The composition of the natural flora changes depending on age, health status, living conditions, and the use of antimicrobial agents: antibiotics, disinfectants, and some cosmetics. The human body is colonized with microorganisms in a differentiated manner, which makes it possible to distinguish the following areas:
2. Microbiota Distribution
2.1. Skin
The skin, being the largest human organ, plays an extremely important role in the immune system. It is the first line of defense both against changes in the external environment and against microbial attacks. Skin colonization depends on its moisture content and pH, and the number of bacterial cells (CFU—colony-forming unit) in 1 cm
2 varies from about 10
4 to 10
5. The natural flora of the skin consists primarily of gram-positive bacteria with a predominance of granulomas—
Staphylococcus epidermidis,
Staphylococcus aureus, and aerobic tentacles
Corynebacterium spp. and
Propionibacterium acnes—which are involved in the formation of juvenile acne
[12][13][14][12,13,14].
In most areas of the skin, there are mainly gram-negative flora, and in the elderly, there are additionally fungi of the
Candida family. The composition of the natural flora undergoes constant changes related to the secretion of glands and the coexistence of skin diseases and systemic conditions. The armpit and groin areas manifest increased sweat production. Areas such as the face and back are richly supplied with sebaceous glands. On the other hand, continuous exposure of the skin of the arms and feet to the temperature of the external environment contributes to their dryness. The skin microflora also depends on age and gender. The skin of the fetus in utero is sterile, after which its first colonization with bacteria occurs during natural childbirth or a caesarean section
[13][15][13,15].
Bacteria of the
Propionibacteriace subfamily predominate on the scalp, including around the nose, ears, and hair, with significantly fewer on the skin of the arms. On the other hand, the trunk and extremities—especially around the armpits, soles of the feet, navel, and popliteal fossa—are dominated by
Staphylococcus and
Corynebacterium bacteria and fungi of the
Malassezia spp. genus. The chest, back, and occiput are populated in the greatest numbers by
Propionibacterium spp. and various species of
Staphylococcus spp. The surface of the forearm, which is a dry area, is dominated by mixed microorganisms represented mainly by the
Betaproteobacteriace group and
Flavobacteriales. Examination of the skin microbiome for the presence of viruses showed that like bacteria and fungi, viruses form both a permanent and transient composition of the skin microflora. Analysis of viral nucleic acid (DNA—deoxyribonucleic acid) sequences on the surface of the skin includes three predominant strains:
Papillomaviridae,
Polyomaviridae, and
Circoviridae. This is in agreement with the fact that in most individuals, papillomaviruses are the most commonly found on the superficial layers of the skin. It is worth noting that eukaryotic viruses can contribute to the development of skin diseases, including cancer
[14][15][16][17][14,15,16,17].
Physiological differences, including different hormones found in men and women, result in differences in the incidence of microorganisms on their skin. Adolescence appears to be a critical point in a person’s life when the skin microbiota is remodeled. Due to increased hormone levels, which contribute to the production of extra sebum, there is a proliferation of lipophilic bacteria
Propionibacterium spp. and
Corynebacterium spp., and fungal bacteria
Malassezia spp. The bacterial microbiota of the skin is also affected by environmental factors, occupation, clothing used, and the use of antibiotics. The use of cosmetics is also important, although the mechanism of their effect is not fully understood
[16][17][16,17].
2.2. Oral Cavity
The oral cavity, due to its contact with air, food, and water environments, is a dynamic yet highly diverse and unique environment for microorganisms. Bacteria residing in the oral cavity are involved in the metabolism of nutritional products. The first colonization of this area begins immediately after birth, and the main source of bacteria is the mother. This area is first colonized by
Streptococcus salivarius,
Streptococcus mitis, and
Streptococcus oralis, and in the next few months, gram-negative anaerobes
Fusobacterium nucleatum,
Prevotella melanogenic, and
Veillonella spp. appear. At a young age, the human oral microbiota becomes very stable and is represented by bacteria of the genus
Streptococcus,
Veillonella,
Fusobacterium,
Porphyromonas,
Prevotella,
Treponema,
Neisseria,
Haemophilus,
Eubacteria,
Lactobacterium,
Capnocytophaga,
Eikenella,
Leptotrichia,
Peptostreptococcus, and also
Propionibacterium. It is assumed that there are more than 700 bacterial species in the human oral cavity, with only about 50% of the bacteria present known. These data are confirmed by the Human Oral Microbiome Database (HOMD), which not only presents the current nomenclature of the oral microbiota but also contains data based on phenotypic, phylogenetic, and clinical studies
[16][18][19][16,18,19]. The high diversity of the oral microbiome is influenced by temperature, pH, oxidation reduction potential, salinity, and saliva, which, in addition to providing nutrients, removes metabolic products. In addition, it contains numerous enzymes, e.g., amylase, antimicrobial peptides, and even antibodies. The condition of the oral cavity depends on the state of hygiene of the host (tooth brushing, mouthwash). The saliva microbiome of people living in different geographic zones has 100 different types of bacteria, including about 40 as yet undescribed. The most common microbes are
Streptococcus,
Prevotella,
Veilonella,
Neisseria,
Heamophilus,
Rothia,
Porphyromonas,
Fusobacterium,
Scardovia,
Parascardovia, and
Alloscardovia. It has been shown that the tongue, as a muscular shaft covered with mucous membranes, is also a site colonized by bacteria. In healthy people, pathogens from the genera:
Prevotella,
Neisseria,
Streptococcus,
Heamophilus, and
Fusobacterium. Bacteria of the genera
Prevotella,
Streptococcus,
Veilonella,
Actinomyces, and
Leptotrichia predominated in the diseased subjects. An important fact about the oral microbiome is the biofilm formed above and below the gums, which differs in composition from the bacterial microflora. The microorganisms present in the biofilm form an extremely organized and active structure, within which they work together to cause the breakdown of organic matter and the extraction of energy. In the supragingival plaque, there are mainly gram-positive bacteria, such as
Staphylococcus mutants and
Lactobacillus spp. On the other hand, gram-negative bacteria, such as
Actinobacillus spp.,
Campylobacter spp.,
Fusobacterium nucleatum, and also
Porphyromonas gingivalis, are present in the subgingival plaque. Bacteriophages have been found in the oral cavity, whose presence is associated with potential bacterial hosts. These mainly include
Aggregatibacter actinomycetemcomitans phages, and their number is positively correlated with periodontal atrophy. It has been proven that oral bacteriophages can exist both as commensals and as pathogens. The ecosystem that is the oral microbiome is an excellent place for certain viruses to thrive: herpesviruses, including HSV (herpes simplex virus) and EBV (Epstein–Barr virus). Studies of the oral microbiome in healthy humans have proven the presence of such fungi as
Candida spp.,
Aspergillus spp.,
Cryptococcus spp.,
Fusarium spp., and
Alternaria spp.
[10][16][10,16].
2.3. The Gastrointestinal Tract
More than a century ago, Russian Nobel laureate Ilja Iljicz Miecznikow hypothesized that the health properties of kefir are related to the presence of live bacteria in it which cause colonization of the intestine. The human intestinal microbiota develops early in fetal life. Moreover, the fact that the placenta is not sterile is emphasized. The creation of the intestinal microbiota is a dynamic process directly dependent on genetic factors, the microbiota of the mother, the type of birth, environmental conditions, as well as the diet used by the mother during pregnancy and, later, the host itself. In the first days of a baby’s life, the large intestine is colonized by strains of bacteria such as
Escherichia coli and
Enterococcus faecalis, followed by
Bacteroides,
Bifidobacterium, and
Clostridium. Literature data indicate that the human intestinal microbiota is not formed until about 2 years of age and that it undergoes continuous modification over the next 3–5 years. The type of birth is important in the creation of the intestinal microbiota. At the moment of rupture of the chorioallantois membrane, the child comes into direct contact with the microorganisms of the mother’s vagina, thus inheriting the original microbiota of the mother and her ancestors. The microbiota of the gastrointestinal tract, due to the functions it performs and the specificity of its structure, is an extraordinary place for the development of microorganisms. It provides living and growing conditions for both commensal microorganisms and those supplied with food. The stomach, as one of the sections of the gastrointestinal tract, is a transitional reservoir of food, where wetting, dissolution, and also mixing of food content with gastric juice takes place. The gastric juice itself is a mixture of proteolytic enzymes and hydrochloric acid and facilitates the absorption of nutrients
[11][20][21][22][11,20,21,22].
Due to the presence of an acidic environment, the stomach is considered an essentially sterile and unfriendly place for microbial growth. However, with the discovery of
Helicobacter pylori, which colonizes the gastric niche, attention has been drawn to the fact that the stomach is populated by a diverse micro-community:
Firmicutes,
Proteobacteria,
Actinobacteria,
Bacteroides,
Fusobacteria,
Lactobacillus,
Streptococcus,
Veilonella, and
Escherichia coli. Numerous scientific studies confirm that as stomach acidity decreases, the risk of developing various diseases, including cancer, increases. It is currently estimated that the microbial environment of the stomach contains 101–103 CFU of bacteria, making it, along with the esophagus and duodenum, the least colonized section of the gastrointestinal tract. The gut microbiota ensures not only the continuity of the intestinal epithelium but also the homeostasis of the immune system while protecting the macroorganism from the adverse effects of pathogenic bacteria, including
Salmonella spp.,
Shigella spp.,
Staphylococcus aureus,
Campylobacter jejuni,
Yersinia enterocolitica, and
Listeria monocytogenes. It should be noted that the microbiota of the stomach is not fully understood—the study of the microbial inhabitants of this part of the gastrointestinal tract is extremely difficult because they are subject to a large selection error, which is due to interfering factors, as well as the inability to detect possible viruses, fungi, etc.
[23][24][25][23,24,25].
The intestinal microbiome is formed by viruses that affect host homeostasis and condition intestinal immunity. Among them are viruses that infect host cells and bacteriophages that attack bacteria. The most widespread are single- and double-stranded viruses of the orders
Caudovirales,
Podoviridae,
Siphoviridae, and
Myoviridae. The intestinal microflora plays an important role in food digestion and energy absorption and are involved in vitamin production. Microbes colonizing the gut cause the breakdown of complex carbohydrates, which are the source of certain nutrients. By breaking down fiber and intestinal mucin, they provide a source of simple sugars and short-chain fatty acids. The genome of bacteria is much richer than that of the host (up to 100 times) so microorganisms provide humans with many enzymes and metabolic pathways. Fermentation carried out by the intestinal microbiota provides up to 10% of energy from food, participates in the regulation of body weight, and regulates the amount of body fat present in the body. The gastrointestinal microbiota contributes to strengthening the integrity of the intestinal epithelium, stimulating processes related to the production and secretion of secretory antibodies and cationic peptides with antibacterial activity. In addition, it is involved in the stimulation of mucin, which is a component of the phenomenon called immune ignorance, responsible for the lack of direct contact between bacteria and immune cells. The composition of the intestinal microflora also affects immune hemostasis by regulating the size of the lymphocyte population and also the ratio of Th1 to Th2 lymphocytes. Bacterial commensals directly protect the host system against pathogenic microorganisms, including
Escherichia coli,
Salmonella or
Shigella, and
Clostridium difficile, mainly by altering the qualitative and quantitative nutrients available in the gut. The intestinal microflora also plays an important role in the synthesis of vitamin K and B vitamins (including B12, B1, and B6), the circulation of bile acids, and the transformation of mutagenic carcinogens (heterocyclic amines and N-nitroso-compounds), the production of which increases in the intestines in the presence of a diet rich in red meat. In addition, gut microbes are involved in the synthesis of amino acids, including lysine and threonine
[26][27][28][26,27,28].
Changes in the composition of the intestinal microbiota are referred to as dysbiosis, which in turn promotes the development of many conditions (irritable bowel syndrome, neuropsychiatric disorders, food allergies, etc.) and contributes to the expansion of inflammation in the body. The microbial environment of the large intestine varies from person to person, and the causes of disorders within this ecosystem include such factors as obesity, the use of antibiotics without medical indications, and a high-fat, processed diet. It is worth mentioning that increased inflammation in the human body can contribute to the development of conditions including metabolic, cardiovascular, and cancerous diseases
[29][30][29,30].
Bacteria are involved in the production of biotin and folic acid and in the absorption of magnesium, calcium, and iron ions. In addition, they enable more efficient energy absorption by breaking down polysaccharides, which are unpalatable to humans in their primary form. Intestinal bacteria participate in the production of short-chain fatty acids, which are a source of energy for intestinal epithelial cells and thus have a beneficial effect on maintaining the continuity of the mucosal barrier and have anti-inflammatory effects by reducing the concentration of pro-inflammatory cytokines. In addition, they induce the synthesis of the aforementioned mucins that protect the epithelium from toxins and pathogenic bacteria, thereby stimulating the immune system to act. In recent years, an increase in the percentage of
Bacteroidetes (e.g.,
Bacteroides vulgatus) and
Proteobacteria (e.g.,
Escherichia coli) has been observed in the gastrointestinal tract of Crohn’s disease patients. The cell membranes of these bacteria contain lipopolysaccharide, which strongly stimulates the immune system. In addition, a reduction in the percentage of
Firmicutes bacteria and thus in the amount of butyric acid they produce was found. Imbalances in the microbiota may also affect the pathogenesis and course of diverticular disease and the incidence of obesity. People with excessive body weight have been found to have an increase in the percentage of
Firmicutes-type bacteria relative to
Bacteroidetes-type. The result of such a change in the intestinal microbiota is greater availability of energy extracted from food, as
Firmicutes bacteria metabolize nutrients to a large extent, which predisposes to obesity. The microbiome has been shown to provide the human body with an additional 80–200 kcal per day
[31][32][31,32].
An example of the correlation between the state of the microbiome and women’s health is the effect of the microbiome on the incidence of cancer, primarily colon cancer. Bacteria that produce butyric acid or are mediated by it inhibit the growth of cancer cells and induce their apoptosis. On the other hand, bacteria such as
Escherichia coli,
Clostridium perfringens,
Bacteroides fragilis,
Bacteroides vulgatus, and
Enterococcus faecalis—via the enzymes β-glucuronidase and β-glucosidase—re involved in the synthesis of toxic and carcinogenic compounds. The composition of the microbiome is also important in the development of an allergic reaction in people with a genetic predisposition. The development of allergy is associated with the dominance of the Th2-dependent response. Bacteria of the species
Bacteroides fragilis have been shown to have a protective effect, not only contributing to the predominance of the Th1-dependent response but also via regulatory lymphocytes, inducing an anti-inflammatory response, thus limiting the development of diseases caused by an excessive Th2 lymphocyte response in the mucous membranes of the gastrointestinal tract and respiratory system. Emerging reports suggest that the onset of allergic symptoms in children is associated with a decrease in
Lactobacillus and
Bifidobacterium. The link between the microbiome and autism spectrum disorders is also being investigated. Attention has been paid to changes in the gut microbiota in children with autism. They were found to have a 10-fold increase in the number of
Clostridium difficile bacteria relative to healthy children. It is likely that the effects of neurotoxins produced by these bacteria may contribute to the manifestation of some of the symptoms
[33][34][35][33,34,35].
2.4. Respiratory Tract
The mucous membranes of the upper respiratory tract are in constant contact with the external environment through the process of breathing. Through the nasal cavity, pathogens are introduced into the airways with each breath. The microbiome of the upper respiratory tract is highly differentiated due to constant contact with the external environment, resulting in each person having a corresponding microbiome. In contrast, the lower respiratory tract, depending on its region and especially the lungs, shows a different microbiota composition
[2][34][2,34]. In healthy individuals, the upper respiratory tract is populated mainly by
Propionibacterium spp.,
Corynebacterium spp., and
Staphylococcus spp. The keratinized squamous epithelium of the nostrils contains sebaceous glands that produce substances that promote the growth of lithophilic bacteria, such as
Propionibacterium spp. Microorganisms of this type are capable of hydrolyzing fats, releasing free fatty acids, which lowers the pH promoting the growth of coagulase-negative staphylococci. In addition, humid conditions and the presence of oxygen in this area affect the growth of
Staphylococcus aureus in this area
[35][36][35,36].
The lower respiratory tract, trachea, and lungs are significantly different in structure and function from the upper respiratory tract. They are lined with ciliary epithelium and numerous secretory cells that release mucin, surfactant compounds, proteases, and immunomodulatory proteins, among others, which form an immune barrier. The immunity of this region of the airways is also determined by macrophages, T lymphocytes, and dendritic cells, including Largenhans cells. Hence, it was assumed that these defensive elements of the respiratory system were sufficient to maintain sterility in it
[37].
2.5. Effects of Hormones on a Woman’s Microbiome
The distribution of the gut microbiota varies according to a woman’s life stage (childhood, adolescence, pregnancy, menopause, old age). The gut microbiota is known to contribute to the development of gastrointestinal diseases, such as irritable bowel syndrome, obesity, inflammatory bowel disease, and colon cancer, but the exact etiology remains elusive. Recently, gender differences in gastrointestinal diseases and their relationship to gut microbiota have been suggested. In addition, estrogen and androgen metabolism are linked to the gut microbiome. Since the gut microbiome is involved in the excretion and circulation of sex hormones, the concept of the “microgenome” has been proposed, indicating the role of sex hormones in the gut microbiota. However, further research is needed for this concept to be widely accepted.
The endocrine function of the reproductive system involves several hormones controlled by complex feedback mechanisms. The ovaries, adrenal glands, and adipose tissue produce estrogen. Estrogens produced in the body or taken in as food can be metabolized by gut microbes
[38][51]. The resulting metabolites again affect the host. Sex hormones directly modulate bacterial metabolism through steroid receptors, including estrogen receptor beta. Meanwhile, the gut microbiome with β-glucuronidase activity deconjugates conjugated circulating estrogens excreted in the bile most often secreted by
Escherichia coli,
Peptostreptococcus,
Bacteroides, and
Clostridia [39][52]. Deconjugation enables the process of reabsorption of estrogens into the system. The deconjugated estrogens circulate and affect many organs, not only reproductive but also the skeletal, cardiovascular and central nervous systems, through estrogen receptors. Typically, estrogens bind to nuclear receptors, causing conformational changes
[40][53].
Progesterone has many important functions in a woman’s body, including being essential for becoming pregnant and maintaining a pregnancy, normalizing blood flow, regulating glucose levels, and regulating zinc and copper levels in the body. Progesterone is also strongly associated with intestinal function, as it affects intestinal sensitivity and motility at the level of prostaglandins
[41][54]. Its adequate levels also affect metabolism and the growth of probiotic microorganisms in the gut
[42][43][55,56].
The prevalence of unfavorable bacteria can disrupt androgen metabolism and underestimation of levels, such as testosterone levels, can occur, leading to varicose veins, bladder weakness, hair loss, muscle weakness, low libido, or osteoporosis. Some species of bacteria (including
Clostridium scindens) can synthesize glucocorticosteroids (e.g., cortisol) into certain androgens (e.g., androstendione, testosterone)
[44][57].
Pregnancy is a condition in which major hormonal and j microbiota changes are observed. There is an increase in estrogen, prolactin, and progesterone, which affects changes in the intestines of women. As a result of the increase in progesterone and prolactin, the number of
Proteobacteria phyla and
Actinobacteria increases, while the number of
Faecalibacterium and other bacteria that produce short-chain fatty acids decreases
[45][46][58,59].
During pregnancy, changes similar to metabolic syndrome occur, mainly in the third trimester. This is when weight gain, insulin resistance, and minor inflammation occur. Therefore, for the fetus to develop properly and for the birth to go well, there is an increase in the number of microorganisms that have strong anti-inflammatory properties
[47][48][60,61].
The gut microbiome has been proven to interact with thyroid hormones and vice versa. It is in the gut, among other things, that the conversion of thyroxine (T4) to triiodothyronine (T3) occurs. In total, 20% of this conversion occurs with the help of intestinal bacteria. Another 70% occurs with the help of the liver, which is also sensitive to changes in the composition of the microbiome. Therefore, dysbiosis is a straightforward path to insufficient levels of thyroid hormones and hypothyroidism
[49][50][62,63].
An abnormal microbiota leads to a softened gut. When this occurs, undigested proteins can enter a woman’s body, and this leads to an immune system response that can result in various types of autoimmune diseases. For example, gliadin, a protein that makes up gluten, is molecularly similar to proteins that make up thyroid tissue, so with the involvement of certain genes, the immune system can also start attacking one’s thyroid, which leads to Hashimoto’s disease
[51][64].
The prevalence of abnormal microbiota also leads to constant inflammation, and this impacts the adrenal glands, which secrete cortisol at all times, which simultaneously reduces active thyroid hormones
[52][53][65,66].
Hypothyroidism itself slows down the entire metabolism, including gastrointestinal peristalsis. Constipation develops, and other digestive problems arise, especially those related to gastrointestinal motility, which itself is a substrate for microbiota disorders such as
Candida albicans overgrowth or SIBO (small-intestinal bacterial overgrowth)
[54][55][67,68].
In terms of the female population’s health, attention is being paid to the growing problem of polycystic ovary syndrome (PCOS). Long-term health consequences include an increased risk of miscarriage and pregnancy complications. PCOS is often accompanied by hyperandrogenism, which is associated with metabolic dysregulation. Thyroid hormones and luteinizing hormone (LH) are responsible for the increased amount of androgens in a woman’s body. Women suffering from PCOS have elevated levels of LH, which in turn contributes to the production of excessive androgenic hormones. Recent scientific reports suggest that intestinal dysbiosis may be responsible for the development of PCOS, including via testosterone, which may contribute to changes in the lower gastrointestinal ecosystem
[56][57][58][69,70,71].
For the moment, scientific studies highlight changes in the abundance of bacteria residing in the gut of PCOS patients, mainly from
Bacteroidetes and
Fermicutes species. It is through the aforementioned bacterial species that adverse metabolic and immunological changes may occur, which are explained by the altered production of short-chain fatty acids. The composition of the intestinal microbiota in women with established PCOS is compared to that of obese women, but
Escherichia and
Shigella bacteria predominate in the group of women in question (PCOS)
[57][70]. Metabolites of the gut microbiota, as well as the microbiota itself, can in turn lead to, among other things, activation of inflammatory pathways or proliferation of pancreatic β-cells, and this leads to the development of, for example, insulin resistance. At this point, a cause-and-effect relationship between dysbiosis and the occurrence of endocrine disorders can be identified
[58][71]. It seems noteworthy that the gut microbiota of the endocrine system has a multidirectional effect. Bacteria residing in the gut can both produce hormones, such as those responsible for general happiness (serotonin and dopamine), as well as perform a regulatory function (glucocorticoids androgens)
[59][72].
Estradiol, which regulates the female monthly cycle, significantly affects the composition of the vaginal microbiota. The female reproductive tract is mainly populated by bacteria of the genus
Lactobacillus, whose number changes significantly depending on the day of the menstrual cycle. The lowest level of the hormone is observed during menstruation, at which time the abundance of
Lactobacillus is markedly reduced, while the balance of microorganisms is restored in the late follicular and luteal phases
[60][73]. Studies highlight the role of dysbiosis in the course of obesity. Estrogen plays one of the most important roles in terms of metabolic processes, this explains the fact that women in the menopausal phase have an increased risk of cardiovascular disease and also obesity. This is because estrogen, along with leptin and the gut microbiota, is deeply involved in the body’s energy balance. The 2019 results on mice from the study by Acharya et al. show that both estradiol and leptin can contribute to the modulation of the gut microbiota in women. In addition, the researchers highlight the role of estradiol as a protective factor against obesity induced by a high-fat diet
[61][74].