TY - JOUR T1 - Quantifying the impact of gut microbiota on inflammation and hypertensive organ damage JF - bioRxiv DO - 10.1101/2021.09.17.460671 SP - 2021.09.17.460671 AU - Ellen G. Avery AU - Hendrik Bartolomaeus AU - Ariana Rauch AU - Chia-Yu Chen AU - Gabriele N’Diaye AU - Ulrike Löber AU - Theda U. P. Bartolomaeus AU - Raphaela Fritsche-Guenther AU - André F. Rodrigues AU - Dmitry Tsvetkov AU - Mihail Todiras AU - Joon-Keun Park AU - Lajos Markó AU - András Maifeld AU - Michael Bader AU - Stefan Kempa AU - Jennifer A. Kirwan AU - Sofia K. Forslund AU - Dominik N. Müller AU - Nicola Wilck Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/09/17/2021.09.17.460671.abstract N2 - Aims Hypertension (HTN) can lead to heart and kidney damage. The gut microbiota has been linked to HTN, although it is difficult to estimate its significance due to the variety of other features known to influence HTN. In the present study, we used germ-free (GF) and colonized (COL) littermate mice to quantify the impact of microbial colonization on organ damage in HTN.Methods and results Four-week-old male GF C57BL/6J littermates were randomized to remain GF or receive microbial colonization. HTN was induced by subcutaneous infusion with angiotensin (Ang) II (1.44mg/kg/d) and 1% NaCl in the drinking water; sham-treated mice served as control. Renal damage was exacerbated in GF mice, whereas cardiac damage was more comparable between COL and GF, suggesting that the kidney is more sensitive to microbial influence. Multivariate analysis revealed a larger effect of HTN in GF mice. Serum metabolomics demonstrated that the colonization status influences circulating metabolites relevant to HTN. Importantly, GF mice were deficient in anti-inflammatory fecal short-chain fatty acids (SCFA). Flow cytometry showed that the microbiome has an impact on the induction of anti-hypertensive myeloid-derived suppressor cells and pro-inflammatory Th17 cells in HTN. In vitro inducibility of Th17 cells was significantly higher for cells isolated from GF than conventionally raised mice.Conclusions Microbial colonization status of mice had potent effects on their phenotypic response to a hypertensive stimulus, and the kidney is a highly microbiota-susceptible target organ in HTN. The magnitude of the pathogenic response in GF mice underscores the role of the microbiome in mediating inflammation in HTN.Translation Perspective To assess the potential of microbiota-targeted interventions to prevent organ damage in hypertension, an accurate quantification of microbial influence is necessary. We provide evidence that the development of hypertensive organ damage is dependent on colonization status and suggest that a healthy microbiota provides anti-hypertensive immune and metabolic signals to the host. In the absence of normal symbiotic host-microbiome interactions, hypertensive damage to the kidney in particular is exacerbated. We suggest that hypertensive patients experiencing perturbations to the microbiota, which are common in CVD, may be at a greater risk for target-organ damage than those with a healthy microbiome.Competing Interest StatementThe authors have declared no competing interest. ER -