The Need for Caution in Microbiome Science

Those of us in the probiotic field are familiar with the criticism that probiotics are more hype than science. An article by Willliam Hanage (2014) in this month’s Nature levels a similar warning to those in the field of microbiome science: be careful of exaggerating results. Case-in-point, a recent report from a 2013 meeting (organized by a trans-NIH working group) on the state of microbiome research concluded that the excellent talks underscored “…the potential for microbiome science to produce a revolution in human health.” (Ravel et al. 2014). But Hanage cautions, “The history of science is replete with examples of exciting new fields that promised a gold rush of medicines and health insights but required scepticism and years of slogging to deliver even partially.”

Hanage posits that microbiome science should be understood not through the hype but through the lens of five important questions. I focus on two of those questions here. (All five questions are footnoted below.)

Can experiments detect differences that matter? Showing differences in bacterial communities at the phylum level, for example, ignores a tremendous amount of within-phylum diversity down to the strain level. To illustrate this point, he uses an example from animal communities: “…an aviary of 100 birds and 25 snails would be considered identical to an aquarium with 8 fish and 2 squid, because each has four times as many vertebrates as molluscs.” The action of demonstrating microbiome composition differences, at any phylogenetic level, may also fundamentally miss the point. The important aspect of studies of bacterial communities likely isn’t the specific microbes that are present, but the functional characteristics of the communities. The future lies in such studies.

Does the study show causation or just correlation? The correlation between a disturbed microbiota and disease or sub-optimal health states has been a cornerstone of microbiota research over the past several years. The list of such dysbiotic states is long, including diabetes, obesity, allergy, inflammatory bowel disease and even autism. Knowing that the microbiota is different between healthy controls and people with disease is a first step. But much more important is determining if targeting the dysbiotic state with interventions that can manipulate the microbiota is a key to regaining health, or even better – preventing the disease in the first place.

Probiotics are an attractive option for such manipulation, in some cases backed by convincing intervention studies. Whether as therapy (such as the defined, microbial consortium as an alternative to fecal transplants proposed by Elaine Petrof and colleagues) or as foods/supplements to maintain health and reduce the risk of disease, probiotics likely exert at least some of their influence by interacting with the microbiome.

In both the case of probiotics and of microbiome research, there remains a need for well-controlled, prospective, longitudinal studies. They are necessary to move beyond the era of association studies in the microbiome field. It may be that disease results in (is not caused by) a dysbiotic microbiota, but the dysbiotic microbiota may propagate the disease phenotype. If so, altering the microbiota may lead to attenuation of the disease phenotype. Properly selected probiotics may be an important tool for altering the microbiota, thereby disrupting this cycle.

Footnote:
According to Hanage (2014), five questions to keep from getting “carried away by hype” surrounding microbiome science: Can experiments detect differences that matter? Does the study show causation or just correlation? What is the mechanism? How much do experiments reflect reality? Could anything else explain the results?

References:

Hanage WP. Microbiology: Microbiome science needs a healthy dose of skepticism. Nature. 2014 Aug 21;512(7514):247-8. doi: 10.1038/512247a.

Ravel J, et al. 2014. Human microbiome science: vision for the future, Bethesda, MD, July 24 to 26, 2013. Microbiome 2014, 2:16.

Petrof EO, Gloor GB, Vanner SJ, Weese SJ, Carter D, Daigneault MC, Brown, EM, Schroeter K, Allen-Vercoe E. 2013. Stool substitute transplant therapy for the eradication of clostridium difficile infection: ‘RePOOPulating’ the gut. Microbiome 1:3.