Living Well with Microbes 1

Beginning immediately at birth, humans are colonized by a myriad of microorganisms that assemble into complex stereotypic communities, creating a beneficial indigenous microbiota. The result is a “supra-organism” in which our microbial partners outnumber our human cells by 10-to-1. Most currently available information about the human microbiota concerns the bacterial component, although they are by no means the only important members. However, bacteria will be the focus of this discussion.

In contrast to the relatively rare harmful encounters with pathogens, indigenous human-microbe relationships are the dominant forms in which we interact with microbes and are fundamentally important to human physiology. Co-adaptation and co-dependency are features of our relationships with these friendly bugs.

This we now know to be true:

• The human microbiota facilitates nutrient acquisition and energy extraction from food,
• It promotes terminal (postnatal) differentiation of mucosal structure and function, and
• It stimulates both the innate and adaptive immune systems.

By so being the primary stimulation of immune system function it helps to create an epithelial boundary and integrity, as well as to “educate” our innate immune defenses. It also provides “colonization resistance” against pathogen invasion, regulates intermediary metabolism, and processes ingested chemicals.

Precisely how this microbial community is assembled is still just being better studied. In the neonatal period, the community assembly process is especially dynamic and is influenced by early environmental (in particular, maternal) exposures. It is believed that the composition and functional capabilities of the indigenous microbiota evolve in a generally orderly fashion, as diet, hormonal environment, other environmental factors, and occasional ecologic disturbances play out their effects on a distinct, albeit diverse, human genetic background.

Despite exposure to more than 100 bacterial phyla in the surrounding environment, members of the phyla Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Fusobacteria dominate human body sites, suggesting a role for strong selective forces and microbial diversification over time.

Of interest, patterns of bacterial diversity in humans display individual-specific features. The uniqueness of an individual’s microbiota is less evident when viewed in terms of the overall functional capabilities of the community, rather than in terms of the names and relatedness of the strains and species; this difference probably reflects the functional redundancy of strains and species within the human microbiota, which, in turn, may contribute to stability of this ecologic system.

Differences in the capability of strains may explain variation among individuals in the metabolism of drugs such as digoxin and other exogenous chemicals. Differences in the capability of strains to tolerate normal inflammation may also influence the composition of the microbiota. Although there is evidence for shared functional capabilities among the intestinal microbial communities of different healthy humans, host genetics is a source of variation in the makeup of the human indigenous microbiota.

Infection (or colonization) is simply the establishment of a microorganism on or within a host; it may be short lived, as in our encounters with “transients”, or be persistent and may result in only low gain or harm to either participant. The term infectious disease applies when an interaction with a microbe causes damage to the host and the associated damage or altered physiology results in clinical signs and symptoms of disease. A pathogen is usually defined as any microorganism that has the capacity to cause disease. It is a medical definition; it is not a biologic definition, and certainly, not all pathogens have an equal probability of causing clinically apparent disease. Virulence provides a quantitative measure of pathogenicity or the likelihood of causing disease. For example, encapsulated pneumococci are more virulent than nonencapsulated pneumococci, and Escherichia coli strains that express Shiga-like toxins are more virulent than those that do not express these toxins. Virulence factors refer to the properties (e.g., gene products) that enable a microorganism to establish itself and replicate on or within a specific host species and that enhance the microbe’s potential to cause overt pathology.

All this to say that we need to distinguish pathogens that regularly cause disease in some proportion of susceptible individuals with apparently intact defense systems from other potentially pathogenic microorganisms, such as Pseudomonas aeruginosa. While this microorganism does not usually cause disease in individuals with intact host defense systems, it causes devastating disease in many immunocompromised patients.

H.pylori would be another example. While it may cause immediate disease (stomach ulcers), it may also lead to chronic, insidious, subclinical effects with long-term consequences (cancer, heart disease). Many microorganisms with a capacity for sustained multiplication in humans, including members of the indigenous microbiota, cause disease more readily in individuals with underlying chronic disease or in those who are otherwise compromised. The common term opportunist suits this category of pathogen well.

An emerging concept of microbial disease causation, with origins in the field of ecology, is the notion of “community as pathogen,” in which a conserved broad feature of the microbial community contributes to pathology, rather than any one specific member or component. This concept may be relevant to a wide variety of chronic inflammatory processes of skin and mucosa, including inflammatory bowel disease and chronic periodontitis. This concept answers questions many clinicians may have encountered as to the difficultly in both isolating and treating an individual pathogen.

In addition, microbial pathogenesis involves synergies between organisms, as well as between gene products, each of which may be insufficient alone in causing disease. For example, several members of the human health-associated nasopharyngeal microbiota, including Streptococcus pneumoniae, Neisseria meningitidis, and Streptococcus pyogenes, regularly cause well-defined, well-known human diseases. One may develop antibodies to individual organisms yet such commensal pathogens persist in a significant proportion and can be associated with both acute and chronic disease.

All this will be discussed in following Blog posts.