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It is believed to be involved in the development of chronic inflammatory bowel disease, to trigger diabetes, to be responsible for obesity, even neurological diseases like multiple sclerosis and Parkinson’s disease could have here their causes, not to mention depression and autistic disorders. We’re talking about the microbiome – the vast collection of bacteria in the human gut. It is estimated that each person carries around 100,000 billion bacterial cells in their digestive tract, belonging to several thousand species.
The microbiome has been the subject of research for 20 years, since a new technique makes it possible to analyze these bacteria quickly and precisely: high-throughput sequencing. Since then, there have been a growing number of discoveries that the microbiome, which is sometimes also referred to as the second human genome, is not only of central importance for digestion, but also influences, if not controls, at least a large number of body functions. The immune system is particularly mentioned.
The microbiome influences the immune system
Scientists from the universities of Würzburg and Marburg have for the first time succeeded in demonstrating experimentally that bacterial metabolites are capable of increasing the cytotoxic activity of certain immune cells and thus of positively influencing the effectiveness of tumor therapies. Ideally, the composition of bacterial species in the microbiome could be used to monitor its influence on the success of therapy.
The research team published the results of their study in the journal Nature Communication. Dr Maik Luu, a post-doctoral fellow in the laboratory of Professor Michael Hudecek at the Medical Clinic and Polyclinic II of the University Hospital of Würzburg, was responsible for the discovery. Another participant was Professor Alexander Visekruna from the Institute of Medical Microbiology and Hygiene at Philipps University in Marburg, where Luu did research before moving to Würzburg.
Fatty acids increase the activity of killer cells
“We were able to show that the short chain fatty acid butyrate and, in particular, the pentanoate are able to increase the cytotoxic activity of CD8 T cells”, describes Maik Luu the central result of the now published study. CD8 T cells are sometimes also called killer cells. As part of the immune system, their task is to specifically kill cells that are harmful to the body.
Short-chain fatty acids, in turn, belong to the most dominant class of metabolites in the gut microbiome. On the one hand, they can stimulate T cell metabolism by inducing central regulators of energy metabolism. On the other hand, they can inhibit specific enzymes that regulate the accessibility of genetic material and therefore the expression of genes in T cells. In doing so, they induce epigenetic changes.
Solid tumor models are combated more effectively
“When short-chain fatty acids reprogram CD8 T cells, one of the results is an increase in the production of pro-inflammatory and cytotoxic molecules,” says Luu. In the experiment, treatment with the fatty acid pentanoate increased the ability of tumor-specific T cells to fight solid tumor models. “We were able to observe the same effect by fighting tumor cells with so-called CAR-T cells”, explains the scientist.
CAR-T cells are written as “chimeric antigen receptor T cells”. While normal T cells are largely “blind” to tumor cells, CAR T cells are able to recognize specific target antigens on the tumor surface and destroy cancer cells through genetic modification. Michael Hudecek is one of the leading experts in the field of CAR-T cell research.
Targeted control via the composition of the microbiome
“The results are an example of how metabolites of intestinal bacteria can alter the metabolism and gene regulation of our cells and thus positively influence the effectiveness of anti-tumor therapies,” says Maik Luu. In particular, the use of CAR-T cells against solid tumors could benefit.
In these cases, therapy with genetically modified cells has heretofore been much less effective than the treatment of hematologic tumors such as leukemia. That could change if CAR-T cells were treated with pentanoate or other short-chain fatty acids before being used in patients, scientists hope.
This effect could be specifically exploited via the composition of the bacterial intestinal colonization – especially since Luu and others involved in the study were also able to identify the essential producer of pentanoate in the intestinal flora: the bacterium Megasphaera massiliensis.
A long way to clinical applications
However, there is still a long way to go before the new findings lead to new therapies for cancer patients. In a next step, the research team will first broaden the spectrum of tumor diseases studied and, in addition to other solid tumors, will also focus on hematological tumor diseases such as multiple myeloma. In addition, he wishes to study more intensely the functioning of short-chain fatty acids in order to identify starting points for targeted genetic modifications.
