Leukemia, a richer microbiota protects children from the risks associated with stem cell transplantation

MODULATING the composition of the intestinal microbiota we can protect children with leukemias and lymphomas facing hematopoietic stem cell transplantation. A study by the Sant’Orsola hospital in Bologna has shown that the greater the abundance and diversity of intestinal microbial species, the lower the risk of complications for children. In particular, the chances of developing graft-versus-host disease (Acute graft versus host disease, or Agvhd), a condition in which the donor’s immune cells attack the patient and which in severe cases is lethal. The study we are talking about was presented during the XLVII National Congress of the Italian Association of Pediatric Hematology and Oncology (Aieop) and is one of the 5 works (the so-called best five) whose results were described during the opening symposium of the congress and will be published shortly.

“In 2015 we began to genetically characterize the microbiota of children who conclude their treatment with the transplantation of hematopoietic stem cells”, explains Riccardo Masetti, of the Pediatric Oncohematology team of IRCCS Sant’Orsola Malpighi, associate professor of pediatrics at the University of Bologna and first author of the research. “We sequenced the DNA of all the species of microorganisms of their intestinal flora starting from stool samples, which we collected immediately before the transplant, and then 20 and 30 days after the infusion. Initially, the collection of samples concerned only the children of our ward, especially with leukemia, then also of other centers, such as those of the pediatric Gaslini in Genoa and the Bambino Gesù in Rome, among others. In all, 90 small patients participated in the study with their stool samples ”.

Immunotherapy to consolidate remission

Stem cell transplantation is an immunological therapy, an integral part of the treatment path of many haematological diseases with a high risk for the child, especially oncological diseases such as leukemia and lymphomas, but also of non-oncological blood diseases such as, for example, thalassemia and immunodeficiencies. The cells come from a national registry bank or from a donor, and are inoculated into the patient once chemotherapy has minimized the diseased cells. “Hematopoietic stem cell transplantation is in fact an immune system transfer that consolidates tumor remission and significantly reduces the risk of relapse. It is done in children who have six months or even a year of chemotherapy behind them ”, explains Masetti. He adds: “We decided to analyze the microbiota of small pediatric patients because in the literature there is evidence that in adults a greater diversity of the intestinal ecosystem protects against some complications that occur during transplantation. There are several, from infections to drug toxicity that we use to prepare for transplantation, but the most serious is Agvhd, a disease that in severe forms represents a serious threat to life “.

Microbiota and immune system: a close relationship

There is a very close relationship between the microbiota and the immune system. The two systems talk to each other, communicate through cytokines and other molecules, with the microbiota influencing the regulation of the immune system and the immune system influencing the composition of the microbiota. The purpose of the study was to understand if the composition of the microbiota, that is the richness and diversity of the species that are part of it, could play a role in the development of Agvhd, which is an immune disease. “We know that there are good microbial species and bad species that populate our intestines”, resumes the doctor. Blautia, for instance. On the contrary, the presence of enterococcus is extremely negative: “we say that the former are very eubiotic, while the latter is very dysbiotic”, adds the pediatrician.

The benefits of diversity

How did things go? “The greater pre-transplant microbiotic diversity protected against complications. The survival of all children with high diversity of eubiotics was higher than 80-82%, while the survival of those with low diversity was around 65%: a statistically significant difference ”, comments Masetti’s results. The idea at this point is clear: if we make the children to be transplanted more eubiotic we can reduce the risk of complications.

But how to do it? “During the transplant, patients are subjected to parenteral nutrition, that is, they are fed through the central venous catheter because they cannot eat normally for 20 days: parenteral nutrition is unfortunately the standard today”, explains Masetti. “We have started to make them eat. with enteral nutrition, that is, we have provided him with a nasogastric tube a liquid that is nothing more than a real liquid meal, which passes through the digestive system and reaches the intestine and which contains the nutrients that feed the good microbiota. In children who received enteral nutrition we have seen a clinical improvement: they start eating earlier, are better off during the transplant, go home earlier than others. And we found a composition of the microbiota with better diversity, richer in good bacteria ”.

Returning a composite ecosystem to those who do not have it: fecal transplantation

So is enteral nutrition the future for all transplant recipients? “The future is fecal transplant. Enteral nutrition is a modulatory tool of bacterial flora; the fecal transplant, on the other hand, inserts a good microbiota into the intestine. It’s another thing. In adults it is done, even if in selected cases and in a few centers, but it must be extended to children. However, some points still need to be clarified: which fecal material to use? That of the patient? A donor’s? That of the same stem cell donor? Of a parent? Many variables still need to be explored, but – concludes Masetti – it must be returned to those who do not have a composite intestinal ecosystem ”.