Normal Human Microbiota | Jawetz, Melnick, & Adelberg’s Medical Microbiology, 27e | AccessPharmacy (2022)

The flora of the nose consists of prominent corynebacteria, staphylococci (S epidermidis, S aureus), and streptococci.

In direct contrast to the highly differentiated communities of their mothers, neonates harbored bacterial communities that were undifferentiated across multiple body habitats, regardless of delivery mode. Thus, at its earliest stage of community development (<5 minutes postdelivery), the human microbiota is homogeneously distributed across the body. Vaginally delivered infants harbor bacterial communities (in all body habitats) that are most similar in composition to the vaginal communities of the mothers; C-section babies lack bacteria from the vaginal community (eg, Lactobacillus, Prevotella, Atopobium, and Sneathia spp.). Infants delivered via C-section harbor bacterial communities (across all body habitats) that are most similar to the skin communities of the mothers (eg, Staphylococcus, Corynebacterium, or Propionibacterium spp.).

Within 4–12 hours after birth, viridans streptococci become established as the most prominent members of the resident flora and remain so for life. These organisms probably originate in the respiratory tracts of the mother and attendants. Early in life, aerobic and anaerobic staphylococci, gram-negative diplococci (neisseriae, Moraxella catarrhalis), diphtheroids, and occasional lactobacilli are added. When teeth begin to erupt, the anaerobic spirochetes, Prevotella species (especially Prevotella melaninogenica), Fusobacterium species, Rothia species, and Capnocytophaga species (see below) establish themselves along with some anaerobic vibrios and lactobacilli. Actinomyces species are normally present in tonsillar tissue and on the gingivae in adults, and various protozoa may also be present. Yeasts (Candida species) occur in the mouth.

In the pharynx and trachea, a similar flora establishes itself, but few bacteria are found in normal bronchi. Small bronchi and alveoli are normally sterile. The predominant organisms in the upper respiratory tract, particularly the pharynx, are nonhemolytic and α-hemolytic streptococci and neisseriae. Staphylococci, diphtheroids, haemophili, pneumococci, mycoplasmas, and prevotellae are also encountered.

More than 600 different species have been described from the human oral cavity, but only limited information is available on the normal microbiota of healthy individuals. The human oral microbiome, as represented by the human salivary microbiome, has recently been characterized in samples obtained from 120 healthy individuals from 12 worldwide locations by 16S rRNA sequencing. There is considerable diversity in the saliva microbiome, both within and among individuals; however, it does not vary substantially around the world. The 16S rRNA sequences could be assigned to 101 known bacterial genera, of which 39 were not previously reported from the human oral cavity; phylogenetic analysis suggests that an additional 64 unknown genera are also present.

Infections of the mouth and respiratory tract are usually caused by mixed oronasal flora, including anaerobes. Periodontal infections, perioral abscesses, sinusitis, and mastoiditis may involve predominantly P melaninogenica, Fusobacteria, and Peptostreptococci. Aspiration of saliva (containing up to 102 of these organisms and aerobes) may result in necrotizing pneumonia, lung abscess, and empyema.

The Role of the Normal Mouth Microbiota in Dental Plaque and Caries

Dental plaque, which has come to be viewed and managed as a complex biofilm, can be defined simplistically as an adherent dental deposit that forms on the tooth surface composed almost entirely of bacteria derived from the normal flora of the mouth (Figure 10-2). Dental plaque is the most prevalent and densest of human biofilms. The advantages for the microbes in the biofilm include protection from environmental hazards (including antimicrobials) and optimization of spatial arrangements that maximize energy through movement of nutrients. Organisms within the biofilm interact dynamically at multiple metabolic and molecular levels. The biofilm first forms in relation to the dental pellicle, which is a physiologic thin organic film covering the mineralized tooth surface composed of proteins and glycoproteins derived from saliva and other oral secretions (see Figure 10-2). As the plaque biofilm evolves, it does so in relation to the pellicle and not the mineralized tooth itself. Plaque formation takes place in stages and layers at two levels. The first is the anatomical location of the plaque in relation to the gingival line; the earliest plaque is supragingival, which may then extend to subgingival plaque. The second level is the layering within the plaque, the bacterial species involved, and the bacteria–pellicle and bacteria–bacteria binding mechanisms involved. The initial colonizing organisms are mainly gram-positive bacteria that use specific ionic and hydrophobic interactions as well as lectin-like surface structures to adhere to the pellicle and to each other. The prototype early colonizer is Streptococcus sanguis, but other streptococci (Streptococcus mutans, Streptococcus mitis, Streptococcus salivarius, Streptococcus oralis, Streptococcus gordonii), lactobacilli, and Actinomyces species are usually present. Late colonizers can appear in the biofilm in as little as 2–4 days and consist primarily of gram-negative anaerobes (eg, Porphyromonas, Prevotella, Fusobacterium, Veillonella species), including anaerobic spirochetes (eg, Treponema denticola), and more Actinomyces species. These bacteria use similar mechanisms to bind to the early colonizers and to each other. High-molecular-weight extracellular glucan polymers are synthesized, which act like a cement binding the plaque biofilm together. The carbohydrate polymers (glucans) are produced mainly by streptococci (S mutans), perhaps in association with Actinomyces species. In all, there are thought to be 300–400 bacterial species present in mature dental plaque.

FIGURE 10-2

Dental plaque biofilm. The stages of formation of the bacterial biofilm called dental plaque are shown. Early colonizers bind to the pellicle, and late colonizers bind to the other bacteria. (Reproduced with permission from Willey J, Sherwood L, Woolverton C [editors]: Prescott’s Principles of Microbiology. McGraw-Hill, 2008. © The McGraw-Hill Companies, Inc.)

Normal Human Microbiota | Jawetz, Melnick, & Adelberg’s Medical Microbiology, 27e | AccessPharmacy (1)

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Caries is a disintegration of the teeth beginning at the surface and progressing inward. First the surface enamel, which is entirely noncellular, is demineralized. This has been attributed to the effect of acid products of glycolytic metabolic activity when the plaque bacteria are fed the right substrate. Subsequent decomposition of the dentin and cementum of the exposed root surface involves bacterial digestion of the protein matrix. S mutans is considered to be the dominant organism for the initiation of caries; however, multiple members of the plaque biofilm participate in the evolution of the lesions. These include other streptococci (S salivarius, S sanguis, Streptococcus sobrinus), lactobacilli (Lactobacillus acidophilus, Lactobacillus casei), and actinomycetes (Actinomyces viscosus, Actinomyces naeslundii). The large amounts of organic acid products produced from carbohydrates by the interaction of S mutans with these other species in plaque are the underlying cause of caries. The accumulation of these acid products causes the pH of the plaque to drop to levels sufficient to react with the hydroxyapatite of the enamel, demineralizing it to soluble calcium and phosphate ions. Production of acid and decreased pH is maintained until the substrate is depleted after which the plaque pH returns to its more neutral pH resting level and some recovery can take place.

Dietary monosaccharides (eg, glucose, fructose) and disaccharides (eg, sucrose, lactose, and maltose) provide an appropriate substrate for bacterial glycolysis (see Chapter 6) and acid production to cause tooth demineralization. Foods with high sugar content, particularly sucrose, which adhere to the teeth and have long oral clearance times, are more cariogenic than less retentive food stuffs such as sugar-containing liquids. A possible edge for S mutans is its ability to metabolize sucrose more efficiently than other oral bacteria. An additional factor is that sucrose is also used for the synthesis of extracellular polyglycans such as dextrans and levans by transferase enzymes on the bacterial cell surface. Polyglycan production contributes to aggregation and accumulation of S mutans on the tooth surface and may also serve as an extracellular storage form of substrate for other plaque bacteria.

Periodontal pockets in the gingiva are particularly rich sources of organisms, including anaerobes that are rarely encountered elsewhere. Plaque-induced periodontal disease encompasses two separate disease entities, gingivitis and chronic periodontitis. Both conditions are caused by bacteria in the subgingival dental plaque found within the gingival crevice or the sulcus around the necks of the teeth. Periodontitis is a biofilm-induced chronic inflammatory disease which affects the tooth-supporting tissues. Although the tooth-associated biofilm plays a crucial role in the initiation and progression of periodontitis, it is primarily the host inflammatory response that is responsible for the damage to the periodontium, leading to tooth loss in some cases. It has been hypothesized that Porphyromonas gingivalis impairs innate immunity in ways that alter the growth and development of the entire biofilm, triggering a breakdown in the normally homeostatic host–microbiota interplay in the periodontium. Although the microorganisms within the biofilm may participate in periodontal disease and tissue destruction, attention is drawn to them when they are implanted elsewhere (eg, producing infective endocarditis or bacteremia in a granulocytopenic host). Examples are Capnocytophaga species and Rothia dentocariosa. Capnocytophaga species are fusiform, gram-negative, gliding anaerobes; Rothia species are pleomorphic, aerobic, gram-positive rods. In granulocytopenic immunodeficient patients, they can lead to serious opportunistic lesions in other organs.

Control of caries involves physical removal of plaque, limitation of sucrose intake, good nutrition with adequate protein intake, and reduction of acid production in the mouth by limitation of available carbohydrates and frequent cleansing. The application of fluoride to teeth or its ingestion in water results in enhancement of acid resistance of the enamel. Control of periodontal disease requires removal of calculus (calcified deposit) and good mouth hygiene.

Normal Microbiota of the Intestinal Tract

The human gastrointestinal tract is divided into sections, allowing digestion and nutrient absorption in the proximal region to be separate from the vast microbial populations in the large intestine. At birth, the intestine is sterile, but organisms are soon introduced with food. The environment (eg, maternal vaginal, fecal, or skin microbiota) is a major factor in determining the early microbial profile. Many early studies reported that the intestinal microbiota of breastfed children is dominated by Bifidobacteria. However, recent studies employing microarrays and quantitative PCR suggested that in most babies, Bifidobacteria did not appear until several months after birth and thereafter persisted as a minority population. In bottle-fed children, a more mixed flora exists in the bowel, and lactobacilli are less prominent. As food habits develop toward the adult pattern, the bowel flora changes. Diet has a marked influence on the relative composition of the intestinal and fecal flora. For example, individuals on an animal-based diet have been shown to have an increased abundance of bile-tolerant microorganisms (Alistipes, Bilophilia, and Bacteroides) and decreased levels of Firmicutes that metabolize dietary plant polysaccharides (Roseburia, Eubacterium rectale, and Ruminococcus bromii). Bowels of newborns in intensive care nurseries tend to be colonized by Enterobacteriaceae, such as Klebsiella, Citrobacter, and Enterobacter.

In normal adults, the esophagus contains microorganisms arriving with saliva and food. The stomach’s acidity keeps the number of microorganisms at a minimum (102–103/mL of contents) unless obstruction at the pylorus favors the proliferation of gram-positive cocci and bacilli. From the hundreds of phylotypes detected in the human stomach, only Helicobacter pylori persists in this environment. The normal acid pH of the stomach markedly protects against infection with some enteric pathogens (eg, Vibrio cholerae). Administration of antacids, H2-receptor antagonists, and proton pump inhibitors for peptic ulcer disease and gastroesophageal reflux disease leads to a great increase in microbial flora of the stomach, including many organisms usually prevalent in feces. As the pH of intestinal contents becomes alkaline, the resident flora gradually increases. In the adult duodenum, there are 103–104 bacteria/mL of effluent; with higher populations in the jejunum, 104–105 bacteria/mL, and ileum, 108 bacteria/mL; and in the cecum and transverse colon, 1011–1012 bacteria/mL, which is the highest recorded for any microbial habitat. In the upper intestine, the bacterial population associated with the mucosa include the phylum Bacteroidetes and members of the Clostridiales, and those of the lumen can include members of the Enterobacteriales and enterococci. In the sigmoid colon and rectum, the bacteria constitute about 60% of the fecal mass. Anaerobes outnumber facultative organisms by 1000-fold. In diarrhea, the bacterial content may diminish greatly, but in intestinal stasis, the count rises.

In a normal adult colon, 96–99% of the resident bacterial flora consists of anaerobes. Six major phyla predominate; these are Bacteroidetes, Firmicutes, Actinobacteria, Verrucomicrobiota, Fusobacteria, and Proteobacteria. More than 100 distinct types of organisms, which can be cultured routinely in the laboratory, occur regularly in normal fecal flora. Archae are represented primarily by the methane producer Methanobrevibacter smithii, a low abundance microorganism that may play an important role in stabilizing gut microbial communities. There probably are more than 500 species of bacteria in the colon, including many that are likely unidentified. In addition to Bacteria and Archae, other types of microbes are present, such as protozoans and fungi, whose functions are less well understood. Viruses, mostly phages whose hosts are prominent members of the microbiota, are remarkably common in the colon. Minor trauma (eg, sigmoidoscopy, barium enema) may induce transient bacteremia in about 10% of procedures.

The important functions of intestinal microbiota can be divided into three major categories (see review by O’Hara and Shanahan, 2006). The first of these are protective functions in which the resident bacteria displace and inhibit potential pathogens indirectly by competing for nutrients and receptors or directly through the production of antimicrobial factors, such as bacteriocins and lactic acid. Second, commensal organisms are important for the development and function of the mucosal immune system. They induce the secretion of IgA, influence the development of the intestinal humoral immune system, and modulate local T-cell responses and cytokine profiles. The third category consists of a broad range of metabolic functions. The microbiota of the small intestine can contribute to the amino acid requirements of the host if they are not provided by the diet itself. Intestinal bacteria produce short-chain fatty acids that control intestinal epithelial cell differentiation. They synthesize vitamin K, biotin, and folate and enhance ion absorption. Certain bacteria metabolize dietary carcinogens and assist with fermentation of nondigestible dietary residue. There is now evidence that gut bacteria can influence fat deposition in the host, leading to obesity.

Methanogenic archae are minor components of the gut microbiota. However, their ability to reduce small organic compounds (eg, CO2, acetic acid, formic acid, and methanol) into methane in the presence of H2 has significant consequences because the removal of excess hydrogen through methanogenesis prevents the inhibition of bacterial NADH dehydrogenase. This will, in turn, lead to an increased yield of ATP from bacterial metabolism (see Chapter 6) and a greater harvest of energy from the diet.

Antimicrobial drugs taken orally can, in humans, temporarily suppress the drug-susceptible components of the fecal flora. The acute effects of antibiotic treatment on the native gut microbiota range from self-limiting diarrhea to life-threatening pseudomembranous colitis. Intentional suppression of the fecal flora is commonly done by the preoperative oral administration of insoluble drugs. For example, neomycin plus erythromycin can in 1–2 days suppress part of the bowel flora, especially aerobes. Metronidazole accomplishes that for anaerobes. If lower bowel surgery is performed when the counts are at their lowest, some protection against infection by accidental spill can be achieved. However, soon thereafter, the counts of fecal flora rise again to normal or higher than normal levels, principally of organisms selected out because of relative resistance to the drugs used. The drug-susceptible microorganisms are replaced by drug-resistant ones, particularly staphylococci, enterobacters, enterococci, protei, pseudomonads, Clostridium difficile, and yeasts.

The feeding of large quantities of L acidophilus may result in the temporary establishment of this organism in the gut and the concomitant partial suppression of other gut microflora.

Fecal microbiota transplantation (FMT) also known as stool transplant is the process of transplantation of fecal bacteria from a healthy individual into a recipient. It has been used successfully as a treatment for patients suffering from C difficile infection (see Chapter 11). The hypothesis behind the success of FMT rests on the concept of bacterial interference, ie, using harmless bacteria to displace pathogenic bacteria. FMT restores the colonic microbiota to its natural state by replacing missing Bacteroidetes and Firmicutes species. However, recent studies suggest that other factors may be important.

The anaerobic flora of the colon, including Bacteroides fragilis, clostridia, and peptostreptococci, plays a main role in abscess formation originating in perforation of the bowel. Prevotella bivia and Prevotella disiens are important in abscesses of the pelvis, originating in the female genital organs. Similar to B fragilis, these species are penicillin resistant; therefore, another agent should be used.

Although the intestinal microbiota is normally an asset for the host, in genetically susceptible individuals, some components of the flora can result in disease. For example, inflammatory bowel diseases are believed to be associated with a loss of immune tolerance to bacterial antigens. This leads to intense inflammation caused by an exuberant immune response. Similar mechanisms may be important in intestinal malignancy such as colon cancer.

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