Antitumor agent of the intestine

The microbiome is the vast collection of bacteria in the human gut. It is estimated that each person carries about 100 trillion bacterial cells into the digestive tract, belonging to several thousand species. It is believed that they are involved in the development of chronic inflammatory bowel disease, to trigger diabetes, to be responsible for obesity, even neurological diseases such as multiple sclerosis and Parkinson’s could have their causes here, not to mention depressions and autistic disorders.

The microbiome has been the focus of research for 20 years, since a new technique made it possible to analyze these bacteria quickly and accurately: high-throughput sequencing. Since then, there have been a growing number of findings that the microbiome, sometimes also known as the second human genome, not only has a central importance for digestion, but also influences, if not controls, at least a large number of body functions. The immune system is mentioned very often.

The microbiome influences the immune system

Scientists at the universities of Würzburg and Marburg have now managed for the first time to demonstrate experimentally that bacterial metabolites are able to increase the cytotoxic activity of certain immune systems. cells and thus positively influence the efficiency of tumor therapies. Ideally, the composition of bacterial species in the microbiome could be used to control their influence on the success of therapy.

The research team published the results of their study in the journal Communications on Nature. Dr. Maik Luu, a postdoctoral fellow in the laboratory of Professor Michael Hudecek of the Medical Clinic and Polyclinic II of Würzburg University Hospital, was responsible for the finding. Another participant was Professor Alexander Visekruna of the Institute of Microbiology and Medical Hygiene at Philipps University in Marburg, where Luu researched before moving to Würzburg.

Fatty acids increase the activity of killer cells

“We have been able to show that short-chain fatty acids butyrate and, in particular, pentanoate are able to increase the cytotoxic activity of CD8 T cells,” Maik Luu describes the central result of the published study. now. CD8 T cells are sometimes also called killer cells. As part of the immune system, its job is to kill cells specifically harmful to the body.

Short-chain fatty acids, in turn, belong to the most dominant class of metabolites in the intestinal microbiome. On the one hand, they can increase T cell metabolism by inducing central regulators of energy metabolism. On the other hand, they can inhibit specific enzymes that regulate accessibility to genetic material and therefore gene expression in T cells. In doing so, they induce epigenetic changes.

Solid tumor models are fought more effectively

“When short-chain fatty acids reprogram CD8 T cells, one of the results is to increase the production of proinflammatory and cytotoxic molecules,” Luu explains. In the experiment, treatment with fatty acid pentanoate increased the ability of tumor-specific T cells to fight solid tumor models. “We were able to observe the same effect in fighting tumor cells with so-called CAR-T cells,” says the scientist.

CAR-T cells are written as “chimeric antigen receptor T cells.” Although normal T cells are largely “blind” to tumor cells, CAR T cells are able to recognize specific target antigens on the surface of the tumor and destroy cancer cells by a genetic modification. Michael Hudecek is a leading expert in the field of CAR-T cell research.

Directed control through the composition of the microbiome

“The results are an example of how intestinal bacterial metabolites can alter the metabolism and gene regulation of our cells and thus positively influence the efficiency of tumor therapies,” says Maik Luu. In particular, the use of CAR-T cells against solid tumors could benefit.

In these cases, genetically modified cell therapy has so far been much less effective than treating hematologic tumors such as leukemia. Scientists hope this could change if CAR-T cells were treated with pentanoate or other short-chain fatty acids before being used in patients.

This effect could be exploited specifically by the composition of bacterial intestinal colonization, mainly because Luu and the others involved in the study were also able to identify the essential pentanoate producer of the intestinal flora: the bacterium Megasphaera massiliensis.

A long way to clinical applications

However, much remains to be done until new findings lead to new therapies for cancer patients. In a next step, the research team will initially broaden the spectrum of investigated tumor diseases and, in addition to other solid tumors, will also examine hematologic tumor diseases such as multiple myeloma. In addition, he wants to investigate the operation of the short chain fatty acids with more intensity to identify the starting points of targeted genetic modifications.