration has no intention of diminishing the desired effects of azithromycin (attenuates Th‐1 responses following LPS or INF‐gamma stimulation of macrophages, shifting polarization of activated macrophages toward the alternative/anti‐ inflammatory M2‐phenotype (which plays a role in directing Th‐2 responses), inhibits IL17‐ induced IL8 and 8‐isoprostane release)—but pointing out the need for its rational application, the "balanced" therapy, new therapeutic modality, especially in the children suffering from wheezing, respiratory infections and obesity.

poorly defined and their biomarkers (modified natural inhibitor of inducible nitric oxide syn‐ thase, asymmetric dimethylarginine in the blood) are still not routinely measured. Identifying phenotypes of asthma in children and adults is important so we could provide the appropri‐ ate treatment. Most children suffering from allergic asthma with nBW are successfully treated according to the recommendations of the Global Initiative for Asthma [31]. Most children suffering from the asthma with the nBW have a good response to inhaled steroids (ICS) and/ or antileukotrienes. In a small number of children, asthma is severe and requires the treat‐ ment with high‐dose of ICS. Poor response to ICS can have children with difficult to treat asthma, asthma induced by viruses and "obese" asthma so the treatment of these patients is

The children of the youngest age predominantly suffer from viral and atypical respiratory infection, which is, often, mistakenly treated with antibiotics, actually, very often with mac‐ rolides. This applies, furthermore, in the children suffering from asthma with accompanying obesity because their asthma exacerbation, very often, triggered with virus and followed by the fever, is often considered to be a respiratory infection with bronchial obstruction and is

The overweight cases, the asthmatics, and the children treated with penicillin or macrolide (one or more times) have the microbiota with the abundance of side bacteria and long‐term reduction in microbial richness [4] (**Figure 1**). For example, one of the macrolides, the azithro‐ mycin, reduces biomarkers of not only environmental enteropathy and pathogenic intestinal bacteria [32, 33], but also commensal and advantage bacteria, which makes restricted (poor) flora. The gut microbiota with restricted flora is mediated by cytolytic CD8+ T cells with depleted iNKT cells that contribute to epigenetically modulating of specific host immune traits (defense and immunoregulation) [6]. It is known that CD8+ T cell responses are elicited by certain microbiota, including Listeria and Salmonella and followed by the local enteric mucosal stress response, which is associated with striking increases in certain chronic inflam‐ matory and autoimmune diseases [6]. Besides that azithromycin inhibits ribosomal translo‐ cation, leading to the inhibition of bacterial protein synthesis, acts bacteriostatic but may be bactericidal at high concentrations, modulates differentiation and lipopolysaccharide (LPS) induces maturation in dendritic cells but decreases transcription and activity of histone deacetylation‐2 promoter, which results in gene repression [32]. After macrolide [3, 4, 32, 33], the microbiota slowly recovers so that it establishes persistence of the antibiotic‐associated microbiota composition, which contributes to the persistence of metabolic changes and com‐ promises the development of a healthy immune system, so that the consequences are early manifestations of asthma and obesity. The mentioned effect of macrolides is not dependent

The impression is that use of antibiotics during early life, linked with poor gut microbial diversity, drive to "preponderance" of side over advantage effects of antibiotics (macrolides and penicillin) [3, 4, 32, 33]. Pronouncedly, in the case of irrational use of antibiotics during early life, the restricted gut flora is followed by a decreased microbial stimulation, which

**4. The obese and asthmatic children treated with antibiotics**

hitherto mistakenly treated with antibiotics.

on the age of the child [4].

complicated.

20 Clinical Trials in Vulnerable Populations

In the mentioned period of 12–24 months, the macrolide use is associated with the increased risk of asthma and it predisposes children to the antibiotic‐associated weight gain. The mac‐ rolides impact on the intestinal microbiota should be considered with mandatory prescribing probiotics [4], which would prevent compromising of a healthy immune system and metabo‐ lism development. It has been proven that "good" probiotic bacteria and "good" probiotic fungi in the mouth and intestines, sufficiently represented, are necessary to compensate destroyed intestinal flora during and after antibiotic therapy and for the health of children [5] (**Figure 1**). We have, also, confirmed that the use of synbiotics in the optimal period of time of 3–6 months can achieve adequate control of respiratory infection and allergic wheezing diseases in children younger than 5 years [34]. Nevertheless, we have found that the time necessary for the restitution of the immune balance between immunoglobulin A and immu‐ noglobulin E was 9 months in the youngest children [34]. Now, we can add a logical setting as hypothesis that should have been assessed in clinical trials, that the everyday application of synbiotic (during several months) after antibiotic using would likely prevent the obesity.

In favor of this Million's findings [35], the probiotics affect the microbiota directly by modu‐ lating its bacterial content and indirectly through bacteriocins produced by the probiotic bac‐ teria, as well as, *L. plantarum* and *Lactobacillus gasseri* (formerly named *L. acidophilus*) strains, which has an anti‐obesity effect in overweight/obese people in terms of reductions in abdomi‐ nal adiposity, body weight, and other measures. Adding a probiotic strain Bacteroidetes can be essential for the body weight loss in obese patients, because Bacteroidetes overgrows the undesirable gut strain named Firmicutes [35].

It is known that the trillions of the side microbial cells in the intestinal microbiota can contrib‐ ute to obesity by increasing energy extraction or by altering metabolic signaling and inflam‐ mation [36], and thus occupy a central role in the pathogenesis of, so far seemingly unrelated systemic auto‐inflammatory and metabolic disorders. As a matter of fact that the condition of basal immune and metabolic homeostasis is mainly controlled by the bacterial microbiome.
