Kidney transplantation (KT) is the best treatment for end-stage kidney disease, with graft survival critically affected by the recipient's immune response. The role of the gut microbiome in modulating this immune response remains underexplored. Our study investigates how microbiome alterations might be associated with allograft rejection by analyzing the gut microbiome using 16S rRNA gene amplicon sequencing of a multicenter prospective study involving 562 samples from 245 individuals of whom 217 received KT. Overall, gut microbiome composition showed gradual recovery post-KT, mirroring chronic kidney disease (CKD)-to-health transition as indicated by an increase in Shannon diversity. Prior to graft rejection, we observed a decrease in microbial diversity and short-chain fatty acid-producing taxa. Functional analysis highlighted a decreased potential for short-chain fatty acid production in patients preceding the rejection event, validated by quantitative PCR for the production potential of propionate and butyrate. Postrejection analysis revealed normalization of these microbiome features. Comparison to published microbiome signatures from CKD patients demonstrated a partial overlap of the microbiome alterations preceding graft rejection with the alterations typically found in CKD. Our findings suggest that alterations in gut microbiome composition and function may precede and influence KT rejection, suggesting potential implications as biomarkers or for early therapeutic microbiome-targeting interventions.

AIMS:Metformin has been attributed to cardiovascular protection even in the absence of diabetes. Recent observations suggest that metformin influences the gut microbiome. We aimed to investigate the influence of metformin on the gut microbiota and hypertensive target organ damage in hypertensive rats. METHODS:Male double transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR), a model of angiotensin II-dependent hypertension, were treated with metformin (300 mg/kg/day) or vehicle from 4 to 7 weeks of age. We assessed gut microbiome composition and function using shotgun metagenomic sequencing and measured blood pressure via radiotelemetry. Cardiac and renal organ damage and inflammation were evaluated by echocardiography, histology, and flow cytometry. RESULTS:Metformin treatment increased the production of short-chain fatty acids (SCFA) acetate and propionate in feces without altering microbial composition and diversity. It significantly reduced systolic and diastolic blood pressure and improved cardiac function, as measured by end-diastolic volume, E/A, and stroke volume despite increased cardiac hypertrophy. Metformin reduced cardiac inflammation by lowering macrophage infiltration and shifting macrophage subpopulations towards a less inflammatory phenotype. The observed improvements in blood pressure, cardiac function, and inflammation correlated with fecal SCFA levels in dTGR. In vitro, acetate and propionate altered M1-like gene expression in macrophages, reinforcing anti-inflammatory effects. Metformin did not affect hypertensive renal damage or microvascular structure. CONCLUSION:Metformin modulated the gut microbiome, increased SCFA production, and ameliorated blood pressure and cardiac remodeling in dTGR. Our findings confirm the protective effects of metformin in the absence of diabetes, highlighting SCFA as a potential mediators.

Introduction: Metformin (Met) is used as a first-line treatment in type II diabetes, reduces the cardiovascular (CV) risk in diabetes and may lead to decreased CV mortality independent of diabetes status. Met treatment has been shown to induce gut microbiome changes leading to enhanced production of protective short-chain fatty acids and potentially harmful metabolites (LPS). Our study aims to examine the effects of Met in a model of RAAS-mediated hypertension with cardio-renal damage. Methods: Four-week-old double transgenic rats (dTGR, transgenic for human renin and angiotensinogen) received oral Metformin (Met) or Vehicle (Veh) for 3 weeks. SD rats served as healthy controls. Flow cytometry (n=10 per group), echocardiography (n=14), radiotelemetric blood pressure (BP) measurements (n=5), clinical chemistry and gene expression analyses (n=14) were used to assess damage to kidney and heart. Results: Met treatment did not influence survival nor lead to lactate acidosis. Met treatment lowered BP significantly (systolic BP: Met: 218±5 mmHg, Veh: 237±3 mmHg). Interestingly, the decreased BP was accompanied by increased cardiac hypertrophy (heart weight to tibia length, SD: 34±1 g/m, Met: 40±1 g/m, Veh: 37±1 g/m). Echocardiographic systolic and diastolic function was deteriorated (EF: Met: 64±2 %, Veh: 68±4 %; E/A: Met: 0.75±0.1, Veh: 0.93±0.1). Plasma BNP and cardiac ß-to-α MHC ratio were higher in Met-treated dTGR. Intestines, spleens, kidneys and hearts of dTGR showed a strong pro-inflammatory phenotype with increased adaptive (e.g. cardiac T cells % of leucocytes: (SD: 10±0.003 %, Met: 15±0.01 %, Veh: 13±0.01 %) and innate (e.g. cardiac monocytes % of leucocytes: (SD: 2±0.001 %, Met: 3±0.004 %, Veh: 5±0.02 %) immune cell subsets in comparison to SD rats; with almost no differences between Met- and Veh-treated dTGR. Fecal metagenomic shotgun sequencing showed no large-scale taxonomic shifts between Veh- and Met-treated dTGR. Conclusion: dTGR display a pronounced pro-inflammatory immunophenotype across several organs. Met did not ameliorate hypertensive target organ damage in dTGR despite the BP lowering effect. These findings could help to understand the effects of Met on the microbiome, immunome and organ damage in the context of hypertension.

BackgroundPeanut allergy is a frequent cause of food allergy and potentially life‐threatening. Within this interdisciplinary research approach, we aim to unravel the complex mechanisms of peanut allergy. As a first step were applied in an exploratory manner the analysis of peanut allergic versus non‐allergic controls.MethodsBiosamples were studied regarding DNA methylation signatures, gut microbiome, adaptive and innate immune cell populations, soluble signaling molecules and allergen‐reactive antibody specificities. We applied a scalable systems medicine computational workflow to the assembled data.ResultsWe identified combined cellular and soluble biomarker signatures that stratify donors into peanut‐allergic and non‐allergic with high specificity. DNA methylation profiling revealed various genes of interest and stool microbiota differences in bacteria abundances.ConclusionBy extending our findings to a larger set of patients (e.g., children vs. adults), we will establish predictors for food allergy and tolerance and translate these as for example, indicators for interventional studies.