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Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996.
Significance of the Normal Flora
The normal flora influences the anatomy, physiology, susceptibility to pathogens,and morbidity of the host.
The varied environment of the skin results in locally dense or sparsepopulations, with Gram-positive organisms (e.g., staphylococci, micrococci,diphtheroids) usually predominating.
Oral and Upper Respiratory Tract Flora
A varied microbial flora is found in the oral cavity, and streptococcal anaerobesinhabit the gingival crevice. The pharynx can be a point of entry and initialcolonization for Neisseria, Bordetella,Corynebacterium, and Streptococcusspp.
Gastrointestinal Tract Flora
Organisms in the stomach are usually transient, and their populations are keptlow (103 to 106/g of contents) by acidity.Helicobacter pylori is a potential stomach pathogen thatapparently plays a role in the formation of certain ulcer types. In normal hoststhe duodenal flora is sparse (0 to 103/g of contents). The ileumcontains a moderately mixed flora (106 to 108/g ofcontents). The flora of the large bowel is dense (109 to1011/g of contents) and is composed predominantly of anaerobes.These organisms participate in bile acid conversion and in vitamin K and ammoniaproduction in the large bowel. They can also cause intestinal abscesses andperitonitis.
The vaginal flora changes with the age of the individual, the vaginal pH, andhormone levels. Transient organisms (e.g., Candida spp.)frequently cause vaginitis. The distal urethra contains a sparse mixed flora;these organisms are present in urine specimens (104/ml) unless aclean-catch, midstream specimen is obtained.
The conjunctiva harbors few or no organisms. Haemophilus andStaphylococcus are among the genera most oftendetected.
Many elements of the normal flora may act as opportunistic pathogens, especiallyin hosts rendered susceptible by rheumatic heart disease, immunosuppression,radiation therapy, chemotherapy, perforated mucous membranes, etc. The flora ofthe gingival crevice causes dental caries in about 80 percent of thepopulation.
A diverse microbial flora is associated with the skin and mucous membranes of everyhuman being from shortly after birth until death. The human body, which containsabout 1013 cells, routinely harbors about 1014 bacteria (Fig. 6-1). This bacterial populationconstitutes the normal microbial flora . The normal microbial florais relatively stable, with specific genera populating various body regions duringparticular periods in an individual"s life. Microorganisms of the normal flora mayaid the host (by competing for microenvironments more effectively than suchpathogens as Salmonella spp or by producing nutrients the host canuse), may harm the host (by causing dental caries, abscesses, or other infectiousdiseases), or may exist as commensals (inhabiting the host for long periods withoutcausing detectable harm or benefit). Even though most elements of the normalmicrobial flora inhabiting the human skin, nails, eyes, oropharynx, genitalia, andgastrointestinal tract are harmless in healthy individuals, these organismsfrequently cause disease in compromised hosts. Viruses and parasites are notconsidered members of the normal microbial flora by most investigators because theyare not commensals and do not aid the host.
Numbers of bacteria that colonize different parts of the body. Numbers represent the number of organisms per gram of homogenized tissueor fluid or per square centimeter of skin surface.
Significance of the Normal Flora
The fact that the normal flora substantially influences the well-being of the hostwas not well understood until germ-free animals became available. Germ-free animalswere obtained by cesarean section and maintained in special isolators; this allowedthe investigator to raise them in an environment free from detectable viruses,bacteria, and other organisms. Two interesting observations were made about animalsraised under germ-free conditions. First, the germ-free animals lived almost twiceas long as their conventionally maintained counterparts, and second, the majorcauses of death were different in the two groups. Infection often caused death inconventional animals, but intestinal atonia frequently killed germ-free animals.Other investigations showed that germ-free animals have anatomic, physiologic, andimmunologic features not shared with conventional animals. For example, in germ-freeanimals, the alimentary lamina propria is underdeveloped, little or noimmunoglobulin is present in sera or secretions, intestinal motility is reduced, andthe intestinal epithelial cell renewal rate is approximately one-half that of normalanimals (4 rather than 2 days).
Although the foregoing indicates that bacterial flora may be undesirable, studieswith antibiotic treated animals suggest that the flora protects individuals frompathogens. Investigators have used streptomycin to reduce the normal flora and havethen infected animals with streptomycin-resistant Salmonella.Normally, about 106 organisms are needed to establish a gastrointestinalinfection, but in streptomycin-treated animals whose flora is altered, fewer than 10organisms were needed to cause infectious disease. Further studies suggested thatfermentation products (acetic and butyric acids) produced by the normal florainhibited Salmonella growth in the gastrointestinal tract. Figure 6-2 shows some of the factors that areimportant in the competition between the normal flora and bacterial pathogens.
Mechanisms by which the normal flora competes with invadingpathogens. Compare this schematic with Figure6-3.
The normal flora in humans usually develops in an orderly sequence, or succession,after birth, leading to the stable populations of bacteria that make up the normaladult flora. The main factor determining the composition of the normal flora in abody region is the nature of the local environment, which is determined by pH,temperature, redox potential, and oxygen, water, and nutrient levels. Other factorssuch as peristalsis, saliva, lysozyme secretion, and secretion of immunoglobulinsalso play roles in flora control. The local environment is like a concerto in whichone principal instrument usually dominates. For example, an infant begins to contactorganisms as it moves through the birth canal. A Gram-positive population(bifidobacteria arid lactobacilli) predominates in the gastrointestinal tract earlyin life if the infant is breast-fed. This bacterial population is reduced anddisplaced somewhat by a Gram-negative flora (Enterobacteriaceae) when the baby isbottle-fed. The type of liquid diet provided to the infant is the principalinstrument of this flora control; immunoglobulins and, perhaps, other elements inbreast milk may also be important.
What, then, is the significance of the normal flora? Animal and some human studiessuggest that the flora influences human anatomy, physiology, lifespan, and,ultimately, cause of death. Although the causal relationship of flora to death anddisease in humans is accepted, of her roles of the human microflora need furtherstudy.
Normal Flora of Skin
Skin provides good examples of various microenvironments. Skin regions have beencompared to geographic regions of Earth: the desert of the forearm, the cool woodsof the scalp, and the tropical forest of the armpit. The composition of the dermalmicroflora varies from site to site according to the character of themicroenvironment. A different bacterial flora characterizes each of three regions ofskin: (1) axilla, perineum, and toe webs; (2) hand, face and trunk; and (3) upperarms and legs. Skin sites with partial occlusion (axilla, perineum, and toe webs)harbor more microorganisms than do less occluded areas (legs, arms, and trunk).These quantitative differences may relate to increased amount of moisture, higherbody temperature, and greater concentrations of skin surface lipids. The axilla,perineum, and toe webs are more frequently colonized by Gram-negative bacilli thanare drier areas of the skin.
The number of bacteria on an individual"s skin remains relatively constant; bacterialsurvival and the extent of colonization probably depend partly on the exposure ofskin to a particular environment and partly on the innate and species-specificbactericidal activity in skin. Also, a high degree of specificity is involved in theadherence of bacteria to epithelial surfaces. Not all bacteria attach to skin;staphylococci, which are the major element of the nasal flora, possess a distinctadvantage over viridans streptococci in colonizing the nasal mucosa. Conversely,viridans streptococci are not seen in large numbers on the skin or in the nose butdominate the oral flora.
The microbiology literature is inconsistent about the density of bacteria on theskin; one reason for this is the variety of methods used to collect skin bacteria.The scrub method yields the highest and most accurate counts for a given skin area.Most microorganisms live in the superficial layers of the stratum corneum and in theupper parts of the hair follicles. Some bacteria, however, reside in the deeperareas of the hair follicles and are beyond the reach of ordinary disinfectionprocedures. These bacteria are a reservoir for recolonization after the surfacebacteria are removed.
S. epidermidis is a major inhabitant of the skin, and in someareas it makes up more than 90 percent of the resident aerobic flora.
The nose and perineum are the most common sites for S. aureuscolonization, which is present in 10 percent to more than 40 percent of normaladults. S. aureus is prevalent (67 percent) on vulvar skin. Itsoccurrence in the nasal passages varies with age, being greater in the newborn,less in adults. S. aureus is extremely common (80 to 100percent) on the skin of patients with certain dermatologic diseases such asatopic dermatitis, but the reason for this finding is unclear.
Micrococci are not as common as staphylococci and diphtheroids; however, they arefrequently present on normal skin. Micrococcus luteus, thepredominant species, usually accounts for 20 to 80 percent of the micrococciisolated from the skin.
The term diphtheroid denotes a wide range of bacteria belonging to the genusCorynebacterium. Classification of diphtheroids remains unsatisfactory; forconvenience, cutaneous diphtheroids have been categorized into the followingfour groups: lipophilic or nonlipophilic diphtheroids; anaerobic diphtheroids;diphtheroids producing porphyrins (coral red fluorescence when viewed underultraviolet light); and those that possess some keratinolytic enzymes and areassociated with trichomycosis axillaris (infection of axillary hair). Lipophilicdiphtheroids are extremely common in the axilla, whereas nonlipophilic strainsare found more commonly on glabrous skin.
Anaerobic diphtheroids are most common in areas rich in sebaceous glands.Although the name Corynebacterium acnes was originally used todescribe skin anaerobic diphtheroids, these are now classified asPropionibacterium acnes and as P.granulosum. P. acnes is seen eight times morefrequently than P. granulosum in acne lesions and is probablyinvolved in acne pathogenesis. Children younger than 10 years are rarelycolonized with P. acnes. The appearance of this organism on theskin is probably related to the onset of secretion of sebum (a semi-fluidsubstance composed of fatty acids and epithelial debris secreted from sebaceousglands) at puberty. P. avidum, the third species of cutaneousanaerobic diphtheroids, is rare in acne lesions and is more often isolated fromthe axilla.
Streptococci, especially β-hemolytic streptococci, are rarely seen onnormal skin. The paucity of β-hemolytic streptococci on the skin isattributed at least in part to the presence of lipids on the skin, as theselipids are lethal to streptococci. Other groups of streptococci, such asα-hemolytic streptococci, exist primarily in the mouth, from wherethey may, in rare instances, spread to the skin.
Gram-negative bacteria make up a small proportion of the skin flora. In view oftheir extraordinary numbers in the gut and in the natural environment, theirscarcity on skin is striking. They are seen in moist intertriginous areas, suchas the toe webs and axilla, and not on dry skin. Desiccation is the major factorpreventing the multiplication of Gram-negative bacteria on intact skin.Enterobacter, Klebsiella,Escherichia coli, and Proteus spp. are thepredominant Gram-negative organisms found on the skin.Acinetobacter spp also occurs on the skin of normalindividuals and, like other Gram-negative bacteria, is more common in the moistintertriginous areas.
The microbiology of a normal nail is generally similar to that of the skin. Dustparticles and other extraneous materials may get trapped under the nail,depending on what the nail contacts. In addition to resident skin flora, thesedust particles may carry fungi and bacilli. Aspergillus,Penicillium, Cladosporium, andMucor are the major types of fungi found under thenails.
Oral and Upper Respiratory Tract Flora
The oral flora is involved in dental caries and periodontal disease, which affectabout 80 percent. of the population in the Western world. The oral flora, itsinteractions with the host, and its response to environmental factors arethoroughly discussed in another Chapter. Anaerobes in the oral flora areresponsible for many of the brain, face, and lung infections that are frequentlymanifested by abscess formation.
The pharynx and trachea contain primarily those bacterial genera found in thenormal oral cavity (for example, α-and β-hemolyticstreptococci); however, anaerobes, staphylococci, neisseriae, diphtheroids, andothers are also present. Potentially pathogenic organisms such asHaemophilus, mycoplasmas, and pneumococci may also be foundin the pharynx. Anaerobic organisms also are reported frequently. The upperrespiratory tract is so often the site of initial colonization by pathogens(Neisseria meningitides, C. diphtheriae,Bordetella pertussis, and many others) and could beconsidered the first region of attack for such organisms. In contrast, the lowerrespiratory tract (small bronchi and alveoli) is usually sterile, becauseparticles the size of bacteria do not readily reach it. If bacteria do reachthese regions, they encounter host defense mechanisms, such as alveolarmacrophages, that are not present in the pharynx.
Gastrointestinal Tract Flora
The stomach is a relatively hostile environment for bacteria. It containsbacteria swallowed with the food and those dislodged from the mouth. Aciditylowers the bacterial count, which is highest (approximately 103 to106 organisms/g of contents) after meals and lowest (frequentlyundetectable) after digestion. Some Helicobacter species cancolonize the stomach and are associated with type B gastritis and peptic ulcerdisease. Aspirates of duodenal or jejunal fluid contain approximately103 organisms/ml in most individuals. Most of the bacteriacultured (streptococci, lactobacilli, Bacteroides) are thoughtto be transients. Levels of 105 to about 107 bacteria/mlin such aspirates usually indicate an abnormality in the digestive system (forexample, achlorhydria or malabsorption syndrome). Rapid peristalsis and thepresence of bile may explain in part the paucity of organisms in the uppergastrointestinal tract. Further along the jejunum and into the ileum, bacterialpopulations begin to increase, and at the ileocecal junction they reach levelsof 106 to 108 organisms/ml, with streptococci,lactobacilli, Bacteroides, and bifidobacteriapredominating.
Concentrations of 109 to 1011 bacteria/g of contents arefrequently found in human colon and feces. This flora includes a bewilderingarray of bacteria (more than 400 species have been identified); nonetheless, 95to 99 percent belong to anaerobic genera such as Bacteroides,Bifidobacterium, Eubacterium,Peptostreptococcus, and Clostridium. Inthis highly anaerobic region of the intestine, these genera proliferate, occupymost available niches, and produce metabolic waste products such as acetic,butyric, and lactic acids. The strict anaerobic conditions, physical exclusion(as is shown in many animal studies), and bacterial waste products are factorsthat inhibit the growth of other bacteria in the large bowel.
Although the normal flora can inhibit pathogens, many of its members can producedisease in humans. Anaerobes in the intestinal tract are the primary agents ofintra-abdominal abscesses and peritonitis. Bowel perforations produced byappendicitis, cancer, infarction, surgery, or gunshot wounds almost always seedthe peritoneal cavity and adjacent organs with the normal flora. Anaerobes canalso cause problems within the gastrointestinal lumen. Treatment withantibiotics may allow certain anaerobic species to become predominant and causedisease. For example, Clostridium difficile, which can remainviable in a patient undergoing antimicrobial therapy, may producepseudomembranous colitis. Other intestinal pathologic conditions or surgery cancause bacterial overgrowth in the upper small intestine. Anaerobic bacteria canthen deconjugate bile acids in this region and bind available vitaminB12 so that the vitamin and fats are malabsorbed. In thesesituations, the patient usually has been compromised in some way; therefore, theinfection caused by the normal intestinal flora is secondary to anotherproblem.
More information is available on the animal than the human microflora. Researchon animals has revealed that unusual filamentous microorganisms attach to ilealepithelial cells and modify host membranes with few or no harmful effects.Microorganisms have been observed in thick layers on gastrointestinal surfaces(Fig. 6-3) and in the crypts ofLieberkuhn. Other studies indicate that the immune response can be modulated bythe intestinal flora. Studies of the role of the intestinal flora inbiosynthesis of vitamin K and other host-utilizable products, conversion of bileacids (perhaps to cocarcinogens), and ammonia production (which can play a rolein hepatic coma) show the dual role of the microbial flora in influencing thehealth of the host. More basic studies of the human bowel flora are necessary todefine their effect on humans.
(A) Scanning electron micrograph of a cross-section of rat colonicmucosa. The bar indicates the thick layer of bacteria between themucosal surface and the lumen (L) (X 262,) (B) Higher magnificationof the area indicated by the arrow in Fig. A, showing (more...)
The type of bacterial flora found in the vagina depends on the age, pH, and hormonallevels of the host. Lactobacillus spp. predominate in femaleinfants (vaginal pH, approximately 5) during the first month of life. Glycogensecretion seems to cease from about I month of age to puberty. During this time,diphtheroids, S. epidermidis, streptococci, and E.coli predominate at a higher pH (approximately pH 7). At puberty,glycogen secretion resumes, the pH drops, and women acquire an adult flora in whichL. acidophilus, corynebacteria, peptostreptococci,staphylococci, streptococci, and Bacteroides predominate. After menopause, pH againrises, less glycogen is secreted, and the flora returns to that found inprepubescent females. Yeasts (Torulopsis andCandida) are occasionally found in the vagina (10 to 30 percentof women); these sometimes increase and cause vaginitis.
In the anterior urethra of humans, S. epidermidis, enterococci, anddiphtheroids are found frequently; E. coli,Proteus, and Neisseria (nonpathogenic species)are reported occasionally (10 to 30 percent). Because of the normal flora residingin the urethra, care must be taken in clinically interpreting urine cultures; urinesamples may contain these organisms at a level of 104/ml if a midstream(clean-catch) specimen is not obtained.
The conjunctival flora is sparse. Approximately 17 to 49 percent of culturesamples are negative. Lysozyme, secreted in tears, may play a role incontrolling the bacteria by interfering with their cell wall formation. Whenpositive samples show bacteria, corynebacteria, Neisseriae, and Moraxellae arecultured. Staphylococci and streptococci are also present, and recent reportsindicate that Haemophilus parainfluenzae is present in 25percent of conjunctival samples.
Host Infection by Elements of the Normal Flora
This chapter has briefly described the normal human flora; however, thepathogenic mechanisms of various genera or the clinical syndromes in which theyare involved was not discussed. Although such material is presented in otherchapters, note that a breach in mucosal surfaces often results in infection ofthe host by members of the normal flora. Caries, periodontal disease, abscesses,foul-smelling discharges, and endocarditis are hallmarks of infections withmembers of the normal human flora (Fig.6-4). In addition, impairment of the host (for example, those withheart failure or leukemia) or host defenses (due to immunosuppression,chemotherapy, or irradiation) may result in failure of the normal flora tosuppress transient pathogens or may cause members of the normal flora to invadethe host themselves. In either situation, the host may die.
Bitton G, Marshall KC: Adsorption of Microorganismsto Surfaces. John Wiley & Sons, New York, 1980 .
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Maibach H, Aly R: Skin Microbiology: Relevance toClinical Infection. Springer-Verlag, New York, 1981 .