Periodic Reporting for period 2 - HyperBiota (Exploring the diet-microbiota axis for immunomodulation and organ protection in hypertension)
Berichtszeitraum: 2021-08-01 bis 2023-01-31
A variety of anti-hypertensive drugs are available since decades. It should be noted, however, that these drugs have been developed decades ago and do not incorporate recent key mechanistic findings regarding the pathophysiology of hypertension. This applies to inflammation in hypertension, whose role has been recognized recently but is insufficiently addressed by today's drugs. The identification of novel treatments targeting inflammation in hypertension is essential to close the treatment gap. While inflammation is now recognized as a hallmark of hypertension and subsequent organ damage, treatment of this chronic inflammation is a challenge. Severe side effects of long-term broad immunosuppression prevented its application in clinical routine.
Instead, the microbiome is a promising target for the prevention and the treatment of inflammation in hypertension. Hypertension and chronic hypertensive kidney damage are associated with an alteration of the microbiome. The effect of the microbiome on the host can in large parts be attributed to the interaction with the immune system, localized near the intestinal barrier and the gut-associated lymphoid tissue (GALT). Many diet-dependent microbial metabolites (e.g. short-chain fatty acids (SCFA), tryptophan metabolites) can modulate the function of specific immune cells.
The overall goal of HyperBiota is to explore the potential of microbiome-guided immunonutrition for anti-inflammatory immunomodulation and thus organ protection in hypertension and CKD. First, we aim to understand the dynamics of the intestinal bacterial ecosystem, the associated inflammatory response in hypertension, and the influence of specific dietary interventions. We then will utilize this knowledge to design personalized dietary interventions based upon the composition and function of the microbial ecosystem in the gut, moving away from generalized recommendations towards a personalized and disease-specific nutrition.
In addition to hypertension, we are placing a focus on established chronic kidney disease (CKD) because we hypothesize that established CKD has a much more pronounced impact on the microbiome and immune system. To this end, we have and continue to use murine models of CKD in which we have previously found marked dysregulation of a wide variety of immune cells, including gut-associated immune cells. We are currently exploring how this immune dysregulation can be altered by changing the colonization status of the intestine.
In addition, we are studying the migration of immune cells from the intestine to hypertensive end organs. In this context, intestinal cells are experimentally labelled (in vivo) to track the migration of intestinal immune cells. We are currently investigating the nature and function of intestinal immune cells that migrate to kidney and heart but also other lymphoid organs in hypertension. We hope to stop the migration of these cells to organs distant from the intestine by anti-inflammatory treatments.
We are also investigating whether human phenotypes in hypertension and CKD can be transferred to murine models by transferring human microbiota from diseased patients and healthy controls. Such transfers of phenotypes would allow us to infer causalities regarding the role of the microbiota in hypertension and hypertensive end-organ damage. In particular, we are interested in similarities and differences in the human and murine immune responses to a hypertensive stimulus.