Like a patient who tells a therapist about a dream she had and in so doing reveals her deepest secrets, I submitted the products of my intestines to two researchers from the Weizmann Institute of Science in Rehovot. My expectation was that I would learn something important about myself. Dr. Eran Elinav, from the institute’s department of immunology, and Prof. Eran Segal, from the department of computer science and applied mathematics, were going to analyze my “second genome,” namely the millions of bacteria that populate my digestive tract and are responsible for some of my key traits: my inclination to put on weight, my chances of developing diabetes and possibly also my prospects for contracting diseases such as cancer and Alzheimer’s. In the interim, I meet with Segal and Elinav to talk about the new genomic revolution.
“The 20th century was the century of the human genome,” Elinav notes. “It showed how our genes function and their connection with our traits, behaviors and diseases. Now a new genome has been discovered, consisting of the millions of microbes that cohabit our body and affect us in a million and one ways. Of course, we’ve known about these bacteria, fungi and so forth since the invention of the microscope, but we didn’t know what to do with the information. These pampered bacteria don’t grow in laboratory conditions, so only when the technology became available were we able to analyze their DNA and for the first time explore this world of the microbiome.”
Says Segal: “We were astounded to see how complex and important this new world is. Our mass consists largely of these microbes. It’s thought that there are as many or more of them in our body than there are human cells, and that they possess 150 times as many genes. In other words, we have so far made huge efforts to understand less than one percent of our body, and have ignored more than 99 percent of it. We are talking about a partnership between the human cells and the bacterial cells. This symbiosis creates a ‘holobiome’ – ‘holo’ is from the word ‘whole’; ‘biome’ is an ecological environment.”
Recently, the two researchers published the results of a study that made headlines, because it concerns a subject that’s close to us all: the food we eat. In the largest nutrition-based study of its kind in history, 1,000 people ate their regular diet for a week, while a small monitor measured their blood sugar every five minutes. Since the participants reported everything they ate in real time, each blood sugar count could be matched with the specific food that was consumed.
The results were dramatic. First, it turned out that there is no item of food whose effects are predictable for everyone. Is it better to eat rice than ice cream? Not necessarily: the blood sugar level of 60 percent of the participants went higher in response to rice than to ice cream. Are potatoes bad? Not for those who showed inner indifference to them. In fact, what was good for one person might be bad for another, and vice versa. In matters of nutrition, too, every person is unique. Segal and Elinav found that the variances in people’s responses are due, in part, to the different microbe populations they host.
Your findings show that there is no such thing as good food and bad food, because it’s all personal. If so, are general recommendations meaningful?
Segal: “The general nutrition labels are still correct. Food coloring and processed food are still not good for most people. But with carbohydrates, the general recommendations are definitely problematic. It’s now understood that not only the caloric value of food is important, but also the glycemic index, which relates to the speed with which sugar is absorbed in the blood. A high GI, such as that of dates, for example, attests to a rapid absorption of the sugar into the blood, which could be followed by a steep fall-off. Such fluctuations in blood sugar levels constitute a meaningful risk factor for weight gain and for the development of diabetes, so the general recommendation is to eat food with a low GI.”
“But how is the GI determined?” Elivan continues. “You take 10-20 people, check their blood sugar after they’ve eaten a particular food, and then calculate the average. The averages in our study match closely the known GI values. But if the differences between people are so great – as we show – we have to ask what meaning this average index has for any one specific person.”
So nutrition recommendations must be personalized.
“Yes,” Segal confirms, “and the absence of this might explain why most people don’t manage to lose weight even when they are persistent in their attempts. Certainly, consuming fewer calories leads to slimming, but calories aren’t the whole story. When people reduce the amount of fats they consume, they generally raise the amount of carbohydrates, and the effect they have differs for every person. Only personalized recommendations can work. When we created personalized menus, based on the GI of each food, people’s blood sugar levels stabilized.”
Where do microbes enter the picture?
Segal: “We wanted to discover which human traits can explain individuals’ distinctive response to food. We created a database of unprecedented scope, containing vast amounts of data that we collected for each participant. We also examined extensive parts of each participant’s human genome and we deciphered the genome of every microbiome, from start to finish. In short, we created a highly detailed, individual profile for each participant. It was a huge challenge to connect and cross-check so many pieces of information, but we succeeded in creating an algorithm that can predict how a specific person will respond to different types of foods. A close examination of all the factors that enabled us to predict each person’s individual response showed that one of the most significant of them was the microbe population. We discovered that each person has a distinctive cocktail of microbes, a kind of characteristic signature, which affects his responses to food.”
So the microbes are part of the variances between people and are also largely responsible for them?
“Indeed,” Elinav says. “Two years ago we also showed that gut microbes are responsible for a surprising and disturbing difference. We found that the artificial sweeteners that millions of people use cause some people to gain weight and develop a risk for diabetes. In other words, the sugar substitutes do exactly what these people want to avoid.
“Suspecting the intestinal microbes, we did an experiment,” Elinav continues. “We gave a group of people an artificial sweetener and monitored their blood sugar. Within five days, we found that there were two groups. One group was unaffected, as expected, but the other displayed instabilities in blood-sugar balance. We found differences in the composition of the microbes in the two groups, but to verify the result, we took microbes from the participants who responded badly and injected them into sterile mice with no microbes of their own. The mice gained weight and developed a diabetic disposition! In contrast, microbes taken from the participants who didn’t respond to the sweeteners had no effect on the mice. Based on the differences in the composition of the microbes between the two groups, we developed an algorithm that can predict who in the general population should avoid using sweeteners.”
These results can explain much more, Segal adds. “For example, the divergent effect of medicines on different people. A recent study shows that the effectiveness of anti-cancer drugs depends on the patient’s microbe population.”
Does it make a difference at what time of day we eat?
“It does,” Elinav replies, “because our microbes behave differently by day and by night. You and I can eat the same meal in the morning and the evening, but where I will have a high blood sugar response in the morning and a low one in the evening, your response might be the opposite.” It turns out that the biological clock that exists in each cell of our body also affects our microbes. Many of the changes we experience in the cycles of day and night, of wakefulness and sleeping, are mediated by them. Disruptions in the biological clock, such as occur during shift work or jet lag, have an immediate effect on the functioning of the microbes, and are liable to cause illnesses.
“It’s long been known that shift workers and long-distance travelers have a tendency to gain weight and to develop diabetes and even cancer, but until now these phenomena were unexplained. Our work suggests that the bacteria of the microbiome are involved.”
On what do you base your hypothesis?
Elinav: “We caused jet lag in a group of students by having them fly all over the world. We asked them to collect their fecal bacteria three times: before the flight, at the height of the jet lag, and two weeks later. We discovered large differences in the three samples of each student. We then transferred the bacteria from each stage into germ-free mice. The results were astounding: The mice who received the microbes from jet-lagged students grew obese and developed diabetes. Those who were given bacteria from samples taken before or after the jet lag set in were unaffected.”
“Yes, it’s not healthy to do shift work or fly so much.”
He and Segal look at each other and sigh.
“We say that regretfully, as people who do it a lot.”
There are millions of types of intestinal bacteria, but each individual’s microbiome consists of only a few hundred of them. We are born sterile – the microbiome forms by about the age of three. How this comes about is under intense scientific investigation, but both genetics and the environment are involved. Because a key factor in this regard is the microbiome of each of the parents, some scientists view the transmission of the microbiotic genome – the second genome – from generation to generation as a type of genetics parallel to that of the human – the first – genome. Breast-feeding also affects the composition of the microbes, as does regular nutrition afterward. Unless a person drastically changes his way of life or contracts certain diseases, the microbiome remains more or less stable until the age of 70.
“Throughout life,” Segal explains, “nutrition exercises a crucial influence on the microbe population. Our large-scale experiment showed that when we changed the participants’ menu, the composition of their microbiome also changed. The interactions between bacteria, nutrition and the human body are multidirectional.”
What happens after the age of 70?
Elinav: “Changes occur in the microbes’ composition and functioning. They may play a part in illnesses and other phenomena that characterize this stage of life. We find support for this in experiments done on simple organisms. For example, when we change the microbiome of fruit flies or certain worms, their lifespan doubles. That makes us wonder whether the microbiome is also instrumental in human aging and is connected to the development of age-specific diseases such as Alzheimer’s.”
Swimming to the brain
Segal adds that the microbiome is known to play a significant role in one’s disposition to such diseases as diabetes and cancer. “We ourselves,” he notes, “showed that certain bacteria affect the growth rate of tumors in colon cancer. Scientists are now also examining the microbiome’s involvement in neurodegenerative diseases such as autism and Alzheimer’s.”
Segal: “Autism is composed of a wide range of conditions. It appears to have a genetic basis, but scientists are examining the possibility that a particular family of intestinal bacteria is involved in some of the symptoms. Based on research done on animals, it’s suspected that certain bacteria secrete substances into the intestine, which ‘swim’ to the brain and alter its functioning. This hypothesis, which is also valid for Alzheimer’s, might explain part of the constant increase in the number of cases of autism and Alzheimer’s in young people.”
Because contemporary nutrition plays havoc with these bacteria?
“Exactly,” Elinav says. “For millions of years, we lived in partnership with our microbes under quite steady conditions, and the symbiosis was perfect. In the past 200 years, we have changed the conditions of our existence drastically. Nutrition changed, we added synthetic substances, we became active during the hours of darkness as well as in daylight, and we discovered antibiotics. Many of the changes improved our health and extended our lifespan, but many also adversely affected our internal bacteria, and that is exacting a high cost in health from all of us.”
Elinav and Segal have been working together harmoniously for four years; each appreciates the other’s advantages. Elinav, a physician who is also a scientist, was awarded the 2015 Rappaport Prize for a young Israeli biomedical researcher. Segal, a computational biologist, fuses experimental biology with mathematics and computer sciences; some of his articles have been chosen as the best in their field. They each head an international group of 25 biologists, mathematicians, computer scientists, physicists and chemists. There is “superb communication” between them, the two agree. A symbiosis, if you will.
The image that comes to mind is that of the famous “selective attention test” in which we are so focused on one thing that we don’t notice the intrusion of something else.
“That’s an excellent analogy,” Segal says. “For years we investigated human cells and didn’t notice the presence of another factor, which is so crucial for our biology. This is a revolution in scientific thought, in that it makes us see things we didn’t see before and obliges us to reexamine everything we think we know.”
Noting that acknowledgment of the microbiome’s existence can shed light even on the process of evolution, Elinav adds, “The fact that this is a genome that can change drastically in response to the environment – unlike our first genome, which remains constant throughout our life – can suggest that the second genome is of great importance in evolutionary development.”
How can we use this new knowledge for our benefit?
Elinav: “We must begin by understanding that every medicine we take has the potential to affect our bacteria as well. People are more aware of this in regard to antibiotics, but it’s true of other medicines, too, such as those for diabetes. This doesn’t mean we should stop taking medicines – sometimes they literally save us – but we should not take them lightly.”
So we have to realize that saving the first genome can entail damaging the second one.
“Exactly,” Segal says. “People have two parts, human and bacterial, and it’s important to maintain the reciprocal relations between them, as this is crucial for health and sickness. And because the bacteria are amenable to change, they are very important in medicine.”
How can we change our bacteria?
Segal : “There are several approaches. First, as we said, they can be changed indirectly through nutrition. For example, fiber-enriched food influences the microbiome in a way that is beneficial to health. That is the ‘prebiotic’ approach. The second approach, known as ‘probiotics,’ refers to the consumption of food that supplies the bacteria directly. In light of everything we’ve said, it’s clear that a recommendation to eat probiotic yogurt, for example, is almost meaningless. How can a certain commercial company decide that the whole population needs to take bacterium X? If you’re lacking a certain bacterium, you need to take the bacterium itself and not substitutes.”
The two have coined a third approach – “postbiotics.” It’s “the most sophisticated of all,” Elinav says, adding, “With this approach we intend to provide people with the products of the microbes that operate in our body. They are, effectively, a pharmacy that produces tens of thousands of molecules. Some are new and some are products of the action of the microbes vis-a-vis the food molecules that we eat. They are secreted by the microbes and are absorbed by our human cells and affect them, including those of the brain. Our challenge today is to decipher this molecular language, with the help of which we and the microbes communicate, in order to use these molecules as medicines. We will be able to give people who are disposed toward certain diseases the molecules they are lacking, or block the activity of other molecules of which they have a surplus. This is a whole new world of treatment.”
Isn’t the fact that we are all different from one another problematic in terms of trying to understand diseases and develop new drugs?
Elinav: “Generally speaking, I agree that variance poses a threat to physicians and scientists. At the same time, recognition of biological variances is critical for understanding the processes of life.”
Segal: “The existence of variance is also a burden on the budget, such as in public health. Nutrition recommendations are constantly updated, but we know now that this approach is doomed to failure, because there are no recommendations that are applicable to everyone. Variance compels us to adopt a different strategy, one that is personalized and hence costlier. The question is how to ensure that it won’t be too expensive. Whoever finds a solution for this will be doing something truly great for humanity.”
Good or bad news?
The analysis of my microbiome arrived two weeks later. I’d been a bit nervous, because the results would be revealing is a biological truth, and even if it’s not deterministic like the one embedded in the genes I inherited from my parents – my “first genome” – it still sets boundaries. So, when the results arrived I chose not to know where my tendency toward gaining weight and diabetes lay. What good would such information do me? If I were told that I have no such tendencies, I might become complacent and be less careful about my way of life; and if it turned out that I have such a tendency, I have no way of influencing it now.
“In principle,” Segal says, “it’s possible to create a ‘good menu’ for you, which matches your personal responses. This would require a complete compilation of data, including many dozens of biochemical blood tests and additional clinical information, as in our large-scale nutrition experiment. Our hope is that eventually such a menu, which would stabilize blood-sugar levels, will be available to every person through the health system.”
In the future, Elinav says, “it will also be possible to identify the connection between the signature of your microbes and different diseases we are investigating and to strengthen your ‘healthy,’ anti-disease signature. In other words, we will be able to set your microbiome in a healthier direction through nutritional, probiotic and medicinal interventions that will be adjusted personally to your microbiome.”
I did get one pleasant gift from the analysis of my bacterial profile: I belong to the fortunate group whose microbiome is not affected by saccharin. That means I can consume it without fear of my blood-sugar level being negatively influenced. But what I experienced most is a change of consciousness, a deep awareness of the constant presence of these little creatures in my body. Whenever I’m offered Acamol, the Israeli pain-reliever (paracetamol), I think about my microbes and decline the offer. It’s the same when I have an urge to eat at night. I’ve hooked up with the bacterial side in me. Reader, you should give it a try, too.