The Human Microbiome: A New Paradigm? John Huss Department of Philosophy The University of Akron

The Human Microbiome: A New Paradigm? John Huss Department of Philosophy The University of Akron

Structure of talk Some thoughts on the HMP and metagenomics Two paradigms of disease/health Old paradigm: Specific causes (good guys/bad guys) New paradigm: Superorganism (homeostatic balance) What is the relationship between these two paradigms? Potential implication for probiotic health claims

Where to place the accent in microbiome research? Two usage patterns in the literature Micro-biome: my crow BYE ohm The microbial biome Fundamentally an ecological conception Microbi-ome: my CROW be ohm The collective microbial genome Fundamentally a genomic conception

The genomic meets the ecological The hypothesis that there is a core human gut microbiome, definable by a set of abundant microbial organismal lineages that we all share, may be incorrect: by adulthood, no single bacterial phylotype was detectable at an abundant frequency in the guts of all 154 sampled humans. Instead, it appears that a core gut microbiome exists at the level of shared genes, including an important component involved in various metabolic functions. This conservation suggests a high degree of redundancy in the gut microbiome and supports an ecological view of each individual as an island inhabited by unique collections of microbial phylotypes: as in actual islands, different species assemblages converge on shared core functions provided by distinctive components (Turnbaugh et al. Nature, 2009).

Metagenomics the functional and sequence-based analysis of the collective microbial genomes contained in an environmental sample (Riesenfeld, Schloss, and Handelsman 2004)

What the researchers say We have embarked on an effort to access the chemical diversity of soil life by cloning the metagenome of the soil without first culturing the microflora, treating the metagenome as a genomic unit (Handelsman et al. 1998) In the end, it may be possible to view ecosystems themselves as biological units with their own genetic repertoires and to sidestep consideration of individual species. Then, both Who is there? and What are they doing? could be replaced with What is being done by the community? (National Research Council 2007, p. 29)

Metagenomic ontology of microbial communities Aggregative concept: the combined genomes of all of the members of a given community (Tringe and Rubin 2005) Systemic concept: communal genome available to a coordinated, developing, multifunctional, multicellular organism composed of large number of cells of different varieties and capabilities, able to work in ways in which the collectivity regulates the functions of individuals (Dupré and O Malley 2007)

Metagenomics: an instance of tools-to-theories heuristic? Metagenomics Metagenome Tools-to-Theories heuristic: model the phenomenon on tool used to study it (Gigerenzer 1991) Cognitive psychologists who used Bayesian methods to analyze their data concluded that their research subjects reasoned like Bayesians. Cognitive psychologists who used Fisherian methods concluded that their research subjects reasoned like null hypothesis testers. Microbiologists who use metagenomic methods conclude that the metagenome is a biological unit. Research tools may be influencing translational concepts.

The Structure of Scientific Revolutions (T.S. Kuhn) Paradigm (narrow sense): a worked example that serves as an exemplar for converting insoluble problems into soluble puzzles Example: Newton s analysis of the sun-earthmoon system

Paradigm (broad sense) Set of commitments Axiological: what constitutes a worthy problem/solution Methodological: how to solve the problem Ontological: what entities, processes, relations are presupposed by the problem/solution Paradigm shift occurs when new exemplar is available for converting insoluble problems into soluble puzzles.

Paradigm shift Specific causation paradigm Superorganism paradigm How different are these two paradigms? Though different, are they nonetheless commensurable?

Specific causation paradigm of disease Exemplar: tuberculosis (Koch 1884) Establish presence of organism in all cases of disease but not in healthy hosts Isolate organism from host and grow in pure culture Infect previously healthy host with cultured organism, causing disease Isolate organism from newly infected host. This is your pathogen.

Specific causation paradigm sensu lato Axiological: what s of value is identifying the pathogen Methodological: identify pathogenic species, extract from host, culture, infect new host Ontological: pathogen, host, disease state

Dualistic view of immune system pathogenic microbes (bad bacteria) elicit pro-inflammatory responses innocuous microbes, including probiotics (good bacteria), elicit anti-inflammatory responses (if detected at all)

Superorganism paradigm Facing the microbes, the immune system does not react to combat evil, but merely shapes the microbial environment to allow the organism to live with the microbes. It is not a fight between good and evil, it is rather an equilibrium between microbes and host that generates a superorganism (Eberl 2010).

Superorganism paradigm: immunological homeostasis [W]hen mice, and humans, were treated with a mix of antibiotics to eradicate most of their intestinal microbiota, they became highly sensitive to infection by an antibioticresistant strain of Enterococcus [Ordinarily], the symbiotic microbiota pulls the string of immunity and induces the production of antibacterial peptides that contribute to defining an intestinal niche permissive for symbionts, but mostly toxic for potential pathogens such as antibiotic-resistant Enterococcus (Eberl 2010)

Superorganism paradigm: weak immunity Too weak an immune system exposes the superorganism to a conversion of mutualists and commensals to pathogens. The immune forces that normally contain symbionts and establish equilibrium are at risk to be overwhelmed, and microbes that are not normally behaving as pathogens may invade forbidden areas and become pathogens The latter include the yeast Candida albicans, a member of the human microbiota of the skin, intestine, and vagina, and Pseudomonas aeruginosa and Staphylococcus aureus, both present in the skin microbiota (Eberl 2010).

Superorganism paradigm: strong immunity Too strong an immune system destabilizes the microbiota and causes dysbiosis, or alteration in the symbiotic microbial community. given the nearly unlimited source of antigens generated by the intestinal microbiota, an aggressive immune system can progress into overdrive, generate acute and chronic pathological inflammation, and cause severe damage to the tissue. Such a scenario unfolds during Crohn s disease (Eberl 2010).

Conclusions Specific causes and superorganism paradigms obviously give quite different accounts of disease, but Superorganism paradigm still presupposes pathogens, but defined contextually, not essentially. Probiotics may play a role in preventing or reversing the ecological context that turns symbiosis into pathogenesis. No special account of positive health is required here.

Thanks to Center for Genetic Research Ethics and Law, especially Eric Juengst. Working group organizers, especially Virginia Rowthorn and Diane Hoffmann.

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