Despite nearly two decades of research and increasingly complex data collection, a single core “healthy” microbiome remains elusive. Read on as I share some key insights that bring together systems biology, immunology, microbiology, and ecology to help reframe how we think about the gut.
Last week, I had the distinct pleasure of meeting Dr. Andreas Baumler and several members of his laboratory at UC Davis. Dr. Baumler has been studying host-microbe interactions for the better part of the last three decades and is considered a leading researcher in the field of microbiology. His past work was primarily focused on the microbes responsible for gut infections, using mouse models to study the interactions of Salmonella with the gut mucosa.
Dr. Baumler’s lab has increasingly moved towards elucidating host-microbe interactions in non-infectious diseases as well. It was his lab that first identified the oxygen-dysbiosis connection, and ongoing experiments are exploring the implications for irritable bowel syndrome, inflammatory bowel disease, and colorectal cancer. They are truly doing some ground-breaking work.
In recent years, his lab has also published a number of review papers that help outline a new context for microbiome research. Simultaneously scientific and philosophical, and drawing on concepts from microbiology, immunology and ecology, this interdisciplinary framework outlines several key missing pieces for gut research and our understanding of the microbiome.
Together, they help to explain things like:
- why a “healthy” microbiome is such an elusive concept
- why probiotics don’t typically colonize the host unless perturbed with antibiotics
- why scientists have struggled to define gut dysbiosis, despite masses of data
In this article, I’ll aim to summarize these new frontiers and break down the core concepts. This topic is fairly technical, but I’ll try to weave in some takeaways and actionable insights throughout and provide a summary section at the end!
The germ-organ theory of chronic disease
Hippocrates famously said, “All disease begins in the gut” around 460-370 BCE, but it would be nearly two millennia before modern science would develop the tools to begin to understand the role of the gut in disease.
In the late 19th century, Robert Koch and Louis Pasteur demonstrated that diseases like tuberculosis, cholera, and anthrax were caused by specific bacteria. This “one microbe, one disease” concept came to be known as the germ theory of disease. Germ theory served as a foundational framework for a ‘golden age’ of advances in microbiology and medicine throughout the early 20th century and was essential for expanding our understanding of infectious diseases.
In only the last few decades, advances in DNA sequencing have made it possible to characterize microbes across a wide range of chronic, non-infectious diseases, including cardiovascular disease, obesity, diabetes, cancer, arthritis, allergies, asthma, and neurological conditions. We’ve come to realize that our normal gut flora is important for the health and function of many diverse body systems.
Unlike infectious diseases, however, chronic diseases cannot be traced back to a single pathogen. Instead, they are characterized by “gut dysbiosis”, or a generally altered state of the gut microbiota:
“…while the germ theory provides a theoretical framework for communicable diseases, there is a need to develop a new theoretical framework that explains how host physiology balances the gut-associated microbial community and how defects in host physiology disrupt this balance, thereby linking microorganisms to non-communicable human diseases.” 1
In 2005, researchers in Ireland proposed that the gut represents ‘a forgotten organ’.2 This concept of the gut as a microbial organ was generally accepted by researchers at the time but remained fairly elusive due to a lack of understanding of how gut tissue and the gut immune system interact with and shape the gut microbiota, and vice versa. Researchers instead took to characterizing the gut microbiota in health and disease:
“Our poor understanding of gut homeostasis has shifted the focus to aspects that are easier to grasp, such as the association of disease with the presence or absence of individual microorganisms.” 1
This search for the illusory microbes that underly chronic disease follows the framework of the original germ theory, though, and fails to consider the importance of the ecosystem as a whole in determining the health status of the host.
In a recent issue of Nature Reviews Microbiology, Drs. Litvak and Baumler encourage reviving the forgotten organ concept and propose a new germ-organ theory of chronic disease, which states that dysfunction of the microbial organ as a whole is a cause or significant contributor to many non-communicable diseases.1
Systems biology: the whole is greater than the sum of its parts
This concept of a microbial organ demonstrates the importance of systems biology. The gut is a complex system, a concept that even the best gut enthusiasts and microbiome researchers can forget in our excitement to understand individual microbes, metabolic pathways, and other components of gut health.
We love the idea that if we can just modulate our Bifidobacteria or increase our Faecalibacterium, our gut will be restored, and our health issues resolved. It’s simple. It’s easy to understand. But it fails to recognize the true complexity of our ‘microbial organ’. I can’t tell you the number of people I’ve seen who will disregard how an intervention affects their symptoms or overall health and well-being in favor of how the intervention affected their abundance of Akkermansia or Lactobacillus!
The reality is: our gut is not the gut microbiota, gut immune system, gut epithelial cells, and enteric nervous system as distinct entities, but the integrated and dynamic interactions between these components and between the gut and the rest of our physiology.
For instance, elevated blood glucose has been shown to impair the integrity of the gut barrier, leading to gut dysbiosis. Prevotella copri has been associated with improved insulin sensitivity but is also associated with autoimmune disease. Host nutrient status can determine the immune function in the gut, thereby regulating the gut immune system and shaping which microbes can thrive. And our stress levels can impact the gut immune system and the microbes that can thrive.
These examples illustrate why context matters, and why systems biology, or systems thinking, is absolutely critical to understanding and improving the health of the gut. When you modulate one microbe, you are inevitably affecting the entire system. And chances are good that the presence or absence of one or two microbes are not the cause of your health issues.
I’m hopeful that this new germ-organ theory proposed by the Baumler lab will provide more researchers with the incentive to explore the gut as a complex, integrated system and expand our limited understanding of how gut-targeted therapeutics affect the system as a whole.
Until then, this means that we should put greater confidence in therapeutic interventions that seem to intervene upstream, impacting the entire gut system (and our entire body) as a whole, rather than targeting any component in isolation. First and foremost, this includes optimizing lifestyle factors like diet, exercise, sleep, stress management, circadian rhythms, time in nature, and social support.
Other interventions that exploit our physiology, like supplements or medications, may have the ability to shift the gut back into a state of homeostasis, but should be used with caution since we do not understand how they impact the entire system. Those things that are more aligned with our natural physiology, have been tested in clinical trials, and have demonstrated benefits in an entire living organism without significant side effects are most likely to be exerting positive effects on the overall system.
For more on systems thinking and how it applies to health optimization, I’d highly recommend watching Dr. Josh Turknett’s talk from the Ancestral Health Symposium 2019.
More data has not yielded greater understanding of our microbial selves
This systems perspective may explain why advances in data collection have not brought us any closer to determining what constitutes a healthy microbiome. DNA sequencing revolutionized the study of microbes, allowing for large-scale projects that would characterize the human microbiome in health and disease.
Interest quickly moved beyond 16S (“which microbes are there?”) to metagenomics and metabolomics (“what are they doing?”). However, despite these advances in technologies, the massive datasets they produced, and more than $1.7 billion of spent research funds, we are really no closer to determining what constitutes a healthy microbiome.3
Much of the excitement around cataloging the human microbiome paralleled the excitement in 2003 about the Human Genome Project. Many people believed that having the entire human genome would finally lead to cures for all human diseases. Of course, we now know that genetics are just a small component of determining our risk for chronic disease. Even 17 years later, the human genome has provided little benefit to our understanding of chronic disease.
So, we next turned to the microbiome. The Human Microbiome Project (HMP), first launched in 2008, was hugely impactful in informing our understanding of the microbial world inside of us. However, like the Human Genome Project, the HMP and other large-scale microbiome studies were simply not the panacea of gut and overall health that we might have expected.
Still, there remains the belief that with more data, complex machine learning, and other supercomputing techniques, we’ll finally have enough data and power to make some hypotheses. Fortunately, some scientists, including Lita Proctor, former HMP Coordinator, are speaking up against continued cataloging and calling for the need for a new, interdisciplinary approach:
“In my view, most of the research so far has placed too much emphasis on cataloging species names. We’ve been characterizing the human microbiome as if it were a relatively fixed property to be mapped and manipulated — one that is separate from the rest of the body. […] Developing a new conceptual framework and applying it to the human microbiome will require much more collaboration between investigators working across disparate fields, including evolution, ecology, microbiology, biomedicine, and computational biology.” 3
Some researcher groups, including Dr. Baumler’s lab, have begun to take this interdisciplinary approach, blending concepts from microbiology, immunology, ecology, and evolution into their understanding of gut microbes In the next few sections, I’ll introduce several concepts from these fields and their implications for how we think about the gut in health and disease. First up: immunology!
Microbiota-nourishing immunity & host control of the ecosystem
We don’t have the same microbiota on our skin or in our nose as we do in our gut. This is because the environment shapes which microbes can survive in each of these body regions. Over millions of years of co-evolution, regulatory systems in each region of the body have shaped our microbiota to be beneficial.4
Our immune system plays a particularly crucial role in determining which microbes are able to colonize and survive. Any invading pathogens are certainly cleared quickly, but other factors are secreted into the gut to shape the ecosystem to benefit the host. In a 2019 review published in the journal Immunity, Drs. Litvak & Baumler propose that we can actually think of these functions as two distinct arms of the immune system:
“Whereas sterilizing immunity removes microbial intruders from tissue solely through host-derived antimicrobial immune mechanisms, microbiota-nourishing immunity repels pathogens from host surfaces using a microbial organ.” 5
In other words, any host mechanism that shapes the gut microbiota to be beneficial can be considered “microbiota-nourishing immunity”. Examples of such mechanisms include:
- Peristalsis (the smooth muscle contractions of the GI tract that move contents along)
- Antimicrobial peptides (small molecules that inhibit the growth of certain microbes)
- Immunoglobulins (antibodies produced by gut immune cells that can bind to certain microbes)
- Mucus (the protective layer that lies on top of the gut epithelium, reducing contact between microbes and gut tissue and serving as a food source for certain bacteria)
- Lack of oxygen (withholding this growth-limiting resource prevents overgrowth of facultative anaerobes like coli, Salmonella, and other opportunistic pathogens.
These components have actually received some attention in the context of small intestinal bacterial overgrowth (SIBO). However, they are highly relevant to shaping the ecosystem of the large intestine as well.
What does this mean for someone trying to improve their gut health? Most gut therapeutics like antimicrobials, probiotics, prebiotics, and even FMT have focused on targeting the microbiota itself. However, a truly systems-based approach would seek to support the microbial organ as a whole through boosting microbiota-nourishing immunity and supporting gut epithelial metabolism. This will kick in the built-in, evolved mechanisms upstream that shape and support a healthy gut microbiome. In my work with clients, I’ve found this approach to be much more successful than targeting the dysbiosis alone. Stay tuned for my upcoming coursee on the gut mucosal immune system!
Nutrient-niches and functional redundancy in the gut microbiome
Next up: ecology! The composition of the gut microbiota varies greatly between individuals. On average, any two people only share about a third of their gut microbiota. This high interindividual variation in microbial composition is one reason why it has been so difficult for researchers to develop a consensus of what constitutes a “healthy” gut microbiota.
However, when we look at the metabolic potential of the gut microbiota across these individuals, we find something rather peculiar. Despite the lack of shared microbes, the total functional capacity of the microbiome is quite similar from one healthy individual to the next.6 In other words, the common “healthy” core is at the level of microbial functions, not the level of microbial species. Many species can perform the same metabolic functions, a concept referred to as functional redundancy.
Another way to explain this is that multiple microbes can fill the same nutrient-niche. A niche is a multidimensional space of resources and environmental conditions that together define where an organism can survive and grow. In the gut, this niche space is thought to be largely determined by the host diet, and to a lesser extent, substrates secreted into the gut by the host, immune status, and health status.
In 1983, Rolf Freter posited the nutrient-niche theory, which states that ecological niches in the gut are defined by available nutrients and that a species can only colonize if it is able to most efficiently use a particular limiting nutrient. The theory has since been supported by numerous diet supplementation studies showing that prebiotics can alter gut composition by altering the available nutrient niches.
The founder hypothesis explains variation in composition
So, what determines which particular microbes will assemble in your gut? The mechanisms that underly assembly and structure of the gut microbiota are still far from fully understood, but one idea that has been supported by colonization studies is the founder hypothesis.8 This states that the first microbe to the scene has a competitive advantage and will gain priority access to a particular nutrient-niche – first come, first served. Once that nutrient niche is filled, any other microbes that require that particular nutrient-niche will find it very difficult to colonize. This is a concept called colonization resistance.
Amazingly, this means that most of the variation in our microbiota composition is simply due to the somewhat random sequence of exposures to microbes in early life that fill our available nutrient-niches. This may be why early life events that influence the microbiota are so crucial for determining health later in life.
This also explains why the healthy adult microbiota is surprisingly stable over time. Colonization resistance prevents new microbes from un-seating our founding microbes. This is crucial to conferring protection against potential pathogens. For instance, Dr. Baumler’s group recently demonstrated that the presence of commensal Enterobacteriaceae protects against Salmonella colonization through consuming all of the available oxygen in the gut.9
However, it also prevents colonization by microbes we might intentionally try to introduce, like probiotics. If they have no new or unique nutrient-niche to fill, they fail to outcompete the microbes already in the gut. (In some cases, providing a probiotic with a unique prebiotic that supports its growth may allow for improved probiotic colonization.)
The exception to this, of course, is after antibiotics. Antibiotics “un-seat” microbes from their nutrient-niches, allowing a new sequence of colonization events determine the resulting composition of the microbiota. I’ve discussed before why introducing a few isolated organisms (i.e. probiotics) after antibiotics may be counterproductive, since they will fill all of the available nutrient niches, preventing the return of the native microbiota. However, this may also explain why pretreatment with antibiotics may enhance the efficacy of fecal microbiota transplant (FMT).10
Other disturbances may also alter the array of available nutrient-niches. Certain pathogenic organisms have been shown to use their virulence factors to open up new nutrient-niches in the gut that allow them to colonize and survive.11 Gut inflammation itself has also been shown to impact the nutritional environment of the gut.12
What this means in practice: if we’re trying to modify the gut microbiota, we really need to alter the nutrient niches available. This might mean the need to alter the diet, introduce new substrates in the form of prebiotics, or support the gut immune system and gut metabolism to reduce inflammation and re-establish host control over the gut.
Dysbiosis as a state of organ dysfunction
With this interdisciplinary, systems biology perspective in mind, it no longer makes sense to define dysbiosis purely in terms of the microbes themselves. After all, just as there are multiple states of a healthy gut microbiota, there are equally infinite possible states of gut dysbiosis.
Tiffany et al. propose that instead, dysbiosis should be viewed as a state of microbial organ dysfunction, where the host no longer maintains proper control over the ecosystem:
“We propose that dysbiosis is a biomarker of a weakening in microbiota-nourishing immunity and that homeostasis can be defined as a state of immune competence. Microbiota-nourishing immunity thus provides a conceptual framework to further examine the mechanisms that preserve a healthy microbiome and the drivers and consequences of dysbiosis.” 13
In other words, while it may still be useful in many cases to assess microbial composition, we should instead be asking what the state of dysbiosis implies about the lack of host control over the ecosystem, microbiota-nourishing immunity, and gut metabolism.
For instance, one common signature of gut dysbiosis, low butyrate-producing microbes and elevated Proteobacteria, is a sign of epithelial energy dysfunction. Very high abundance of Akkermansia is usually a sign of non-specific gut inflammation and possibly malnutrition.14 Characterizing which host mechanism dysfunctions underly the different patterns of gut dysbiosis may aid to more targeted gut therapeutics in the future.
Summary & key takeaways
1) The gut is a microbial organ that affects a wide range of chronic diseases. Dysfunction of the organ as a whole is connected to chronic disease, rather than the absence or presence, underabundance or overabundance, of one or two microbes.
2) A systems biology approach is key to understanding gut health and how it influences our physiology. The gut is a dynamic network of interactions between microbes, the immune system, the gut barrier, the nervous system, and the rest of our physiology. We should always start by reducing evolutionary mismatch to optimize the system as a whole.
3) The host exerts top-down control over the ecosystem, shaping it to be beneficial. The immune system and other host control mechanisms determine which microbes can thrive in the gut. Dysbiosis can therefore be seen as a lack of immunocompetence and a loss of control over the ecosystem.
4) “Random” exposures may explain our variation in microbial composition, but the functional capacity of the gut is defined by distinct nutrient niches. Rather than looking at microbial abundances and trying to fit them within defined reference ranges, perhaps we need to rely more on gut metabolic capacity or other markers of gut health.
5) The priority for microbiome research needs to be a greater focus on interdisciplinary study, utilizing knowledge from microbiology, immunology, evolution, and ecology, rather than just cataloguing microbial species. I look forward to incorporating more of these concepts into future articles and courses, as understanding these areas is critical to helping us understand how to restore gut health across individuals.
What do you make of this new interdisciplinary framework? How does this shape your view of gut health? Be sure to comment below and subscribe!