The Human Microbiome
Microbiome Part 1: Introduction
Key Takeaways:
- The trillions of microbes (bacteria, yeast, fungi, viruses, archaea) that we carry around with us play an important role in human health.
- We are born with very few microbes — most are acquired in our first 3 years of life.
- The microbes in our guts play important roles in breaking down food, making nutrients, and communicating with our immune system.
- We are learning to be better “gardeners” — encouraging some microbes to grow and discouraging others. There is a huge potential to improve our microbiome gardening skills in the future.
There are microbes everywhere. Despite how many times we wash our hands these days, a huge array of bacteria, yeast and other organisms follow us about our daily routines. These tiny, microscopic organisms (microbes) live in communities on our skin and in our mouths, guts, and other parts of our bodies. Over the last decade, we learned that these communities of microbes play a key role in keeping us healthy. We started referring to these communities by a catchy name — the “human microbiome”.
If you are also slightly late to the microbiome hype train, welcome. Understanding and collaborating with our microbes is a huge opportunity to improve human health, and an opportunity for entrepreneurship as well. This is an incredibly rich area, which a few blog posts can’t entirely do justice. For starters, I highly recommend Ed Yong’s book I Contain Multitudes (2016), [1] which blew my mind multiple times and gives a beautiful account of big discoveries in this space. Through this post, I hope you get a flavor of why our microbiomes are important, and why investment in this space is increasing.
The Microbes Inside Us
What are these trillions of microbes, and where do they live? How did they get there in the first place? What are they doing there? A healthy $1.7B [2] has been spent on human microbiome research in the past ten years to begin answering these questions and more.
Although we typically think of microbes (specifically bacteria) as disease-causing germs to be destroyed, the vast majority of the microbes on us, and within us, are neutral or even beneficial. A healthy person’s microbiome contains more than 10,000 different species of microbes. [3] Your skin, mouth, nose, gut, lungs, genitals, and other organs all contain distinct ecosystems, determined by temperature, acidity, oxygen levels, nutrients, and the local human cells. These communities are mostly made up of many species of bacteria, but yeast, fungi, viruses and archaea can also be present. (Note: viruses are not technically alive — sometimes they are included in the definition of microbe, sometimes not.)
Today almost all of these communities are being actively researched, and companies are springing up to help us get to know our microbes better. To touch on a few of these ecosystems:
The environments experienced by the microbes on your skin vary from dry and bright to dark and moist. Dry areas are the most diverse because of their higher exposure to the environment — surprisingly, only 1/6th of the microbes on your right hand also inhabit your left! [4] While most skin microbes can tolerate oxygen, the bacteria that causes acne, Propionibacterium acnes*, hates it — however, it can thrive deep in sweat glands. Our armpits are an entirely different environment, harboring bacterial chemical factories that convert sweat, hormones, etc to create our signature body odor. [5]
*A quick note on scientific names for microbes: They are long and terrible. Here’s a hack: when you see a name like Bifidobacterium, mentally rename it something that makes sense to you, like “Fido” or “David Bowie”. Or skip over them entirely.
Our mouths also harbor a huge array of microbes — over 700 species. Dental plaque contains a lot of microbes, their effects on oral hygiene are a big topic of research. Comparatively, the stomach is so strongly acidic that only a few acid-tolerant microbes make it their home.
The gut takes the main stage in human microbiome research. If you were a country for bacteria to occupy, your gut would be New York City. By far the greatest number and diversity of microbes live in our guts —along your stomach, small intestine, large intestine, through the rest of the waste management system. Each segment is like a different neighborhood, with different species and densities of microbes. These microbes help us extract energy from food, make necessary vitamins, and defend against disease-causing invaders.
While microbes perform important functions, the balance is tenuous. The human cells that line our guts are only one cell thick. This means that a single layer of human cells separates everything passing through our gastrointestinal (GI) tract — food, toxins, microbes, stomach acid, the works — from the blood vessels that carry nutrients and signals to other parts of our body.
Recent science suggests that our immune system and our gut are intimately linked. This may be surprising initially — how does the gut signal the immune system? As it turns out, they are in close proximity. Our GI tract is surrounded and patrolled by lymphoid (immune system) cells. [6]
Our immune system’s job is simple in principle — identify and eliminate intruders to protect our own cells. The presence of neutral or beneficial bacteria blurs this line. Disruptions to the gut cells, or the protective layer of mucus that covers them, can allow good and bad microbes to leak out and start an immune response, causing inflammation. Both escaped microbes and activated immune cells can travel to other parts of the body and cause damage. A growing amount of scientific research suggests that microbes and immune cells can also interact in more complicated ways across this narrow space.
How I Met My Microbes
We start building our microbial communities at birth. Infants initially have very few microbes in their guts. By 3 years old, they have a fairly stable adult microbiome. (Gensollen et al 2016) Many microbes come from Mom, through several possible routes — skin, breast milk, fecal, vaginal, and oral. (Ferretti et al 2018) Researchers have also shown that early environments, from the hospital to the presence of a family dog, influence the types and diversity of microbes. (This knowledge brought to you by — you guessed it — testing lots of baby poop. Researchers, we thank you.)
There is a growing amount of research by the medical community on how cesarean sections, breast-feeding and other factors affect infant microbiomes. Correlations have been found between the diversity of microbes present and the species that dominate baby guts early in life, albeit there are many complicating factors. [7] For instance, we know that human breast milk contains sugars that infants cannot digest, but feed a type of gut bacteria called Bifidobacterium that dominates the guts of healthy infants. (Lawson et al 2019) Both in infants and in adults, the antibiotics we use to kill bad bacteria can drastically change the microbes present, and potentially make these ecosystems unstable. Bottom line: there are complicated connections between human development and the growth of our microbiomes that are fascinating and still coming to light.
Lastly, one of the more recent and debated routes for new microbes to get into our guts is (yes, we’re going there) through fecal matter transplants, FMTs. At this point in 2020, FMTs have been shown to be an effective treatment for Clostridioides difficile (C-diff) infections, which are notoriously difficult to cure with antibiotics alone. Beyond C-diff infections, the use of FMTs for other conditions varies by doctor and country. [8]
The Human Microbiome and Health
A mindboggling amount of data on the species making up our microbiome is now available, and we are only getting started (more on this in future posts). Researchers have learned that the types of microbes we carry are related to conditions ranging from obesity and asthma to chronic diseases, including Irritable Bowel Disease (IBD) and Crohn’s Disease. The presence or absence of certain microbes has also been connected to immune system function. [9]
For example, certain bacteria in our guts make a type of molecule called short-chain fatty acids (SCFAs). The SCFAs provide an energy source for the human cells lining our guts, which can’t make these molecules themselves. In addition to providing energy, the SCFAs made by different bacteria send signals to other gut microbes and human cells. For example, people with the SCFA-making bacteria Akkermansia muciniphilia in their guts were were less likely to suffer from obesity and malnutrition — scientists think there might be a link.
To date, most of the research on gut bacteria has been done in mice and in small groups of human volunteers. However, many researchers and companies are pushing forward and performing clinical trials in humans.
Perhaps the biggest challenge is that scientists don’t yet agree on what a healthy microbiome looks like. There is a huge amount of variability in just “healthy” humans. In many cases, we also don’t know which microbes are causing health, and which are just correlated — i.e. they tend to ride along in normal people. Even less is known about how the microbiomes of other body parts, such as the mouth, gut or skin, and how they interact with each other.
What is clear is that the trillions of microbes in our bodies play an active role in our metabolic and immune systems, and we could get healthier by understanding them better.
Becoming Better Gardeners: Managing our Microbiomes
As we’ve learned, we are teeming with microbes that serve many important functions. In the past, people have focused on seeking out and destroying microbes — kill the germs! However, this picture is starting to evolve. I love the analogy that Ed Yong makes in I Contain Multitudes: our microbiomes are like gardens, and we should think of ourselves as gardeners. Some microbes are weeds to be pulled up, others should be planted and encouraged to grow.
We are no strangers to domesticating microbes. Most of us are familiar with the concept of using yeasts to make bread, beer, and yogurt. Kombucha is made by using a more complex Symbiotic Culture Of Bacteria and Yeast (SCOBY) to ferment tea. The relatively new field of synthetic biology is based on manipulating and controlling microbes as tiny factories. As we become more familiar with our microbiomes, people are turning these tools to our own bodies.
There are several pictures of what microbiome gardening might look like. The first and simplest is to modify our diets to promote some microbes but not others. The field of Functional or Integrative Medicine takes this approach, and there are many stories of people changing their health dramatically by changing what they eat (including our Founding General Partner who cured his Crohn’s disease this way).
If that doesn’t work, we could identify a type of bacteria that is missing or underrepresented in our microbiomes, and try to add it back. For example, the absence of F. prausnitzii seems to be correlated with metabolic disorders like obesity. In response, French company Exelium is working on a drug containing a single strain of this bacteria as a replacement. Similarly, another French company, TargEDys, recently announced positive results of a clinical trial with a strain of enterobacteria (Hafnia alvei), also to combat obesity.
Getting a new bacteria to take up residence is not as simple as it sounds. First, it needs to arrive at the right neighborhood of the gut alive and intact. Then it needs to out-compete the current residents for resources. If key nutrients aren’t available, if the area is inflamed, or if it is missing other bacteria friends that it likes to live with, this approach may not work.
These challenges are one reason why the concept of personalized medicine has become so popular. In this vision, your doctor would measure your microbiome and prescribe a mixture of live microbes (probiotics), small molecules to help them (prebiotics), and other factors to help an improved ecosystem take root. We could even engineer new genes into our existing microbes, which are already adapted to our unique ecosystems. Should be simple, right?
In the next Human Microbiome post, we’ll meet the technology we are using to explore and manipulate the human microbiome. This will set us up to plow into the subject of future microbiome “gardening”.
Once again, I also gratefully acknowledge several scientists, researchers, and in this case other venture capitalists for their help and input. I would also like to thank Ed Yong, the author of “I Contain Multitides”, for informing this blog post. As always any mistakes are my own, and I would welcome the opportunity to correct them!
Notes
- See website for more info about I Contain Multitudes. For some cultural context, the line “I contain multitudes” is from the poem “Song of Myself” by Walt Whitman (link to the poem on Poetry Foundation). Bob Dylan also released a song with the same title in April 2020 (youtube).
- Source: Lita Proctor, “Priorities for the next 10 years of human microbiome research,” Nature 2019. To put this in perspective, the National Cancer Institute (NCI)’s annual budget was $5.7B in 2019, and NASA’s annual budget is $22.6B.
- With over 10,000 different species, the human microbiome is pretty diverse. For context, an NYC subway pole houses <100 different microbes (for more: WSJ summary of a medical study, a pop culture article, and subway bacteria as art). The amazon rainforest is home to more than 5 million different species!
- Source: E. Grice and J. Segre, “The skin microbiome”, Nature Reviews Microbiology 2013.
There is also a link between the skin biome and the immune system. An important early example was a study by Richard Gallo and his team at UCSD showing that the bacteria S. epidermidis produces antimicrobial compounds, which kill other microbes that trigger inflammation. (Reference) - For example, “Corynebacterium reportedly converts testosterone into something that smells either like vanilla, urine, or nothing, depending on the sniffer’s genes” (from ICM chapter 4). A person’s armpit microbiome and scent is apparently stable over time.
- Our gut cells are usually protected by a protective mucus layer. When the mucus and gut cells are damaged, microbes from inside the GI tract can leak out, creating a strong immune response. The byproducts of this immune response result in inflammation. Source: Peters and Wekerle, “Autoimmune diabetes mellitus and the leaky gut,” Proceedings of the National Academy of Sciences (PNAS) 2019.
- Complicating factors include exposure to antibiotics, weight and health of the mother, labor complications, genetics, nutrition, and more. Some examples of journal articles in this area: breast-feeding and infant gut bacteria, delivery method and infant gut bacteria.
- In the US, the FDA regulates stool as a drug in non-C-diff cases. This creates a high bar for approval (although this seems reasonable, given the sample variability, potential for contamination, and unknown long-term effects). Anecdotely, some practices in Europe have explored the use of FMTs to treat other disorders, including obesity, IBD and autism.
While the success rates for treating C-diff with FMT are high, success rates for Irritable Bowel Disease (IBD) and other conditions are lower and side effects are more common. In IBD cases, the new microbes delivered through FMT “would have to colonize a hostile, inflamed environment that’s already full of indigenous, well-adapted microbes.” (ICM Chapter 9) - Faecalibacterium prausnitzii is thought to be anti-inflammatory and is noticeably absent from the guts of people with IBD. Adding F. prausnitzii reverses IBD symptoms in mice; as a result, this bacteria has become a target as a potential therapeutic. Bacteroides fragilis in the gut also seems to stoke the anti-inflammatory side of the immune system.
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