Myths, Facts, and Mysteries Surrounding the Gut Microbiome

Geoffrey A Preidis, MD, PhD, from the Baylor College of Medicine, Jack Gilbert, from University of California San Diego, Eugene B. Chang, MD, from the University of Chicago, and Sean Spencer, MD, PhD, from Stanford University School of Medicine, Puma Kashyap, MBBS, from Mayo Clinic, and Jessica R Allegretti, MD, MPH, from Brigham and Women’s Hospital fielded questions from the moderator and the attendees. Major themes included:

Defining a healthy gut microbiome.

The gut is a unique place, where diet, the microbiome, and the immune system interact. The goal is to understand how all three work together and then manipulate each to improve overall health. The field is not able to measure the “health” of the microbiome that is relevant to the clinical setting. The healthy microbiome must be defined first in order to use it for diagnosis or treatment of disease through precision interventions. Lack of disease does not always mean an individual is healthy, and there are many factors outside the gut microbiome that influence health. Aging is a process of oxidative stress and inflammation; theoretically, a “young” microbiome that counteracts these processes could be seen as a “healthy” microbiome. It is far easier to characterize a disease-associated gut microbiome.

Lack of reproducibility among clinical trials.

Available data comes from clinical trials that were small, underpowered, and used unvalidated methods. If potential microbiome predictors of health were found in the gut, the studies are not able to be replicated. There is a need for standardized quantification of specific characteristics of the microbiome that are associated with particular health outcomes. In every other disease state, normal ranges and thresholds of various biomarkers are defined; aspirationally, this could be done for the microbiome as well.

The functional gut microbiome.

There is a need to view the gut microbial community as a whole, with interspecies interactions that create a shared metabolic output that affects human health. The gut microbe cannot be reduced to just the numbers and types of species present based on gene sequencing. It needs to be defined based on the metabolic output as a whole. The field also needs to expand its focus beyond gut bacteria metabolism of polysaccharides, and understand enzymatic activity and metabolic output in response to diet, as well as hormones at key points in the lifespan, medication exposures, physical activity, and social determinants of health. It is not sufficient to take a reductionist approach and focus on a few species.

Combining methods for a more global view.

New tools, from next-generation sequencing to functional analyses, are making it possible to understand what gut microbes are doing that affect human health, but the field remains nascent. Classical techniques, such as animal modeling, need to be applied along with newer methods to characterize every aspect of gut microbiome components and their collective function.

Changing behavior to improve clinical care.

One of the biggest future challenges is how to convince people to change their behavior in response to what is learned about diet, the microbiome, and health. Will knowing that you have a disease associated with the gut microbiome be sufficient to change behavior? The field will need to venture into social science to move microbiome research into clinical care.

The newborn gut as a test case.

The simplest system within humans is the newborn gut, which is primarily sterile, but the first stool samples have microbial species. This discovery has yet to be translated into gut microbiome therapeutics for infants, to prepopulate the infant microbiome and set them up for a lifetime of metabolic health. This may be a low-cost way to normalize what a newborn gut “should” look like.

Current microbiome therapeutics.

There are only two FDA-approved microbiome therapeutics for the treatment of C. difficile infection, and many phase 3 trials are underway. It is not clear who will benefit from these treatments and there are significant disparities in access.

Engraftment vs. safety concerns.

One ongoing debate in microbiome therapeutics is whether it is preferable to achieve engraftment and colonization, or have the treatment ultimately leave the body. On one hand, engraftment is a measurable endpoint that can be correlated to clinical outcomes. On the other, non-colonization may be associated with greater safety, with more control over the therapeutic effects. In some cases, what the therapy “leaves behind,” such as metabolites or stimulated pathways, may be more important than the microbes themselves. In reality, the answer is dependent on context.

Engraftment as ecosystem management.

Live biotherapeutics (LBTs) are modifying the ecosystem to a new state. Engraftment represents management of the new state and produces a larger efficacy signal in trials. The challenge now is defining the “native ecosystem” and accurately measuring the relevant changes to the ecosystem that occur following treatment. This data is essential for improving LBTs.

Therapeutic development challenges.

The field has jumped to develop microbiome therapeutics without strong evidence. The pipeline is large but slow moving because designing trials is difficult without knowing exactly what outcomes to measure. Many studies measure changes in symptoms rather than changes in the gut microbiome in response to microbiome therapy. The C. difficle indication was a promising start, but it is still not clear why FMT worked. Now LBTs are being applied to address complex diseases, such as obesity, without knowing what needs to be changed in the gut microbiome in order to have a health effect. As a result, funders see microbiome studies as risky. Most of the gut microbiome targets being investigated are also modifiable with diet, which is not a druggable target. Industry is not investing in food-as-medicine programs.

Inclusion criteria could incorporate baseline microbiome function, but again, it is not clear how to measure it. Trials could be designed with subsets of patients that have specific microbial functional “lesions” that can be corrected by engrafting microbes that reintroduce that function, for example, a missing metabolite that is reintroduced to recover an important pathway. Removal of oxylate to prevent kidney stone formation is another example of a simple and targeted application.

View of commercial activity.

Most of what is seen is marketing is based on assumptions rather than scientific evidence. The industry has been booming over the last decade with home microbiome testing kits and specific prebiotics to “fix” a “dysbiotic” microbiome. It is leading to additional anxiety and unnecessary testing. However, there is a large opportunity for collaborations with industry to conduct microbiome research and overcome the “noise” so that the field can move the forward.

Origins of the gut microbe.

Although there are several theories, one is that the gut microbiome co-evolved with the body, with co-dependency between the two. This theory explains why gut microbiomes are species-specific. Gut microbes and the body’s immune system are two sides of the same coin, which may reveal specific pathways as therapeutic targets.

The gut microbiome as an element of resilience against disease.

An ongoing question is medicine is not “Why does this person have a disease?” but rather “Why doesn’t everyone have this disease?” It may be that the gut microbiome is a source of resilience against disease development, particularly for diseases with long prodromal periods. In this setting, FMT and LBTs might be preventive, which will require very large longitudinal studies to explore.

Need for medical education.

It will be important to introduce the concept of microbiome therapeutics early in medical education to ensure that future doctors are familiar with the terminology and have a foundation to analyze the data from microbiome studies.