Microbiome Research: Hope over Hype

The story of microbiome research is one of hope and hype, both elevated to an extreme and fraught with controversy. You need look no further than popular blogs and high profile review articles to see this conflict play out. 

As a passionate microbiome researcher, I like to highlight the hope that I see -- the hope that humans will be able to understand and harness the microbiome to improve human health. 

The story of hope I have for you today is a story of the heart. The human heart. Well, heart disease. Reducing heart disease, really.

Setup

When I was in graduate school I saw the most fascinating lecture. It was from Stanley Hazen, a researcher at the Cleveland Clinic, and he was describing an experiment in which it appeared that bacteria in the gut were responsible for converting a normal part of our diet into a molecule that promoted atherosclerosis (heart disease). With a combination of (1) molecular analysis of the blood of humans with heart disease and (2) experiments in mice varying the diet and microbes present in the gut, they showed pretty convincingly that bacteria were converting phosphatidylcholine from food into TMAO, which then promoted heart disease (Wang, et al. 2011 Nature). 

Payoff

Fast forward 7 years, and the microbiome research field has advanced far enough to identify the exact bacterial genes involved in this process. Not only that, they are able to inhibit those specific bacterial enzymes and show in a mouse model that levels of harmful TMAO are pushed down as a result (Roberts, et al. 2018 Nature).

 Fig. 5: A microbial choline TMA lyase inhibitor reverses diet-induced changes in cecal microbial community composition associated with plasma TMAO levels, platelet responsiveness, and in vivo thrombosis potential. Schematic of the relationship between human gut commensal choline TMA lyase activity, TMA and TMAO generation, and enhanced platelet responsiveness and thrombosis risk in the host

Fig. 5: A microbial choline TMA lyase inhibitor reverses diet-induced changes in cecal microbial community composition associated with plasma TMAO levels, platelet responsiveness, and in vivo thrombosis potential. Schematic of the relationship between human gut commensal choline TMA lyase activity, TMA and TMAO generation, and enhanced platelet responsiveness and thrombosis risk in the host

Bioinformatics Aside

One aspect of this story that I'll point out for the bioinformatics folks in the audience is that the biological mechanism involved in choline -> TMAO is not a phylogenetically conserved one. It is mediated by a set of genes that are distributed sporadically across the bacterial tree of life. For that reason and others, I am a strong supporter of microbiome analysis tools that enable gene-level comparison between large sets of samples in order to identify mechanisms like these in the future. 

Summary

My hope, my dream, is that the entire human microbiome field is able to eventually follow this path. We observe that the microbiome influences some aspect of human health, we identify the biological mechanism responsible for this effect, and then we demonstrate our knowledge and mastery of this biology to such an extent that we can intentionally manipulate this system and eventually improve human health. 

We have a long way to go, but I believe that this is the path that we can follow, the example we can aspire to. I hope that this story gives you hope, and helps cut through the hype.