ABOUT THE BOOK
TITLE PAGE
DEDICATION
FOREWORD
INTRODUCTION
1. What Is the Microbiota and Why Should I Care?
2. Assembling Our Lifelong Community of Companions
3. Setting the Dial on the Immune System
4. The Transients
5. Trillions of Mouths to Feed
6. A Gut Feeling
7. Eat Sh!t and Live
8. The Aging Microbiota
9. Managing Your Internal Fermentation
MENUS AND RECIPES
ACKNOWLEDGMENTS
APPENDIX
NOTES
BIBLIOGRAPHY
INDEX
ABOUT THE AUTHORS
COPYRIGHT
First we’d like to thank our editor, Virginia “Ginny” Smith; Ann Godoff; and the team at Penguin Press for their vital role in helping us realize our shared vision in this endeavor. Ginny was with us every step and word of the way, and aided us immensely in shaping this book. Dr. Andrew Weil was the catalyst for this project. He saw the need for this new research to be made accessible to all and we thank him for his encouragement and guidance. Richard Pine, our agent, was critical in helping us navigate the unfamiliar terrain of the publishing world. We are grateful for his sage advice throughout this process.
We thank our wonderful colleagues at Stanford and around the world for many enlightening discussions and ideas. Our mentors and teachers along the way are too numerous to mention by name, but we are grateful for all that each of them has given to us. The research covered in this book is the collective effort of many scientists working to decode the mysteries of the human microbiota. Their creativity, intelligence, and tenacity inspired not only this book but also our continued work in this ever-expanding field of medical research. We are particularly indebted to the scientists mentioned in the preceding pages for taking the time to speak to us about their research and the field in general. Numerous colleagues read through portions of this book and provided valuable comments and fact-checking, including Kristen Earle, Jon Lynch, Angela Marcobal, Katharine Ng, Sam Smits, Liz Stanley, and Weston Whitaker.
We are fortunate to work in a field with so many brilliant, generous, and collaborative people. Our mentor Dr. Jeffrey Gordon deserves special praise in this regard. He ignited our passion for the microbiota years ago and his continued work in this area serves as a source of constant awe and admiration. We also humbly thank the past and present members of our laboratory at Stanford. Their excitement is truly inspiring and their discoveries are shaping how we think about the microbiota.
This book would not have been possible without the support of numerous friends and family members. We are indebted to our parents, Dennis and Bonnie Sonnenburg and Aime and Lise Dutil, for too much to comprehensively enumerate. From the extra babysitting to the constant encouragement we are very grateful for their undying support. Finally we need to thank our ultimate inspiration, our two daughters, Claire and Camille. Their willingness to try unusual fermented foods and eat a diet that cares for their microbiota taught us that this next generation can reverse the course of the Western dietary deterioration. We are very proud of their blossoming wisdom that is perfectly captured every time they say they want more kale because their microbiota is hungry … and because it’s delicious!
Dairy-based: look for those that are labeled “live and active cultures”
Buttermilk
Crème fraiche
Cultured butter
Cultured cream cheese
Cultured sour cream
Kefir
Lassi
Some cheeses
Yogurt
Vegetable-basedfn1
Kimchee
Pickles
Sauerkraut
Grain-or legume-basedfn1
Miso
Natto
Tempeh
Other
Kombucha—fermented tea
Nondairy probiotic beverages
Children |
Recommended grams of fiber |
1–3 y |
19 |
4–8 y |
25 |
|
|
Men |
Recommended grams 16of fiber |
9–13 y |
31 |
14–18 y |
38 |
19–30 y |
38 |
31–50 y |
38 |
51–70 y |
30 |
> 70 y |
30 |
|
|
Women |
Recommended grams of fiber |
9–13 y |
26 |
14–18 y |
26 |
19–30 y |
25 |
31–50 y |
25 |
51–70 y |
21 |
> 70 y |
21 |
During pregnancy |
28 |
During lactation |
29 |
fn1 Note that heating or cooking will reduce living bacteria.
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We like to think of the world as being dominated by humans. Our species has created complex societies, built elaborate cities, and produced amazing works of art, music, and literature. Evidence of human activity on this planet, such as highways, dams, and illuminated skylines, is even visible from space! While it is clear we’ve had a large impact on Earth, the reality is that humans are relatively new and numerically minor inhabitants of our planet. We live in a microbial world. The earth is covered in microorganisms, or microbes, and has been for billions of years. Microbes are microscopic life such as bacteria and archaea. There are more microbes present on your hand than there are people in the world. If you lumped all the bacteria on Earth together they would form a biomass larger than all the plants and animals combined. (Keep this mental image in mind for an update on our antibiotic war with these microbes as described in the pages to come.) One estimate places the number of bacteria on Earth at 5 million trillion trillion or, in geekier terms, 5 nonillion. If you want to write it out, it’s a 5 with 30 zeros after it.
Bacteria are everywhere, from cold, dark lakes buried a half mile under the Antarctic ice to deep-sea hydrothermal vents reaching temperatures over 200˚F to the lump in your throat that developed at the thought of so many bacteria. If we ever do find extraterrestrial life, chances are they will be microbes. (This is why one of the tasks of the Mars rovers is to search for signs of an environment capable of supporting microbial life.) At more than 3.5 billion years old, single-celled microbes are the oldest form of life on Earth. By comparison, humans emerged just 200,000 years ago. If you set the history of earth to a twenty-four-hour day, with the planet’s creation occurring at midnight, microbes would have appeared a little after 4 a.m., while humans would have appeared only a few seconds before the end of the day. Without microbes, humans would not exist, but if we all disappeared, few of them would notice.
Despite their seemingly primitive forms, present-day microbes are the product of billions of years of evolution. These microbes are therefore just as evolved as we are—in fact, considering the many more generations microbes have gone through (they reproduce on the time scale of minutes to hours), you could argue that they are better adapted to the current environment than humans. For example, within just a few decades fungi able to harvest energy from radiation have become prevalent near the site of the Chernobyl disaster.1 Should widespread devastation strike the planet, certain microbes would likely be able to quickly adapt to the new environment and proliferate. Our human bodies, on the other hand, cannot adjust as readily.
Every newborn child represents a habitat of fresh real estate for microbes. Since microbes are so plentiful and have an amazing ability to rapidly acclimate to new environments, they immediately take up residence on every body on the planet, human or otherwise. They find homes on our skin, in our ears and mouths, and in every other orifice on our body, including the entire digestive system, where most of them live. Although the microbes that inhabit us were, in the beginning, just looking for food and shelter, over the course of our coevolution they have become a fundamental part of our biology.
The human body essentially is a highly elaborate tube that starts with the mouth and ends at the anus. The digestive tract, or gut, is the inside of the tube. As Mary Roach noted in her highly entertaining book Gulp: Adventures on the Alimentary Canal, in this way we are not that different from the earthworm. Food goes in one end of the tube, gets digested as it passes through the tube, and is then excreted as waste at the other end. Before you get depressed about how “unsophisticated” our digestive system is, remember that the two-opening tube was a major advance over earlier one-opening tubes. The hydra, a microscopic animal that lives in ponds, has only a mouth. That means that ingested food and excreted waste share the same opening. Now our “tube” doesn’t seem so shabby, right?
Unlike the worm, our tube has an assortment of accoutrements that have evolved to nourish and protect it. To feed our tube, arms and hands serve to reach for and grab food. We have evolved legs and feet to help us move around and find more food. All of our senses and our highly complex brain can be thought of as “extras” to get more food for our tube, protect our tube from harm, and to procreate, thereby making more tubes. Additional tubes provide new habitats to be occupied with ever more bacteria.
Despite the tremendous impact our gut-residing microbes have on digestion, food travels most of the length of our digestive tract before encountering the bulk of these microbes. The food we ingest makes its way down the esophagus to the stomach, where it lands in a bath of acid and enzymes tasked with starting the process of digestion and nutrient extraction. After about three hours of mechanical churning in this harsh, acidic environment that is relatively devoid of microbes, the partially digested food is slowly emptied into the small intestine. This is where the digestive system truly begins to resemble a tube. This flexible passageway is approximately twenty-two to twenty-three feet long, an inch in diameter, and piled like a plate of spaghetti in the middle of our body. The interior of the small intestine is covered with finger-like projections called villi that absorb nutrients into our bloodstream.
The food traveling through the small intestine is soaked in enzymes secreted by the pancreas and liver to help digest the proteins, fats, and carbohydrates we’ve consumed. Here in the small intestine the microbe count is relatively sparse, with only about 50 million bacteria per teaspoon of contents.
A scanning electron micrograph of villi within the mouse small intestine. © Justin Sonnenburg, Jaime Dant, Jeffrey Gordon
The last stop in this roughly fifty-hour journey is the large intestine, or colon, where food moves through at a snail’s pace. The large intestine is not as long as the small intestine—less than five feet on average—but its name comes from its width, about four inches in diameter. A layer of slimy mucus coats the inside of the large intestine. It is here that the remainder of the food we’ve eaten first encounters the dense and voracious community of microbes referred to as the microbiota. (The large intestine contains about 10,000 times more bacteria per teaspoon than the small intestine.) Gut bacteria live, and in fact thrive, on leftovers, primarily the complex plant polysaccharides known as dietary fiber. Whatever the bacteria don’t (or can’t) consume, for example seeds or the outer skin of corn kernels, is excreted some 24 to 72 hours after the initial esophageal descent. Included in this waste are lots of bacteria, some dead and some still living, that get swept along with the current. Close to half of the mass of stool are bacteria, but they leave plenty of their brethren behind to ensure the tube remains densely populated. Depending on the existing sanitation standards, some surviving microbes may spread to a nearby water source, allowing them to find a new home in someone else’s tube.
How did all these bacteria get into our digestive system in the first place? We often think of our insides as being, well, inside of us. The reality is that the inside of our tube is exposed to our external environment in the same way our skin is exposed on the outside of our body. That is the nature of a tube, after all. Through repeated exposure to the microbes that surround us—on our hands, in our food, and on our pets—our tube is constantly exposed to microbes. Some of them pass through us, but some of them stick around for years or even our entire lives.
Despite their prevalence in the colon, the life of a gut microbe is not easy. First they need to withstand the acid bath that is our stomach and then ultimately find shelter in the dark, damp cavern of the colon, which is inhabited by more than a thousand different species. While food periodically arrives in the cave, competition for resources within the gut is fierce and survival depends on snatching what you can before others get their microbial hands on it. In between meals, some microbes survive by dining on the layer of mucus that coats the intestine.
While life has always been a struggle for gut microbes, never has this been more the case than today, given what they are facing in the Western world.
A scanning electron micrograph of a rod-shaped member of the human microbiota embedded within mucus. © Justin Sonnenburg, Jaime Dant, Jeffrey Gordon
Imagine that your first image of an airplane was a picture of a debris field after a plane had crashed. Knowing nothing about aviation, you’d find it difficult to piece together what the airplane looked like before the crash. This analogy is akin to what researchers face when they try to understand how the human microbiota works. The vast majority of microbiota research has been performed on people from the United States or Europe—the same individuals who are predisposed to Western diseases. When scientists compare the microbiota of people with inflammatory bowel diseases (IBD) to those without it, they are cognizant that the “healthy” group, by living a Western lifestyle, may not provide an accurate definition of a healthy microbiota. One of the hazards of modern society is the increased risk for developing IBD. Although an individual may not have IBD yet, their microbiota could already be in an unhealthy state, tending toward illness in the relatively near future. It would be like comparing someone with a cold accompanied by a fever and a cough to someone who has a fever but hasn’t yet developed the cough. In this scenario it could appear that having a fever is normal (even the “healthy” person has a fever) but that coughing is the problem. Because our definition of a healthy microbiota comes from studying Americans and Europeans, it’s likely that our view of what is normal is highly distorted.
From the birth of humanity until about twelve thousand years ago (a time span of about two hundred thousand years), humans obtained their food exclusively through hunting and gathering. The ancient human diet consisted of sour, fibrous, wild plants and lean, gamey, wild meat, or fish. The birth of agriculture marked a dramatic change in the way people ate. Domesticated fruits and vegetables (selectively bred for increased sweetness and plumper, less fibrous flesh), grain-fed animals and animal products like dairy, and cultivated grains like rice and wheat became common fare for our species. Over the past four hundred years, the Industrial Revolution brought unprecedented and rapid change to our diet, which increasingly relied upon mass-produced food. Modern-day technology over the past fifty years has resulted in grocery stores filled with a seemingly endless supply of highly processed, overly sweetened, calorie-dense foods that have been stripped of dietary fiber and sanitized to prolong their shelf life. A diet filled with these new food products represents a huge deviation from what we have eaten over most of our evolutionary history. The gut microbiota has ridden this dietary roller coaster throughout human history, constantly adjusting to each shift in food technology and dietary patterns. Unfortunately, it now appears to be on a potentially disastrous trajectory.
One of the marvels of the gut microbiota is how rapidly it adjusts to dietary changes. The bacteria in the gut divide quickly, capable of doubling in number every thirty to forty minutes. Species that thrive on the types of food an individual regularly consumes can become very abundant relatively quickly. However, species that require food that are not a part of the person’s normal diet can become marginalized, relegated to subsisting on intestinal mucus or, in the most extreme conditions, face extinction. In biology, this ability to change is known as plasticity, and the gut microbiota has it in spades. Microbiota plasticity ensured that when our ancestors’ hunter-gatherer diets changed with the seasons, their microbiota could easily adjust to extract the maximal nutritional benefit. However, this plasticity also means that once-abundant species, well suited to a foraging diet, have now disappeared in the face of our modern diets. Conversely, microbes that thrive in today’s burger-and-fries environment are becoming a larger proportion of the microbiota. This Western microbiota is the one most of us now harbor in our gut, even those of us who consider ourselves healthy; and unfortunately, the picture probably looks more like a crashed airplane than a fully functional one.
To get a sense of what a fully functional microbiota might look like, we can look to the last remaining full-time hunter-gatherers in Africa, the Hadza. They live in the cradle of human evolution, the Great Rift Valley of Tanzania, home to some of the most ancient remains of our human ancestors dating back millions of years. Their diet and microbiota provides the closest modern-day approximation to that of our ancestors who lived before the advent of agriculture.
The Hadza consume meat from hunted animals, berries, the fruit and seeds of the baobab tree, honey, and tubers—the underground storage organs of plants. The tubers they eat are so fibrous that after a period of chewing diners spit out a cud of the toughest fibers.
Those who have studied the Hadza estimate they consume between 100 to 150 grams of fiber per day. To put these numbers into context, Americans typically eat only 10 to 15 grams of fiber per day. The Hadza microbiota houses a much greater diversity of microbes than a Western one does.2 If you think of the microbiota as a jar of jelly beans with the different flavors representing different species of bacteria, the “hunter-gatherer” microbiota is like a jar filled with a complex mixture of many different colors and flavors, some of which are very unusual. The jar representing the Western microbiota has far fewer flavors in a more homogenous or simple mix.
A young Hadza girl with a freshly cooked and peeled piece of Vigna frutescens tuber. © Pascal Gagneux
The microbiota from individuals living a traditional agrarian lifestyle similar to how humans lived ten thousand years ago also contains a more diverse collection of microbes than Westerners typically house.3 These Western versus traditional differences are not just confined to the microbiota of adults. Children living in a rural village in Burkina Faso and in the slums of Bangladesh also have a microbiota that looks different from that of their European and American counterparts.4 Similarly to what has been observed in adults, Western children have a less diverse collection of microbes in their gut compared with children living a less modern lifestyle. Evidence is thus mounting that the Western microbiota contains a less diverse collection of microbes compared with the microbiota of people who don’t consume much, if any, processed foods, aren’t prescribed multiple rounds of antibiotics annually, and don’t carry hand sanitizer in their purses and backpacks.
Diversity matters. In an ecosystem like that of the gut, diversity can be a buffer against system collapse. Imagine an ecosystem that contains a large variety of insects and birds. If one species of insect disappears, the birds still have a selection (albeit smaller) of insects to feed on. If, however, more and more species of insects disappear, eventually the birds will starve, compounding the depletion of species within the ecosystem. As diversity is lost in the Western microbiota, this ecosystem is at greater risk of collapse—a collapse that could affect the health of the human hosting the flailing ecosystem.
Humans are the evolutionary product of a lineage of organisms that continually figured out how to play nice with their gut microbes. Because the colonization of our gut by microbes was inevitable, our body had to learn how to interact with them in a positive way. The harsh reality of natural selection is that humans and bacteria are locked into a relationship by force. We have no choice but to coexist with them, so by making this partnership positive, both humans and bacteria can benefit.
Although some species, such as Salmonella, Vibrio cholera, and Clostridium difficile, commonly referred to as pathogens, have taken the route of antagonistic interaction, these are the exceptions to the masses of friendly microbes that we harbor. Unfortunately, pathogens have driven the overuse of antibiotics to the detriment of the rest of the well-behaving members of the microbiota. If we cast our gut resident bacteria as invaders—or even as unimportant, as evidenced by our casual approach to antibiotic consumption—we risk harming this community and in the end harming ourselves.
Each species of microbe within your microbiota has its own genetic code, or genome. The collection of genes encoded within all microbes is called your microbiome, a second genome. Just as your human genome is uniquely yours (with the exception of identical siblings) no two gut microbiotas are identical. Therefore your microbiome is a major contributor to your individuality (especially if you have an identical twin). You can think of your microbiome as an internal fingerprint of sorts. Your microbiome may encode the ability to degrade a certain type of carbohydrate that someone else’s microbiota can’t. For example, some Japanese host a seaweed-consuming gut bacterium that is typically absent in the microbiota of Westerners. Because seaweed is such a large part of the Japanese diet, their microbiota has evolved a way to utilize this ubiquitous food source. Hopefully the hallmark of the Western microbiota is not the ability to consume hot dogs!
We need our gut microbiota. Because humans had no choice but to house this dense collection of bacteria, we did what all evolutionarily successful organisms do: we entered into a mutually beneficial symbiotic alliance. In other words, we made them work for their keep. Symbiosis is defined as a close and extended relationship between two or more organisms. Some symbiotic relationships are parasitic, meaning one organism benefits at the expense of the other, like the unwanted houseguest who eats all your food, leaves a mess, and doesn’t get the hint that it’s time to go. On a microscopic level, hookworms are a great example of an unwanted houseguest. Commensalism is a second type of symbiotic relationship, one that benefits one participant but has little or no effect on the other—imagine a dog that raids your trash for food. In mutualism, a third kind of symbiosis, both parties benefit. Now imagine that the dog raiding your trash is also keeping disease-spreading rats away. This arrangement is analogous to the relationship we are in with our gut microbiota.
The most obvious way that we benefit from the microbiota is from the chemical products they release (and we absorb) during the fermentation reactions they carry out in the gut. These chemical reactions allow us to salvage calories from food that would otherwise be wasted, something that would have been critical to our ancient ancestors in their calorie-sparse environment. While extracting extra calories is less important in the modern world, these reaction products still perform important biological tasks for us: tuning our immune system, helping us fend off disease-causing bacteria, and regulating our metabolism.
Gut microbes receive a steady supply of food, provided by us, without having to expend much effort other than to wait for its appearance. So instead of “you scratch my back and I’ll scratch yours,” it’s more like “you eat food for me and I’ll help you digest it into molecules that you need.” But why doesn’t the human genome just encode the ability to completely digest our food so that we don’t have to deal with these freeloading microbes? One reason our digestive tract is not free of microbes is because the task of microbe elimination would be nearly impossible to accomplish. Trying to maintain a microbe-free existence in our microbial world would be a herculean effort requiring our immune system to work around the clock to evict the plethora of microbes we are constantly encountering.
Another reason we don’t eradicate all our microbes is because their genes function as an extension of our own genome. Each gene within the human genome provides a benefit, but also comes at an energetic cost. Every time a human cell divides, the genetic material from the entire human genome contained within that cell (roughly twenty-five thousand genes) needs to be replicated. We profit from microbial genes that perform a variety of functions that our genome cannot. For example, the microbial genomes provide the ability to convert otherwise indigestible food into key molecules that regulate many aspects of our biology, from the amount of inflammation in the gut to how efficiently we store extra calories. This coevolved division of labor is so successful that it has been used by organisms for eons.
Tremblaya princeps is a bacterium that lives inside of a garden pest known as the mealybug. This microbe is special because it has one of the smallest genomes of any bacteria presently known and represents a minimal number of genes required for life. Scientists are interested in small genomes because they provide a good starting point for engineering microbes from scratch to perform helpful tasks, such as cleaning up oil spills in the ocean or converting cornstalks into fuel. After the genome of Tremblaya princeps was sequenced, it became obvious that this bacterium was missing key genes required for even the most basic cell functions. Nested inside Tremblaya princeps is another bacterium called Moranella endobiaTremblaya princep5Tremblaya princepsMoranella endobia