BOX 2-1
Research on the Microbiome: Major Research Questions

Understanding human biology and the complex interactions that determine individual and population phenotypes, including disease risk factors and etiopathogenesis, demands a systems-level approach, Jeremy Nicholson asserted. Understanding the microbiome is a core component of that approach:

  • Who is there? That is, what microbes are present? What genes are present? The gut microbiome alone contains an estimated 3.3 million genes, but scientists know very little about what most of those genes do, or how they interact (Qin et al., 2010).
  • How did they get there? The microbiome is a dynamic system, with gut microbes regularly swapping genes with environmental microbes via horizontal gene transfer. For example, Hehemann et al. (2010) reported that gut microbial metagenomes in Japanese individuals code for seaweed-digesting enzymes that the gut microbial metagenomes of North American individuals do not encode. It is likely that the Japanese individuals acquired the microbial genes from marine bacteria associated with nori. Nori is seaweed traditionally used to prepare sushi, which is a daily component of the Japanese diet. (See the summary of Ellen Silbergeld’s presentation in Chapter 5 for a more detailed discussion of the impact of horizontal gene transfer on the microbiome.)
  • What are they doing (besides digesting seaweed)? In Nicholson’s opinion, metabolic profiling via reconstruction of genomic readouts indicates only what the microbes could be doing, not what they actually are doing.
  • How are they doing whatever it is they are doing? For example, how are they communicating? What metabolic and immunological signals are they sending?
  • How does what they are doing impact the host?
  • Finally, how can all of this knowledge about the microbiome be made into something useful? How can the microbiome be manipulated for health, for example, through diet?

SOURCE: Jeremy Nicholson’s workshop presentation, February 22, 2012.

assess disease risk by measuring metabolite levels. Metabolite analysis falls under the purview of what Nicholson calls “metabonomics,” which he defined as “the quantitative measurement of the multi-parametric (time-related) metabolic responses of complex systems to a patho-physiological stimulus or genetic modification” (Nicholson et al., 1999). Some scientists, such as Fiehn (2002), use a slightly different term: “metabolomics.”

Regardless of terminology, the idea that changes in metabolic products are an indication of disease is not new. For example, urine wheels were



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