What is a “healthy” microbiome? Is there such a thing? And why does it matter?
Is your microbiome healthy? A seemingly simple question, but the answer is a lot more complex than you might imagine.
It is widely accepted that our gut microbiome is important to health. Many studies have shown differences in the composition of the microbiome of people with and without disease. These findings have sparked the search for microbiome-based biomarkers that could be used to predict individuals at a higher risk for disease and to develop therapeutics to treat disease. But before we can mainstream effective biomarkers and microbiome-based therapeutics, we need to establish a baseline understanding of what constitutes a “healthy microbiome.” And that’s a lot harder than it sounds.
Even “dysbiosis,” our current term for what is “unhealthy” cannot be a consistent marker without a clear understanding of what healthy means. Dysbiosis is used to define a microbiome that has “changed” or shifted in composition (1). It implies that the same microbiome examined over multiple time points shows a shift in its composition. While the term dysbiosis is used in over 10% of scientific papers published on the microbiome, it’s hard to say what dysbiosis means in these cases without consensus on what constitutes a healthy microbiome to use as a baseline (1). Further, most of these papers use the term dysbiosis to describe the microbiome of a person with a disease compared to the microbiome of another seemingly healthy individual. That’s a problematic comparison because it’s still unclear if dysbiosis is a cause or consequence of disease, in part due to the lack of a healthy baseline. The term dysbiosis should only be used when comparing the same microbiome in the same person before and after disease. Further complicating matters is that dysbiosis is disease specific and is inconsistently observed across different studies.
So we don’t have a standard for what constitutes a “healthy” microbiome that we should be aspiring towards. And dysbiosis, the term used for understanding what’s unhealthy or what we should be moving away from, is less useful because of our lack of understanding what healthy means. If the need to establish a healthy baseline for the microbiome is such an important part of microbiome research, what keeps us from doing so?
The obstacles
There are several major obstacles that one must consider when defining a healthy microbiome. First is the sheer number of microbes and the genetic material they contain. Our bodies contain thriving ecosystems teeming with microbes, estimated at roughly 40 trillion microbial cells, a number that is nearly equal to our own human cells (2). If we consider all the genes associated with these microbes then the number of microbial genes in our “collective” microbiome is a number close to, if not exceeding, the number of stars in our night sky. In this vast star-filled sky, how does one identify those stars that are healthy from those that are not?
Another obstacle in defining a healthy microbiome is the uniqueness of each of our microbiomes. There is a huge amount of variability in the composition of the microbiome between individuals, yet this variability is not well understood. In adults, the gut microbiome is stable yet highly adaptable (3). Its high adaptability helps it to respond to changing environmental and lifestyle factors which account for 20% of the variation in composition between individuals, while genetic factors account for only 10% (4, 5). This leaves more than 50% of the variation between individuals unknown and makes your microbiome as personal to you as your fingerprint. Put another way, each microbiome has a unique structure, much like two snowflakes never share the same shape.
The impact of environmental and lifestyle factors on the composition of an individual’s microbiome is another obstacle one must consider when trying to identify a healthy baseline. Our microbiomes are with us from birth, so everything that you experience in your life, these microbes also experience. Whether it is the food you eat, the community you live in, or the stress you carry around - these tiny passengers also are exposed and will respond. Many lifestyle factors are within our control such as diet, smoking, alcohol consumption and BMI, but we have less control over other factors. These include socioeconomic status and geography, which both consistently emerge as major factors impacting composition and variations in the microbiome6. How does one consider these factors in determining a healthy microbiome? Or should they even be considered?
The type of data being generated and the analysis of that data may also confound the hunt for a “healthy” microbiome. Compositional analysis of the microbiome is achieved through the study of microbial genes. This tells us who is there, but does not tell us what these microbes are doing. A seemingly healthy microbiome could be functioning poorly. A better approach may be to perform a metabolic analysis. The advantage to studying metabolites is that while there is a large variability in the composition of the microbiomes between individuals, metabolic function is more highly conserved and less variable. This is due to the redundancy in metabolic pathways between different types of bacteria within the microbiome and suggests that a more functional and less compositional approach may be an important tool for defining a healthy microbiome.
Finally, research of the different microbial players in the gut has been uneven. Most of the work has focused on the bacterial inhabitants with much less work characterizing the viruses and fungi that also are a part of this community. We know that certain bacteria can be more beneficial than others, but what if in the presence of fungi or viruses these beneficial bacteria become harmful? Until we understand these microbial interactions, defining a healthy microbiome may be difficult.
What do we need to do to start navigating (or overcoming) these obstacles?
In defining a healthy microbiome some assumptions and some concessions will likely have to be made.
Accept there will not be a one size fits all definition. A healthy microbiome will likely not be identified as a set of specific bacteria that when found together indicates a pinnacle of health. Instead, a healthy microbiome will likely look very different between individuals but will share some common features.
Go deep on diversity. A healthy microbiome must be diverse. Diversity refers to the number of different bacterial species present in the gut (richness) as well as the number of each of these species (evenness). Diversity is believed to make the gut more resistant to stress related changes. For example, it is harder for infectious, disease-causing bacteria to set up camp and cause an infection in the gut if our microbiome contains a multitude of bacteria that will compete with this pathogen for nutrients and space. Diversity also makes our microbiome more resilient if a stress related change does happen. Resilience is defined as the ability of the microbiome to return to its stable state after a disturbance (such as antibiotic use, or infection). This could be the ability for a low abundant species of bacteria to step in and “take over” for a more abundant bacteria that is reduced due to a stress related perturbation.
Focus on function more than composition. “Healthy” may not depend on who is there but rather on what they are doing. Functional profiling using metabolomics (as opposed to using genetic information) can tell us about the health of the microbiome and reduces the variability between individuals that is so high compositionally. Mapping of functional pathways using metagenomic data can also provide information regarding the functional capacity or potential of the microbiome.
Expand our understanding to ALL members of the microbiome. More research is needed on defining the non-bacterial members of the microbiome and how these microbes influence and interact with each other.
While that scientific work happens, there are moves you can make toward your body’s version of “healthy”
Although a scientifically defined healthy microbiome may be a long way off, there is plenty you can do to make sure your gut microbiome is as healthy as it can be.
Avoid fad and crash diets. Starving yourself also starves your microbiome.
Diversify your diet. This will also diversify your microbiome. Eat fermented foods which contain both probiotic bacteria as well as prebiotics nutrients. Eat vegetables of every color because that color comes from natural compounds called phytochemicals which promote health and act as antioxidants.
Exercise and get enough sleep. Both have been shown to help increase the diversity of the microbiome.
Reduce your daily stress. Meditating, yoga, a daily walk, or whatever calms you can also mitigate unnecessary stress to your gut.
Minimize processed foods and sugar.
In conclusion - getting to a definition of “healthy” is a big job but we should keep trying, while each of us works toward our own version of “healthier.”
Defining a healthy baseline for the microbiome would help scientists and clinicians to better assess changes that occur during disease and could be used as a way to test whether new treatments or therapies are having a desired effect. However, defining healthy is a complicated process because ‘healthy’ is a subjective term and the sheer magnitude and variation of the microbiome between individuals makes it harder to define. Difficult as it may be, the potential outcomes are well worth the effort required. And while the scientific community travels that road, there’s a path to a healthier microbiome for each of us with steps we can control. Let’s do both.
References:
(1) Hooks KB, O'Malley MA. Dysbiosis and Its Discontents. mBio. 2017 Oct 10;8(5):e01492-17.
(2) Sender R, Fuchs S, Milo R. Revised Estimates for the Number of Human and Bacteria Cells in the Body. PLoS Biol. 2016 Aug 19;14.
(3) Antonopoulos DA, Huse SM, Morrison HG, Schmidt TM, Sogin ML, Young VB. Reproducible community dynamics of the gastrointestinal microbiota following antibiotic perturbation. Infect Immun. 2009 Jun;77(6):2367-75.
(4) Wang J, Thingholm LB, Skiecevičienė J, Rausch P, Kummen M, Hov JR, Degenhardt F, Heinsen FA, Rühlemann MC, Szymczak S, et al. . Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat Genet. 2016 Nov;48(11):1396-1406.
(5) Rothschild D, Weissbrod O, Barkan E, Kurilshikov A, Korem T, Zeevi D, Costea PI, Godneva A, Kalka IN, Bar N, Shilo S, Lador D, Vila AV, Zmora N, Pevsner-Fischer M, Israeli D, Kosower N, Malka G, Wolf BC, Avnit-Sagi T, Lotan-Pompan M, Weinberger A, Halpern Z, Carmi S, Fu J, Wijmenga C, Zhernakova A, Elinav E, Segal E. Environment dominates over host genetics in shaping human gut microbiota. Nature. 2018 Mar 8;555(7695):210-215. 6Ahn J, Hayes RB. Environmental Influences on the Human Microbiome and Implications for Noncommunicable Disease. Annu Rev Public Health. 2021 Apr 1;42:277-292.