The advent of affordable, next-generation sequencing technology has democratized the study of the microbiome, the vast collection of microbial life both within and on us, and has enabled the discovery of hundreds of host-microbiome interactions. This has brought with it a wave of optimism, leading scientists and the public alike to seek new avenues for health and a panacea in the microbiome for many diseases. As with all new areas of research, once the initial wave of optimism subsides, we realize that targeting the microbiome will not cure all. However, it is also clear that there are areas where it will be a key strategy. In this article, we will highlight a few of these key areas: infections, host metabolism, cardiovascular disease and pharmacotherapy.
The best-studied example of resistance to pathogen invasion is in C. difficile infection. The disruption of gut microbial community by antibiotics and other factors alters the gut metabolic milieu allowing C. difficile to colonize. Restoration of the microbial community by fecal microbiota transplant or defined microbial communities can drive C. difficile out, effectively restoring colonization resistance. A similar paradigm likely holds true for other infections like Salmonella.
2. Host Metabolism
The role of gut microbiota in regulating host metabolism, including weight gain and impairment of glucose tolerance, is another key area. An example of this is seen with improvement in glucose tolerance by transplanting gut microbiota from lean to obese individuals.
3. Cardiovascular Disease
Gut microbiota was noted to be a driver of atherosclerotic plaques by facilitating the conversion of dietary L- carnitine found in red meat to Trimethylamine N-oxide (TMAO), further confirmed by a complimentary finding that plasma L-carnitine levels with concurrently high TMAO were predictive of increased risk of cardiovascular disease in humans. The recent study on small molecule inhibitors of microbial trimethylamine lyases holds promise as a strategy to curb the epidemic of cardiovascular disease.
The role of gut microbiome in mediating side effects of drugs such as irinotecan for colorectal cancer is yet another example where targeting the microbiome can potentially improve outcomes. While the majority of other findings implicating the microbiome have not yet been translated to impact human health, the above few examples underscore the rapidity with which we are getting there.
There are also significant limitations to understanding the microbiome and related research. The most important of these is lack of a mechanistic approach in studying the microbiome and its effects on the host. To date, the majority of the studies have focused on disease association with changes in microbial composition, with little attention to microbial function, which is much more relevant. But identifying functions within the microbiome is no simple task. In the gut microbiome, at least, it appears that function depends on individual genes carried by organisms at the species/strain level, complicating our search to hundreds of slightly different organisms (as opposed to being able to study a handful of related organisms within the same phylogenetic lineage, i.e. a family). Furthermore, unlike eukaryotic organisms where single genes are translated to single functional proteins, bacteria can utilize multiple gene segments to synthesize a single protein and can switch the synthesis of such proteins, responding to stimuli within the environment, either from the host or from other bacteria or non-bacterial organisms such as viruses and fungi. Efforts characterizing these nonbacterial members of the microbiome are still at their early stages, with limited availability of databases of information on them. Some functions in the microbiome can also be highly specialized, limiting them to certain members of the microbial community, which compose less than 1 percent of the total, complicating the search for them and making them similar to searching for a needle in a haystack.
Lastly, research about environmental factors affecting the function of the microbiome also needs development to make a significant impact on health. One example is diet: research suggests that one factor in the diet that affects the microbiome can no longer be operational when another dietary component is added, and additives in the diet that make up less than 1 to 2 percent of food can have effects on both function and colonization in the gut. Characterizing such interactions and effects of minor components are still difficult, especially on a large scale.
Not only we are just scratching the surface when it comes to determining function, but we are also in our infancy in understanding the variation in the microbiome from one person to another, in our quest for the “healthy/ normal microbiome.” Common demographic factors such as age, race/ethnicity and BMI have little impact on an individual person’s gut bacterial fingerprint, implying that we will need to look for single time events, either in childhood or adulthood, which can have long lasting consequences on microbiome composition and function. Such legacy events can be in individual organisms (i.e., in their appearance or disappearance from the gut microbiome) or in individual gene elements within organisms. These can be passed on from one bacteria to another or through shared genetic elements via viruses, especially bacteriophages. We also now know that the gut microbiome has a luminal and a mucosal component, which differ in terms of their composition, and much work needs to be done to understand the dynamics within these compartments.
It is clear that gut microbiota plays a key role in several functions that are vital for our health, and we have made huge leaps over the past decade in terms of accelerating microbiome research and translating the early findings. We are at a point, however, that this long-neglected organ needs further inquiry. Studying the microbiome in health and disease will likely need long-term and larger scale investigations, collaboration between researchers not only in medicine but also in ecology, epidemiology, nutrition, statistics and computing. Looking for the needles in our large microbial haystacks requires persistence, invention and dedication to finding new animal models, new high throughput experimental and analysis techniques, and the embrace of this multi-dimensional science into clinical research.
Dr. Mutlu has no conflicts to disclose.
Dr. Kashyap has two licenses with Mycrobiomics.