**2. Structure and dynamics of the healthy adult microbiota**

Oral microbiota was described to be dominated by *Streptococcus*, followed by *Haemophilus* (buccal mucosa), *Actinomyces* (supragingival plaque), and *Prevotella* (near the subgingival plaque) [11, 12]. *Porphyromonas gingivalis (P. gingivalis)*, a bacterium that colonizes the oral mucosa, was found through immunohistochemical techniques in 61% of the cancerous esophageal tissue examined. Thus, experts suggest it is a potential biomarker for assessing cancer progression. Originally located in the mouth, *Fusobacterium nucleatum* is linked with colonic adenocarcinoma development, strong evidence of its tumor protective role against the immune system cells arises from recent research [13].

Skin microbiota differs between different topographical regions, being under the influence of lifestyle conditions, hygiene, and antibiotic use. The microorganisms present on the skin are involved in the pathophysiology of different dermatological conditions, such as atopic dermatitis, psoriasis, acne, and seborrheic dermatitis. In a study conducted by Grice et al., although based on a limited number of subjects, the most frequent phyla identified were *Actinobacteria, Firmicutes, Proteobacteria* and *Bacteroidetes* and the most common genera were *Corynebacteria (Actinobacteria), Propionibacteria (Actinobacteria)*, and *Staphylococci (Firmicutes)*. Propionibacterium species preponderate in sebaceous locations, *Corynebacteria* in moist locations, while *Staphylococci* species were present in significant amounts in both sebaceous and moist sites [14]. Regarding dry areas, high levels of *beta-Proteobacteri*a and *Flavobacteriales* were observed [14]. Although human skin microbiota consists mostly of bacteria, several types of fungi are also present. A combination of the genera: *Malassezia, Aspergillus, Cryptococcus Rhodotorula*, and *Epicoccum* was found located mostly in the foot skin area [15].

The vaginal microbiome is dominated by bacteria that can produce lactic acid, mostly *Lactobacillus* species (*Lactobacillus iners*, *Lactobacillus crispatus*, *Lactobacillus gasseri, Lactobacillus jensenii*), coexisting with other types of bacteria, such as *Gardnerella, Atopobium, Megasphaera, Eggerthella, Aerococcus, Alloiococcus, Streptococcus, Leptotrichia/Sneathia, Prevotella, Papillibacter* and anaerobic microorganisms [16]. They lower the local pH due to lactic acid production and have bacteriostatic and bactericidal properties [17, 18]. The uterine microbiome is similar in composition to the vaginal population with a predominance of *Lactobacillus* colonies together with *Bifidobacterium, Gardnerella, Prevotella,* and *Streptococcus* types of microorganisms. Uterine dysbiosis due to contraceptive medication usage, untreated or chronic bacterial vaginosis, or other physiological factors can lead to fertility issues (loss of fetal implantation ability, bacterial overpopulation, and uro-genital

infections) [4]. The uterine microbiome and the interactions between the microbiome and the human reproductive system are currently being studied for enhancing the current approach to assist reproductive techniques, by targeting specific phyla and the results are promising [19].

The predominant bacterial genera found in the eyes conjunctiva and ocular surface are gram-positive pathogens like *Staphylococcus, Streptococcus, Propionibacterium, Diphtheroid* bacteria, and *Micrococcus*. While gram-negative genus is mostly found in the gut, anaerobes or fungi are rarely observed in this particular site. It is unclear how the intraocular immune environment and microbiome interact to control inflammatory eye disorders like uveitis [20].

Airways are largely populated by *Actinobacterium (Corynebacterium, Aureobacterium,* and *Rhodococcus)*, but there is a significant microbiome diversity difference between nasopharynx microbiota and pharynx commensal bacterial population. *Corynebacterium, Aureobacterium, Rhodococcus*, and *Staphylococcus*, including *S. epidermis, Staphylococcus capitis, Staphylococcus hominis, Staphylococcus haemolyticus, Staphylococcus lugdunensis,* and *Staphylococcus warneri,* compose the majority of the nasal microbiota [2].

Although previously believed that the lungs are sterile, and the first evidence of commensal bacterial population in the lungs where initially attributed to contamination from upper airways through bronchoscopy, it is now clear that the majority of lung microbiota consists of *Firmicutes, Bacteroidetes, Proteobacteria, Fusobacteria,* and *Actinobacteria* and alterations at this level can be linked to lung diseases (asthma, chronic obstructive pulmonary disease, and chronic suppurative lung disease) occurrence [6].

The human gut hosts thousands of microbial species [21], which have a gene pool larger than the human genome, which determined its name as a metagenome [22, 23]. There are two major phyla, *Bacteroidetes* and *Firmicutes*, representing 90% of the total bacterial species found in the human gut, the remaining 10% consisting of *Actinobacteria, Cyanobacteria, Fusobacteria, Proteobacteria,* and *Verrucomicrobia* [7, 23].

Several factors can alter the composition and evolution of gut microbiota over the years. Firstly, differences between newborns are noted: babies delivered vaginally have gut microbiota consisting of *Lactobacillus, Prevotella, and Atopobium*, while, in comparison, the gut of babies delivered by caesarian section has maternal epidermal microflora, mostly represented by *Staphylococcus* [18, 23]. With age, anaerobic microorganisms become more abundant, with significant concentrations of *Bifidobacteria* and *Clostridia* in teenagers when compared to adults and higher levels of facultative anaerobes in the elderly [10]. The microbiota of infants was observed to be rich in *Clostridium coccoides* and *Clostridium leptum*, while elevated levels of *Escherichia Coli* and *Bacteroidetes* were observed in older people [10, 23].

Changes in the gut microbiota composition are in correlation with the physiological age-related processes. A systematic review conducted by Badal and colleagues presented some of the microbiota variations throughout the years. In older subjects, alpha diversity of the microbial taxa, functional pathways, and metabolites were enhanced, while beta diversity fluctuated significantly through different age groups. *Akkermansia* was described to be relatively plentiful with aging, while *Faecalibacterium, Bacteroidaceae,* and *Lachnospiraceae* were relatively diminished [24]. Elders possess different properties and functions of the microbiota: decreased activity of carbohydrate metabolism pathways and amino acid synthesis, higher production of short-chain fatty acids (SCFA) and butyrate derivatives (gamma-aminobutyric acid - GABA and DL-3-amino isobutyric acid) [24, 25].

For older people with ages ranging from 66 to 80 years old, lower levels of *Bifidobacterium, Faecalibacterium, Bacteroides*, and *Clostridium* cluster XIVa were noted. However, elevated aggregations of the *Akkermansia* and *Lactobacillus* group were detected in the cluster of people over 80 years old, compared with adults. Moreover, lower fecal SCFA concentrations were associated with aging, with statistical significance [26].

Diet plays a major role in the diversity of the human gut microorganisms and David et al. [27] compared plant-based diet microbiome with animal produce consumption microbiome and concluded that a shift in diet from mostly fibers to high fats and proteins can lead to only 24 hours to an increased population of *Alistipes, Bilophila* and *Bacteroides* and decreased levels of *Firmicutes (Roseburia, Eubacterium rectale,* and *Ruminococcus bromii)* known for their ability to metabolize dietary plant polysaccharides [27]. Several studies comparing the African diet with European food underline the same conclusion: different food components can alter the human gut microbiota very quickly and in different ways, leading to variability in the microorganism population found in the digestive tract [28, 29].
