People often ask me for a quick description of the human microbiome. I appreciate their interest, although it’s actually a difficult request: the microbiome is extensive and capable of vast range of behavior. Nevertheless I’ll usually say something like this:
“When I refer to human microbiome I’m talking about the trillions of bacteria, viruses, fungi, bacteriophages and other microrganisms now understood to persist in complex communities in all human tissue and blood.”
But beyond that: how do I best summarize microbiome ACTIVITY? Aka: What are these microbes in and on us are doing?? I’ve learned that most friends expect a response along these lines:
“The microbes in and on us are our friends. They work night and day to defend us from disease, improve our metabolism, break down our food, control our digestion, educate our immune systems and beyond.” In such a description, all the microbes we harbor are portrayed as allies or even heroes: organisms that continually devise ways to benefit or support our health and well-being.
This kind of description is often accompanied by a specific mindset: the belief that microbiome pathogens (those that cause disease) are of secondary importance to those that “help” us. And that to strongly focus on the presence of these myriad pathogens is to give microbes in general an overly “bad reputation.”
In my opinion, this portrayal the microbiome is too one-sided: At the very least it should be accompanied by an asterisk stating something like: “this is an attempt capture microbiome behavior under conditions of extreme health.” And it’s true, of course, that people with extensive microbiomes (take Olympians!) can function with incredible vigor and ability.
But the vast majority of us sustain a range of minor to major inflammatory health issues. Some people deal with acne, others have trouble tolerating or digesting certain foods. Insomnia, anxiety, metabolic problems…are all extremely common in today’s human population. Beyond that, we are living in the midst of an epidemic of chronic disease, in which the incidence of nearly every well-characterized inflammatory condition is on the rise (diabetes, obesity, heart disease, the “autoimmune diseases” to name just a few). In fact, an estimated 60% of Americans suffer from at least one chronic condition (and that number only includes people who have been officially diagnosed).
A growing number of these inflammatory conditions/symptoms are tied to microbiome dysbiosis: cases in which a microbiome community shifts towards a state of imbalance. This dysbiosis can be severe: pathogens tend to outcompete their more symbiotic neighbors, leading to drops in community diversity that promote an inflammatory environment.
This means that in the vast majority of people, the microbiome is acting in a nuanced fashion. Some of the microbes we harbor may perform health-related functions, BUT a significant number of others may be acting as pathogens. In fact, certain pathogens are so effective at promoting chronic symptoms that they can “push” the microbes around them towards a dysfunctional state. These pathogens are sometimes called “keystone pathogens.” A good way to remember that is that the activity and gene expression of keystone pathogens are KEY to promoting disease.
In my opinion then, it is vital that we continually recognize and encourage the general public to understand that persistent, chronic, pathogens can also play a central role in any microbiome community. To do so is not giving microbes a “bad reputation.” It is simply accurate. In fact, the current, alarming epidemic of chronic disease begs that we study these persistent pathogens with more urgency than ever before.
It also helps to interpret microbiome activity via the lens of evolutionary biology. When microbes are described as “friendly” people often assume that there is actual intent on their part to help us. In reality, any symbiotic or “commensal” microbe/human relationship is still driven by the most basic tenants of evolution: “survival of the fittest” and “reproductive fitness.” The goal of any microbe in/on our bodies is to stay alive and pass its genes (encoding its particular traits and characteristics) to the next generation. So if a microbe is, for example, breaking down our food, it’s because doing so also benefits its own ability to survive and reproduce. The fact that such behavior also helps its human host is simply an evolutionary coincidence.
In most ecosystems on earth (like the rainforest), commensal relationships are actually rare. This is partly because one species in a commensal relationship has only to slightly change its gene expression and/or metabolism for the relationship to shift, and begin to favor one species over the other. This “shifting” happens very easily with microbes because they can quickly adjust their gene expression patterns: they turn certain genes “on” or “off” in order to functional optimally under different environmental conditions. Microbes can also – through a process known as “gene transfer” – acquire completely new genes: genes that allow them to function in totally new ways. And, as with most organisms, a chance mutation in a microbe’s genetic code (their DNA or RNA) can endow it with yet other novel traits and abilities.
Take E.coli. Strains of E.coli are detected in almost every analysis of the human microbiome, even in studies conducted on healthy people. This makes sense, since people digest seemingly innocuous E.coli strains on a regular basis. But most of us are also familiar with E.coli’s ability to cause severe food poisoning and other forms of illness. This range of E.coli behavior is due to the fact that it can evolve to persist in many, many different states – some WAY more pathogenic (or able to cause disease) than others. Take a study done by researchers in Portugal. The team found that when “commensal” E.coli were exposed to human white blood cells, they rapidly mutated and changed their gene expression: the commensal E. coli evolved, in less than 500 generations, into virulent, or disease-causing, clones. When these virulent clones were injected into mice, the mice suffered an increase in inflammatory symptoms.
This “virulence”, or ability of a microbe to cause disease, is dictated in large part by the activity of genes that express “virulence factors”: molecules that help bacteria, viruses and other microbes better persist inside the cells of the immune system, better penetrate host tissue, better obtain key nutrients from the host, better produce toxins…and better engage in many other behaviors that cause human health to suffer.
Every microbiome community (even in healthy individuals) harbors microbes capable of expressing these virulence factors. These include potential pathogens present in the earliest microbiome communities that an infant inherits from its mother (microbes generally acquired via the placenta, vaginal canal, and/or breast milk.) In other words, every human is “seeded’ with potential pathogens from the beginning of life.
It follows that pathogens capable of expressing virulence factors can evolve and “emerge” from microbes already present in a “healthy” microbiome community. Let me give you an example. Researchers in England recently published a paper called “Severe infections emerge from commensal bacteria by adaptive evolution.” The team studied the bacterial species S.aureus. Like E.coli, S.aureus is frequently detected in the nasal (nose) microbiome of healthy individuals. However, S.aureus can mutate and change its gene expression so profoundly that it can also cause life-threatening infections.The English research team found that these life-threatening strains of S.aureus could easily descend from commensal S.aureus bacteria already colonizing a person’s nose. In other words, depending on conditions in the body, S.aureus is able to mutate from a harmless microbe to a major pathogen within the same person. This progression towards virulence involved an increase in the activity of genes that promote toxin production, abscess formation, immune evasion and many other processes that harm the human host.
Also key to the study’s findings was that, in the majority of cases, this within-person evolution towards S.aureus virulence occurred in subjects that had “risk factors for infection”: these included a weakened immune response, co-morbid conditions (the subject was sick with one or more inflammatory diseases), and/or medical interventions (subjects had undergone surgery or a procedure).
That brings me to my main point. To best understand microbe behavior we must not ignore the elephant in the room: the human immune system. The human immune system, and its extensive army of immune cells and antimicrobial molecules, plays the greatest role in determining how the microbes in any human ecosystem act, survive, and behave. Lately I’ve been describing this relationship with the following analogy:
“Imagine a school. The children in the classroom are different microbes in a human microbiome community. The teacher and her support staff (like the principal) are the human immune system. Some of the children in the classroom are trying hard to get work done. Others are not so studious and hope to cause trouble. But these potential “bad students” don’t act out when the teacher is in the room and they can be disciplined by the principal and other staff. HOWEVER – if the teacher leaves the room, and her support system dwindles, these “bad influence” students can easily change their behavior to cause trouble. Without supervision they stop doing work. Further, they begin to encourage the better students around them to join them in promoting disorder. Little by little, even the best students find it hard to behave in the unsupervised classroom environment.”
For example, take the bacterial species Lactobacillus (which is added to many common probiotics). It is often regarded as a purely “good” microbe. However, as this article on the vaginal microbiome points out, some strains of Lactobacillus help maintain a healthy, acidic vaginal environment. BUT other strains can put women at a higher risk of acquiring a sexually transmitted infection. Indeed, Willa Huston, a professor at the University of Technology Sydney states the following about Lactobacillus and vaginal health: “It depends on the type of Lactobacillus, it might depend on the function of that Lactobacillus…and perhaps how it’s interplaying with the genome type of the woman.”
If you’re not convinced, let me give you a great example of how a “good” microbiome community can go bad (evolve in a direction of virulence). We’re all familiar with the fact that our teeth can develop cavities. The process that drives this cavity formation is called periodontitis. Periodontitis is now understood to be an infectious condition in which different oral microbes work together to damage tooth tissue and bone.
But aside from teeth brushing, what factors determine if a tooth develops a cavity or remains healthy? A team in Boston addressed this question by studying how the entire oral microbiome changes its gene expression during cavity progression. They found that community-wide gene expression did not change in teeth that remained cavity-free. But, the oral community dramatically altered its gene expression in sites that progressed to periodontitis. These changes involved genes that control oxidative stress, iron transport, sulfur metabolism, intracellular survival, and bacterial movement among many others. Cavity formation was also correlated with increased expression of virulence factors and higher levels of viral activity.
The team concluded that the entire oral microbial community, and not just a few select pathogens, drives the increase in virulence that leads to periodontitis. In effect, under conditions of increasing immune suppression, imbalance and inflammation, the whole oral microbiome community appeared to act together as a pathogen. This was supported by the fact that, in cavity sites, groups of microbes not usually considered to be pathogens expressed a large number of the disease-promoting virulence factors. Two of these microbes were S.mitis and S.intermedius – bacterial species usually associated with dental health that are commonly described as “good.”
Many cavity forming microbes also team up to persist in communities called biofilms. These biofilm communities are surrounded by a matrix that protects the different microbes inside from the human immune system. Participating microbes use electrical and chemical signals to communicate. This allows them to split up jobs important for their own survival – for example, virulent bacteria may protect the biofilm from outside intrusion, while other bacteria on the inside focus on obtaining nutrients for the community.
Few people would argue that microbes in a biofilm are “helping” their human host. They have instead joined forces in a manner that promotes their own survival over ours. It’s not surprising then that biofilms are connected to an increasing number of inflammatory conditions. In fact, some researchers estimate that the majority of bacteria in the body persist in a biofilm state.
So the way I see it, the human immune system and the human microbiome are actually in a continual state of competition and evolution. In healthy people the immune system has gained “an edge” over the microbiome. It is successfully able to keep microbiome pathogens in check. In inflammatory disease however, the opposite happens. The microbiome – or pathogens (or groups of pathogens) – begin to gain “an edge” over the human immune system…and its various defense strategies. This last situation is especially true in our modern world where an increasing number of environmental exposures and drugs are wearing down the human immune system.
And that’s what I’ll be talking about in one of my next podcasts: What factors most knock down or debilitate the human immune system in our modern society? And how can we help bring our immune systems back to a state of better activity and health? – a state that will help keep our microbiomes in a state of balance.
I will also do another podcast that explains more about how pathogens, and the metabolites they produce, are able to interfere with the human immune system and human pathways that control metabolism.
Excellent, Dr. Proal. I look forward to your next podcast with much anticipation. Best always, Sherry
Thanks Sherry! I always appreciate your support and kind words:)
Thank you for your podcasts. I have just recently subscribed and am very pleased with their informative and challenging content.
Thanks for writing. So glad you find this site interesting. There are many more topics to discuss so stay posted!
This is fantastic – great to see our work on Staphylococcus aureus discussed in this wider context. The challenges to studying it are huge, but the human-pathogen interaction has got to be the unit we aim to understand.
Thanks for your comment. Your study on S.aureus virulence/adaptive evolution is major. Keep up the good work (despite its challenges!) and I look forward to reading your next papers.
Interesting to read….Dr Proal, you successfully described the characteristics of microbiome in an impartial and balanced way….
Thank you Dr. Dhaka! I really appreciate your support and interest.
Good article. But periodontal disease is not characterised by tooth decay. In fact the tooth loose they attachement when you have PD.
But in tooth decay recent studies have also found evidence of dysbiosis.
Agreed Philipp – I oversimplified there a bit too much. I’ll re-work the working soon.