The human microbiota, as we stated previously, is divided according to the sites of interest, the disruption of its homeostasis mainly in response to changes in environmental factors, diet or antibiotic therapy, with the effect of increasing the risk of atopy, autoimmunity, heart diseases or malignancy [26,27].

Taking the intestinal microbiota (in a perpetual change until the age of 3 years, later with small variations) whose relationship with the maternal component is intensively studied as a model, Kim H. et al. have brought to attention, in addition to the impact played by living in the vicinity of pets, the influence of the prenatal and perinatal period in shaping the predisposition towards certain pathologies. In this sense, in addition to its role in nutrition and the maternal–fetal emotional bond, breast milk (colonized with Streptococcus, Staphylococcus, Propionibacteria, lactic bacteria and Bifidobacterium) proved to be an important prebiotic, probiotic and vector of vertical bacterial transmission, modulating Bifidobacterium/Firmicutes balance, with the cessation of breastfeeding leading to the maturation of the intestinal microbiota with the inversion of the ratio of the two, in detriment of Bifidobacterium. Antepartum, intrapartum or postnatal antibiotic therapy, as well as antifungal therapy, also lead to the reduction of Bifidobacterium, Bacteroides and Actinobacteria species, promoting the dominance of Enterococcus, Clostridium, Proteobacteria and Firmicutes. A benefit of natural food is the objective of a reduced rate of colonization with Escherichia coli, Clostridium difficile, Bacteroides and lactobacilli. Last but not least, the type of birth and the gestational age seem to influence dysbiosis in the same way as previously described, being thus preferable to natural birth that promotes fetal insemination with vaginal bacteria, to the detriment of cesarean surgery, considered a trigger factor for imbalance [28,29,30,31,32]. After the threshold of 3 years and until adulthood, Derrien M. et al. note a gap in the collection of data regarding the structure of the microbiome, while at the same time reiterating its evolutionary directions [33].

The skin represents the system with the widest distribution in the body, modulating through its functions both the interaction between the exogenous and the endogenous environment, as well as the variability and viability of the microorganisms that can colonize it permanently or accidentally. This inter-relationship can be influenced by ultraviolet radiation, thermogenesis, humidity and local pH. The predominant bacterial species at its level are Actinobacteria, Firmicutes, Proteobacteria and Bacteroides, while among fungi we note Malassezia, Cryptococcus, Rhodotorula, Aspergillus and Epicoccum. Dysbiosis at this level intervenes in the pathogenesis of conditions such as atopic/seborrheic dermatitis, acute urticaria, alopecia, acne, psoriasis or skin malignancies [34,35,36,37]. Besides the well-known factors that modulate skin colonization, Bouslimani A. et al. also underline the impact of chemical products applied to the skin on biodiversity, the level of steroids and pheromones, with particular reference to facial care products and deodorants [38]. Regarding the effects of the establishment of optimal treatment, a randomized study regarding the restoration of balance in children with atopic dermatitis (moderate/severe) treated with emollients, anti-inflammatory agents (corticosteroids) and antiseptics (diluted bleach) shows that the levels of Staphylococcus aureus at the end of the follow-up period were lower in the case of patients who received antiseptics, unlike those who received standard treatment [39]. Taking note of these findings, we bring into consideration the current lines in restoring microbial homeostasis, namely probiotics, phage therapies, humanized monoclonal antibodies against bacterial toxins or quorum sensing inhibitors [40].

Regarding autoimmune diseases, Zhou HY. et al. note the presence of a particular skin microbiota with affected bacterial diversity both in eruptive and non-eruptive areas in the case of patients with SLE, unlike healthy controls and those with rosacea (chronic inflammation of the skin that predominantly affects the medio-facial area, being characterized by erythema, telangiectasias, eruptions of small pimples and papules and, in advanced cases, increase in the volume of the nose -rhinophyma-). From the point of view of the identified microorganisms, a discrepancy was objectified between the regions affected by SLE and the unaffected skin areas, which was characterized by the increase of the genus Halomonas together with the decrease of the genera Pelagibacterium, Novosphingobium and Curvibacter [41].

Having a diminished immune defense during childhood, especially at the level of the mucous membranes, objectified by the increased incidence of various pathologies in the respiratory sphere, maintaining the balance of microorganisms that usually or occasionally colonize the respiratory tract (spread out between the nostrils and the pulmonary alveoli, with a role in humidification air, filtering inhaled particles and oxygen-carbon dioxide exchange) represents a topic of interest in current pediatric practice by proving its involvement both in its maturation and in the regulation of immunity. And at this level, the type of birth, nutrition and antibiotic therapy, in addition to seasonal influences, vaccination, history of respiratory tract infections, living together with siblings, frequenting collectives and exposure to smoke have been shown to have a dynamic imprint on the microbial balance (Staphylococcus, Corynebacterium, Dolosigranulum, Moraxella, Haemophilus, Neisseria) of the upper and lower respiratory tract, which was considered a sterile structure until recently [42,43]. Cao W. et al. underline that pathogenic microorganisms are mainly confined to the lymphoid organs (tonsils, adenoid vegetations, oropharynx or nostrils) [44]. Dysbiosis within this system can lead to diseases such as acute otitis media, chronic rhinosinusitis, bronchiolitis, pneumonia, asthma or post-injury residual sequelae (e.g., SARS-CoV-2 infection, the severity of which was inversely correlated with the diversity of the oropharyngeal microbiome) [42,43,45,46]. It is also worth mentioning the connection between SARS-CoV-2 and SLE, both the infection and the vaccination, seemed to influence the course of the patients despite the summary data from the literature, especially regarding the pediatric population [47].

Being the well-known connection between the intestine and the lungs, the current specialized literature recommends the maintenance of balance and the modulation of the former (with the help of probiotics based on Lactobacillus and Bifidobacterium) during the evolutionary course of children with recurrent respiratory diseases [48,49].

The genitourinary tract is made up of the urinary system (kidneys, ureters, bladder and urethra) in close connection with the genital organs (internal and external, different between the sexes) and the digestive tract, especially at the level of the external openings. Thus, the microbiota of the three systems, although individual for each one, can show similarities, potentiating each other. In the female sex, the main organs whose bacteriological study is easy are the vagina and the uterus, which have structures that show variable colonization through a retrograde mechanism, hematogenous transmission or the seminal fluid, which, after the onset of puberty, is dependent on the phases of the menstrual cycle and the presence/absence of possible pregnancies, and which are separated from each other by the cervical mucus plug that acts as a barrier to the ascent of pathogens (Ureaplasma). Microorganisms present at this level are Lactobacillus, Bifidobacteriaceae, Gardnerella vaginalis, Actinobacteria, Prevotella, Enterobacter, Streptococcus, Proteobacteria and Bacteroides, whose fragile balance is incriminated in the pathogenesis of bacterial vaginitis, pelvic inflammatory disease, hysteromyoma, endometriosis, adenomyosis, transmission infection sexual or those with the human papillomavirus, which can evolve into cervical dysplasia [50,51,52,53]. Also, vaginal dysbiosis can be incriminated in the production of neonatal infections, spontaneous abortions and premature birth, in the case of young mothers [54]. Ling Z. et al. record a more pronounced vaginal dysbiosis, in contrast to that found in the examination of fecal matter in the case of patients with SLE, characterized by a different predominance of frequently encountered species, but also by an intense association between the vaginal microbiome of the patients and the immunological picture of the disease (negative correlation between the C4 fraction of complement and Bacteroides, Escherichia and Shigella) [55]. In boys, the microbiota of the genital tract remains open to research, in part due to the invasive methods required to study it. As a compromised option, the seminal fluid was studied, with the results showing the presence of Lactobacillus, Bifidobacterium, Faecalibacterium, pathogenic microorganisms characteristic of sexually transmitted diseases, Enterobacteriaceae, Escherichia coli, Ureoplasma, Prevotella, Corynebacterium, Enterococcus and Staphylococcus aureus, microorganisms whose balance imprints the development of inflammatory conditions, male fertility and even the risk of malignancy in the prostate [56].

While the colonization of the urethra mostly respects the bacterial species identified at the level of the genital system, we emphasize here the need to know the variations of the bladder microbiome and urinary pH, depending on age and pathogen, respectively. A good diagnosis of these leads to the prophylaxis and optimal treatment of renal lithiasis or urinary tract infections, thus eliminating the risk of long-term complications such as the chronicity of the condition, renal scars or resistance to antibiotics [56,57,58,59].

Starting from the upper orifice, the microbial components that populate the oral cavity of children are in constant evolution, the key moments of which are birth (the intrauterine colonization model is still under research, with the similarity between the placental microbiome and the oral microbiome of maternal origin being certified), with the dental eruption and the finalization of the dentition, being, however, also influenced by diet, type of birth, environmental factors, ethnic or geographic belonging, genetic determinants and horizontal transmission from the people with whom they interact [54,60]. Thus, divided by age groups, among the most known microorganisms that colonize the oral cavity are bacteria (Streptococcus, Staphylococcus, Fusobacterium, Veillonella, Haemophilus, Escherichia coli, Pseudomonas and Lactobacillus), viruses (rotavirus, norovirus, hepatitis C virus, herpes simplex 1/2, flu, Coxsackie A or Epstein–Barr) and fungi (Candida, Cladosporium, Saccharomycetales, Aspergillus and Cryptococcus) [54].

The main diseases in which the microbiome of the oral cavity plays an essential role are certified to be dental caries that appeared during early childhood, inflammatory bowel diseases (Crohn’s disease, ulcerative colitis), post-infectious irritable bowel syndrome, celiac disease, diabetes, autism, Henoch–Schonlein purpura, Wiskott–Aldrich (defined as the presence of micro-thrombocytopenia, recurrent infections and eczema), appendicitis and sleep apnea syndrome. In their production, the main microorganisms incriminated are Streptococcus (mutans, salivarius, sobrinus, parasanguinis), Lactobacillus, Bacteroidetes, Vaillonella, Candida albicans, Prevotella, Limnohabitans, Rothia, Neisseria, Pasteurella stomatis, Spirochaets or Campylobacter, doubled by a decrease in the abundance of Actinomyces, Corynebacterium, Haemophilus, Eikenella, Ramlibacter, Mucilaginibacter, Proteobacteria, Pseudomonas, Moraxellaceae, Fusobacterium and Firmicutes, which are currently intensively studied components, the variety of which proves to be different even in comparison with first-degree relatives and is the basis of the development of new biomarkers used in microbiota research, but also of the current principles of its modulation, through food means or substitution (probiotics, prebiotics, symbiotics or transplant of fecal matter) [54,61,62,63,64,65,66]. Knowing the characteristics of oral dysbiosis during the evolution of various pathologies, as well as the mechanisms of action through which it exerts its influence, has a vital role in the study and development of new therapeutic targets, the hypothesis exemplified by Xiao E. et al. on murine models, with reference to the diabetes-IL-17 activity-microbiota triad, where the de-escalation of the inflammatory and periodontal destruction processes was demonstrated together with the inhibition of IL-17 (cytokine with a role in promoting the inflammatory process and, indirectly, osteoclast activity) through means of monoclonal antibodies directed against them, effects doubled by a decrease in the pathogenesis of the oral microbial flora [67].

With reference to the stomach, the main lines of research regarding bacterial colonization include its modification in Helicobacter pylori (H. pylori) infection, but also in chronic gastritis, duodenal ulcer or carcinogenesis, conditions in which the microbiota has been shown to have an altered diversity compared to the batches of control subjects, with part of its components showing causal relationships with the incriminated pathologies (e.g., Bacteroides—H. pylori in children or Methylobacterium in gastric carcinogenesis, being also a negative prognostic marker) [68,69,70]. About the influence of H. pylori and gastric dysbiosis among duodenal ulcer patients, Zheng W. et al. postulated that in this situation, the character of infected/uninfected has the potential to modulate the community of genotoxic bacteria present at the level of the microbiota [71]. A role in this process seems to be played by iron, a constituent that, when found in low quantities, imprints the carcinogenic potential of H. pylori, possibly through the interaction with the metabolism of bile acids (especially deoxycholic acid) [72]. Due to the ever wider spread of H. pylori, doubled by the negative impact of the infection and the development of antibiotic resistance, it is necessary to know alternative therapies such as probiotics based on Limosilactobacillus reuteri, a Gram-positive bacterium resistant to gastric and bile juice, which maintains homeostasis in the environment by inhibiting the development of pathogenic species, while at the same time increasing adherence and therapeutic efficiency by improving digestive symptoms [73].

Dysbiosis at the intestinal level has been shown to be involved in multiple pathologies, starting from local ones (inflammatory intestinal diseases, celiac disease), osteoarticular (osteoarthritis), skin (psoriasis, acne vulgaris), vascular (atherosclerosis or thrombosis), chronic renal, hepatic, pulmonary (obstructive diseases, asthma) and metabolic (obesity, diabetes, dyslipidemia) and culminating with those in the neuropsychiatric sphere (depression, Alzheimer’s or Parkinson’s disease, autism, schizophrenia, multiple sclerosis) or neoplastic (oral, esophageal, pulmonary, pancreatic, colorectal), with all these processes being under the empire of the main axes formed by intestine and lung, brain, heart or skin [54,74,75,76]. From this wide range of diseases whose pathogenic process is based on disturbances in the intestinal microbiota caused by various individual or environmental factors, we note autoimmune diseases such as SLE, anti-phospholipid antibody syndrome, Sjogren’s syndrome, systemic sclerosis or rheumatoid arthritis, which appeared as an effect of the bidirectional microbiome–immune system relationship [77,78]. The connection between the components of the microbiome and SLE was also demonstrated with the help of a randomized study carried out by Xiang K. et al.; the authors underlined the possible existence of both provocative and protective factors that can guide the appearance and evolutionary course of the condition [79].

Taking the microbiome–SLE relationship as a model, a first change objectified by current studies is the inversion of the relationship Firmicutes/Bacteroidetes, overwhelmed by the escalation of species such as Rhodococcus, Eggerthella, Klebsiella, Prevotella, Eubacterium and Flavonifractor and the reduction Lactobacillaceae, which is a dysbiosis that leads to the potentiation of the chronic inflammatory response and the decrease of immune tolerance, with the increase of anti-double-stranded DNA antibodies and possible imprinting of renal function [77,80]. Chen BD. et al. also draw attention to the existence of pathogenic species such as Clostridium ATCC BAA-442, Atopobium rimae, Shuttleworthia satelles, Actinomyces massiliensis, Bacteroides fragilis and Clostridium leptum in samples collected from patients positive for SLE, compared to healthy subjects, with their levels decreasing after treatment [81]. The main mechanisms by which microbial metabolites (such as short-chain fatty acids, free fatty acids, amino acids and arachidonic acid) interfere with autoimmune processes mediated by T, B lymphocytes, dendritic cells or macrophages have been incriminated to be translocation, molecular mimicry and stimulation antibody production due to the presence of various epitopes. The biological arguments brought forward in favor of the incrimination of bacterial translocation consist of the objectification of increased levels of procalcitonin, a marker of inflammation and damage to the intestinal barrier, together with the escalation of CD14 and α1-acid glycoprotein values, although the subject is still being researched. Regarding the microbial metabolites involved in various pathologies, in SLE a vital role seems to be played by short-chain fatty acids (acetate, propionate, butyrate) and polyamines due to the effects exerted on autoimmune processes, promoting the integrity of the intestinal barrier, both being an important source of energy. Modulation of immune functionality is achieved by decreasing the production of pro-inflammatory cytokines (IL-6, IL-12, IL-17, IFN-γ and tumor necrosis factor α) in parallel with the promotion of anti-inflammatory cytokines (TGF-β and IL-10). In this sense, the hypothesis of the benefit obtained from the involvement of the two constituents in the diagnostic and therapeutic course of the condition is raised. At the same time, by studying a group of 61 pediatric patients, Wen M. et al. note a decrease in the values of essential amino acids (especially Valine, Leucine, Tryptophan and Phenylalanine, whose level is strongly correlated with immune, metabolic, neuronal activity and, in part, with favoring the presence and activity of certain pathogenic agents) in the plasma accompanied by the intensification of their presence in feces; together with the growth of Proteobacteria (genus Sphingomonas), which interferes with the digestion and absorption of proteins, the data regarding the model of change in diversity between positive subjects for SLE and healthy controls is contradictory to other studies with similar themes in the literature, which is possibly due to the influence of age and gender differences between the groups. Research in the gastrointestinal field associates the disturbance of the balance of amino acids and fatty acids with symptoms such as abdominal distension, pain, nausea, vomiting and anorexia, which were found in the clinical picture of SLE. The biological profile reveals an increased prevalence of lipid metabolism disturbances, with bile acids (deoxycholic, isohyodeoxycholic and arachidonic) being strongly correlated with the SLEDAI score, an aspect doubled by the discordance identified between the metabolites present in the serum and those detected in the feces [82,83,84,85,86,87,88,89,90].