Exploring the diet-microbiota axis for immunomodulation and organ protection in hypertension

Informations projet

HyperBiota

N° de convention de subvention: 852796

DOI

10.3030/852796

Projet clôturé

Date de signature de la CE 12 Novembre 2019

Date de début 1 Février 2020

Date de fin 31 Janvier 2026

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 1 497 250,00

Contribution de l’UE

€ 1 497 250,00

Coordonné par

CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Germany

Periodic Reporting for period 3 - HyperBiota (Exploring the diet-microbiota axis for immunomodulation and organ protection in hypertension)

Période du rapport: 2023-02-01 au 2024-07-31

Résumé du contexte et des objectifs généraux du projet

High blood pressure (also called hypertension) ranks among the most prevalent non-communicable diseases worldwide. Large epidemiological studies have identified hypertension as the leading global risk factor for non-communicable diseases. Persistent hypertension causes organ damage to vessels, brain and retina, heart, and kidneys. Accordingly, hypertension poses enormous challenges to our society and healthcare systems, as inadequately treated hypertension leads to chronic disease with the need for ongoing medical treatment, loss of quality of life, and premature mortality. Hypertension also plays a prominent role globally from a socioeconomic perspective.
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.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

Since the beginning of the HyperBiota project, important insights have been gained to quantify the actual contribution of the gut microbiota to hypertension-related organ damage. In experimental models with or without gut microbiota, it could be shown that the gut bacteria indeed play an important modulating role here. In this context, the healthy gut microbiome has a protective role, as a ‘germ-free status’ without bacteria predisposes to more hypertensive end-organ damage. In particular, the kidney seems to be particularly susceptible to gut microbial influence compared to other hypertensive end organs, as the most prominent hypertensive organ damage was detectable here. Surprisingly, inflammatory responses to hypertension were also more pronounced in the absence of gut microbiota. Metabolite profiles confirmed the absence with metabolites of bacterial origin in germ-free status. SCFA were also absent here, some of whose anti-inflammatory effects are known. The absence of SCFA could explain the marked inflammation, again confirming the important role of SCFA in this context.
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.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

We aim to gain fundamental insights from Hyperbiota into the mechanistic role of the gut, including its bacterial community and associated immune cell associations, in hypertension and consequent organ damage. We will use these findings to identify gut-associated treatment targets to incorporate the gut into future treatment strategies. Thus, HyperBiota moves beyond previous mechanistic findings and established hypertension therapies.