Opinion – Fundamental Science: What the Gut Teach Us About Tolerance


The immune system’s function is to fight pathogens that come from the outside, right? Not exactly. Most microbes that reach our bodies are not harmful. For immunologist Daniel Mucida, it’s more or less like former president Donald Trump’s immigration policy in the US: it assumes that immigrants are like pathogens to be fought when, in fact, they do more good than harm to the parents. “We must develop tolerance rather than walls,” he says.

In the case of our bodies, the gateway for these welcome immigrants is the intestine. In your immune system, most interactions do not happen with pathogens, but with microorganisms and food molecules. There are trillions (trillions really, it’s not a figure of speech) of harmless bacteria that form the so-called microbiota.

But how is the body able to identify which organisms can harm us and which we should tolerate and assimilate? In other words, how does your body know to fight off harmful bacteria and leave the beans you eat for lunch alone? Understanding how this balance of the immune response takes place is the goal of Mucida, professor and head of the Laboratory of Mucosal Immunology at Rockefeller University, USA.

With an area of ​​about 300 square meters, the human intestinal mucosa is the largest body surface exposed to the outside world – from which it is separated only by a thin and permeable epithelial layer. So it is not surprising that in the intestine there are more lymphocytes, the defense cells, than in the rest of the body. This is where our most complex and developed immune system is, with more antibodies than in the blood. And, even with this high immunological activity, in addition to fighting pathogens, the organ finds a way to exercise assimilation. So how does the organism’s immunology actually operate?

“To understand the immune system, we have to understand what is around it,” says Mucida. This is where the famous concepts of immunology of self and non-self (which here have nothing to do with psychology) come into play, much studied by Portuguese immunologist António Coutinho: the differences between molecules that are proper to the body and those that come from outside.

What Mucida’s group has already demonstrated is that the intestinal environment itself facilitates this balance between tolerance and walls by compartmentalizing the response. The immune system prepares some immune cells to accept dietary nutrients found in the small intestine, while it prepares others to deal with organisms that are in the large intestine. The nature of the signals coming from different parts of the intestine and the mechanisms by which they influence the adaptation of immune cells, however, is still not well understood. “How does the intestine see a protein ingested in the diet differently from the protein in a vaccine that will generate an immune response?” the scientist asks.

Of course, this balance, as fascinating as it is, is not perfect. The immune system can overreact and launch unnecessary attacks, triggering food allergies or celiac disease. The books teach that this is a failure in the immune response, but Mucida has another view, shared with Ruslan Medzhitov, an immunologist at Yale University. “Allergy is not necessarily an error in the immune response. It may have been evolutionarily selected to combat or eliminate harmful substances; something that can be seen as bad for the organism, which can be in the shrimp shell or the peanut lipid. part of the nutritional control of the intestine.”

Another phenomenon that has become more studied in the field of immunology is tolerance to the inflammatory response itself. That’s when the attempt to eliminate a virus generates an inflammation that is more harmful than the virus itself — the case of the coronavirus, whose immune response has caused damage to the lungs of infected people. “Here the question is: how can the nervous system of the intestine, an organ permanently inflamed by nature because of high immune activity, manage to cope well with this chronic inflammation?”

To investigate all this in practice, Mucida’s laboratory uses gnotobiotic mice, that is, free from microorganisms. Animals are colonized with specific bacteria and researchers study responses to those bacteria. Studies also advance. in vitro with organoids — a kind of mini-gut in which they induce the interactions they want to observe. It is an option that vegetarian immunologists tend to prefer for the future, as technology evolves, as it preserves animals.

With a degree in biological sciences from UFMG and a doctorate in immunology from USP, the 42-year-old Minas Gerais native from Belo Horizonte was one of the 33 recipients, at the end of September, with funding of 9 million dollars from the prestigious Howard Hughes Medical Institute ( HHMI). But outside the laboratory, Mucida thinks more about politics than science — and, of course, about the intersection between the two.

The analogy between the intestinal immune system and Donald Trump, by the way, is not random: in the US since 2010 as a professor at Rockefeller (where he was appointed tenured in March of this year), Mucida is a staunch critic of governments with antidemocratic and conservative tendencies. In Brazil, he sees structural problems in the research ecosystem that go beyond the shrinking budget and hinder the development of science.

“The scientific research system in Brazil does not facilitate the presence of foreigners, and it is very difficult to carry out relevant cutting-edge science without diversity, in every sense”, he comments. “Furthermore, the Brazilian researcher’s class workload is very high and makes dedication to the laboratory difficult, and the exaggerated bureaucracy hampers what can be done. But all of this has secondary priority to research funding. With the current budget, it is impossible do science. It’s very sad.”

During her postdoc at the La Jolla Institute of Immunology, in California, Mucida became addicted to surfing. Since then, he travels every two years to Indonesia to dedicate himself to the sport, in addition to climbing. These are the scientist’s distractions when he’s not thinking about tolerance — both the one that the gut seems to dominate well and the one that we have yet to learn.


Clarice Cudischevitch is a journalist, coordinator of the Ciência Fundamental blog and Communication Manager at Instituto Serrapilheira.

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