Listening to Your Gut
Andreas Diefenbach, a microbiologist and immunologist at Charité, studies the role of the microbiome in the immune system.
May 15, 2019
Alongside the human genome, the human microbiome is a subject of increasing focus in research. The totality of all microbes that live in and on the human body evidently plays a much greater role in the emergence of disease than was previously thought.
Although genetic research has shed a great deal of light on how various diseases and conditions arise – the various forms of cancer, for example – the development of another large group of diseases, comprising autoimmune disorders and chronic inflammation, is still puzzling to medical researchers. This group includes Crohn’s disease, type 1 diabetes, and rheumatoid arthritis. “There are mutations in genes associated with the immune system, but their predictive value, meaning whether or not a person actually gets the disease, is minor,” says Professor Andreas Diefenbach, a microbiologist and immunologist at the Benjamin Franklin campus of Charité – Universitätsmedizin Berlin.
External factors, such as what kinds of microbes live in and on the body, seem to play an important role in these chronic inflammatory conditions, in which the immune system attacks the body’s own tissue and destroys it. The vast majority of the human microbiome is located in the gut, which is home to as many as one thousand different species of bacteria, coexisting with fungi and viruses.
Every day, we excrete anywhere from one billion (1,000,000,000) to one trillion (1,000,000,000,000) of them in our stool – per gram! Diefenbach is interested in how gut flora affects the immune system. The microbiome develops in stages. A child gets the “basics” from his or her mother. At first, the only microbes present are those from the mother’s vaginal tract, but the child’s flora soon comes to be dominated by the microbes found in the mother’s milk: lactobacilli and skin bacteria, which take up residence in the infant’s intestine.
“Overactive” immune cells attack the body’s own tissue when there is no enemy present
Diefenbach and his team were able to show in mice that the microbiome literally trains the immune system an organism is born with: Rodents raised in a germ-free environment that came into contact with a virus were helpless to fight it, falling severely ill. Animals that had not grown up in a sterile environment, by contrast, easily fought off the infection. Phagocytes, such as macrophages and monocytes, which already exist in the embryo, start out performing only a kind of “garbage can” function: They dispose of cells that are no longer needed. “We think the initial microbial colonization is the trigger that turns a passively consuming phagocyte into a fierce defender against infections,” Diefenbach explains.
That means there must be signals from the gut that put the immune system on the alert. And indeed, microbes lead to production of signaling substances known as cytokines, and especially type 1 interferons, which reprogram peaceful “eaters” into fighters. Is there a connection between a person’s individual cytokine generation and the composition of that individual’s gut flora?
In a study of 400 subjects, researchers from the United States and the Netherlands took blood and stool samples. They put the leukocytes from the blood into contact with various components of bacteria and fungi and then measured how many cytokines were produced. They also sequenced the bacterial community from the subjects’ stool samples. In the end, they did find a correlation between certain signaling substances (and the volumes thereof) and the composition of the intestinal flora.
Together with colleagues from the German Rheumatism Research Centre Berlin (DRFZ), an organization dedicated to research on rheumatism, Diefenbach now plans to study type 1 interferons in particular, as they play an important role in the emergence of diabetes and lupus. “People whose immune cells are exposed to high doses of interferons might be more susceptible to developing an autoimmune disorder than others,” Diefenbach suggests.
If so, the triggers of autoimmune diseases would be “overactive” immune systems that are spoiling for a fight, so to speak, and attack the body’s own tissue when they cannot find an enemy. That tissue can be the intestinal mucosa (in Crohn’s disease), the skin (in eczema), the hair follicles (in alopecia areata), the thyroid gland (in Hashimoto’s disease), or the pancreas (in diabetes). That might also explain why many affected patients will develop a second autoimmune disease in their lifetime.
“A century ago, inflammatory intestinal diseases were unknown there”
But how individual is a person’s microbiome, anyway? As individual as the person him- or herself? On the contrary. Genetic studies of stool samples taken from thousands of subjects all over the world have shown that there are only three basic enterotypes – classifications based on the composition of the gut flora – and that these types do not vary much and are dominated by different classes of bacteria. The microbes coexisting in the gut are determined first and foremost by a person’s diet. Surprisingly, the similarities even show up across different species. “Apes with a purely plant-based vegetarian diet have gut flora like that of vegetarians,” Diefenbach explains.
And speaking of diet, do vegetarians and vegans have a “better” microbiome? “No,” Diefenbach says. “It just has a different composition from that of meat eaters.” The “multicultural society” living in the gut also changes as a person’s diet changes, bringing with it shifts in susceptibility to certain diseases. This has been observed to impressive effect in Asia. “A century ago, inflammatory intestinal diseases were unknown there. These days, new cases are at the same level as in Europe, all due to a far-reaching shift in eating habits.”
Microorganisms have colonized other organisms for millions of years. There is practically no such thing as an animal that does not host bacteria – even roundworms have their own gut flora. How this situation came about has not been clarified conclusively. It is likely that bacteria took up residence in search of rich food sources. In return, they gradually came to serve certain functions for the host organism, like the “immune coaching” discussed above, along with production of a number of vitamins (thiamine, riboflavin, B12, K) and healthful short-chain fatty acids. It became a real win-win situation, in other words.
Aside from the gut, the internal organs and, of course, the entire surface of the skin are densely populated by bacteria. The ears, nose, armpit, crook of the arm, palm of the hand, navel, groin, base of the buttocks, hollow of the knee, heel, and the spaces between the toes – each area is a biotope unto itself, home to a resident “society” with a specific composition. Scientists know relatively little about the functions of the skin microbiome so far. Is there anything people can do to keep their microbiome healthy? Diefenbach laughs. “Good question! We don’t have specific recommendations yet. But a varied diet rich in vitamins and plant-based foods is definitely a good idea. And, of course, as little antibiotics as possible!”