Periodic Reporting for period 2 - STRATEGY-CKD (System omics to unravel the gut-kidney axis in Chronic Kidney Disease.)
Reporting period: 2022-02-01 to 2024-07-31
Chronic kidney disease (CKD) remains a major public health problem. CKD is projected to be the 5th leading cause of years of life lost by 2040. Cardiovascular disease (CVD) is the major cause of death in CKD patients The accumulation of uremic toxins (UTs) in is an important risk factor for CVD in CKD. Several of these uremic toxins find their origin in the gut. Addressing the gut microbial metabolism could offer a cost-effective therapy for improving CKD outcomes.
Early-stage researchers (ESRs) were trained to gain excellent scientific and transferable skills with exposure to both academic and nonacademic environments. This training now allows them to tackle complex diseases, to build bridges between researchers and entrepreneurs and to support the future translation of research findings in innovative therapies. Different training activities have been organized and attended in cooperation with complementary research consortia to synergistically improve structural training on European level, building a network. On top of that ESRs were encouraged to engage in scientific outreach to create awareness for CKD and to share their scientific findings with peers, colleagues and the general public.
Early-stage researchers (ESRs) were trained to gain excellent scientific and transferable skills with exposure to both academic and nonacademic environments. This training now allows them to tackle complex diseases, to build bridges between researchers and entrepreneurs and to support the future translation of research findings in innovative therapies. Different training activities have been organized and attended in cooperation with complementary research consortia to synergistically improve structural training on European level, building a network. On top of that ESRs were encouraged to engage in scientific outreach to create awareness for CKD and to share their scientific findings with peers, colleagues and the general public.
In STRATEGY-CKD, we worked towards the identification of novel targets related to the gut-kidney axis to improve outcome of patients with CKD. For this aim patient sample collections were used, and cell culture set-ups and animal models were established. State-of-the-art -omic approaches, bioinformatics and systems biology were trained and applied. ESRs collaborated intensively and shared their expertise. Intestinal bacterial metagenome data of CKD patients in different stages of the disease pointed out changes in composition and function in different patients cohorts. The results support further research into preserving or restoring the balance between saccharolytic and proteolytic fermentation. On parallel samples, plasma metabolomic, urinary proteome and fecal proteome analyses was performed Applied systems biology approaches to study cell-cell and host-microbiome interactions from omics technologies and multi-omics were developed. In a mouse model and in kidney-on-a-chip bioengineered human tubular cells, short-chain fatty acid (SCFA), an important product of saccharolytic fermentation, was found to promote kidney resilience to acute kidney injury (AKI), decreasing inflammation and preserving the downregulation of kidney protective genes such as klotho, respectively. Also in a CKD rodent model, gut microbiome proteolytic fermentation was also found to be enhanced. Moreover, the absorption of UT precursors increased in CKD rats. Lastly, SCFAs were identified as a potential therapeutic agent able to boost the activity of the organic anion transporter-1 in proximal tubule cells. A novel in vitro model in both 2D and 3D systems, stimulating caco2 cells to secrete an apical homogeneous mucus layer, was developed. These systems allowed confirmation of a role mediated by the mucus as a protective barrier against biological fluids as well as its role as a modulator of cell metabolism, enhancing detoxification processes from intestinally UT precursors. A rodent model of subtotal 5/6th nephrectomy fed with a high phosphate and vitamin D diet (SNx-vascular calcification (VC) model) was characterized by a decrease in mucus production in colon and ileum that correlated with calcification severity. Studies also focused on gender differences in pharmacokinetics and haemostatic dysfunction in CKD patients with a UT of intestinal origin exerting both pro-inflammatory and pro-coagulant effects. Finally, the effects of an orally administered human milk oligosaccharide, in a 5/6th nephrectomy CKD rat model revealed significant changes in various inflammatory parameters. Also in an AhR-KO Caco-2 cell line, the oligosaccharide was shown to have potential beneficial effects on the intestinal barrier. All combined, the ESRs have joined efforts to set-up the technical methods and to establish the experimental models to explore the gut-kidney axis in CKD, indicating new mechanisms, which can be targeted by future therapies to further improve cardiovascular outcome of CKD patients.
Chronic kidney disease forms a major socio-economic problem. Its high and still increasing prevalence (will) impact(s) the lives of millions of people worldwide. Dialysis required at kidney failure comes at a high societal cost. Ideally preventive therapeutic measures which could help to decrease comorbidities and delay disease progression towards kidney failure are urgently needed.
Within the STRATEGY-CKD project strong efforts have been made in optimal dissemination of the scientific results and in scientific outreach to increase public awareness of CKD and its large socio-economic burden. Identification of the pathological mechanisms involved and of novel therapeutic targets related to the gut-kidney axis will enhance the search for preventive treatments to improve outcome of patients with CKD in a less invasive and cost-effective manner.
In relation to training the multi-disciplinary training program ensures that the ESRs are graduating as scientists trained in facing current scientific challenges using advanced technological tools that are widely applicable in both academia and industry, thereby substantially enhancing their research career prospects.
Also on research level, STRATEGY-CKD has advanced beyond the current state of art by applying a holistic approach and combining different aspects of disease research (advanced experimental models, translational studies, mechanistic insight, therapeutic interventions). ESRs have published recommendations for future research on the gut microbiome in CKD. The application of different omics analyses in diseased conditions have pointed out potential biomarkers and novel targets for evaluation of future interventions be it in the intestine, at the side of the liver and the kidneys. Some of these targets have been reported in publications by our ESRs and some publications are still in preparation and/or will shortly be published. State-of-the-art methods and in vitro and in vivo animal experimental models have been established to study the pathophysiological mechanisms involved and the to explore potential interventions to decrease toxic and increase beneficial intestinally generated metabolites, to e.g. reduce inflammatory response, encounter comorbidities in CKD,… The use of bioinformatics/systems biology integrating data and revealing potential targets to treat diseases and translate research results into innovative health care products has been enabled. The results will open novel paths for further in-depth research to further improve outcome in patients with CKD and to decrease the burden of the disease.
Within the STRATEGY-CKD project strong efforts have been made in optimal dissemination of the scientific results and in scientific outreach to increase public awareness of CKD and its large socio-economic burden. Identification of the pathological mechanisms involved and of novel therapeutic targets related to the gut-kidney axis will enhance the search for preventive treatments to improve outcome of patients with CKD in a less invasive and cost-effective manner.
In relation to training the multi-disciplinary training program ensures that the ESRs are graduating as scientists trained in facing current scientific challenges using advanced technological tools that are widely applicable in both academia and industry, thereby substantially enhancing their research career prospects.
Also on research level, STRATEGY-CKD has advanced beyond the current state of art by applying a holistic approach and combining different aspects of disease research (advanced experimental models, translational studies, mechanistic insight, therapeutic interventions). ESRs have published recommendations for future research on the gut microbiome in CKD. The application of different omics analyses in diseased conditions have pointed out potential biomarkers and novel targets for evaluation of future interventions be it in the intestine, at the side of the liver and the kidneys. Some of these targets have been reported in publications by our ESRs and some publications are still in preparation and/or will shortly be published. State-of-the-art methods and in vitro and in vivo animal experimental models have been established to study the pathophysiological mechanisms involved and the to explore potential interventions to decrease toxic and increase beneficial intestinally generated metabolites, to e.g. reduce inflammatory response, encounter comorbidities in CKD,… The use of bioinformatics/systems biology integrating data and revealing potential targets to treat diseases and translate research results into innovative health care products has been enabled. The results will open novel paths for further in-depth research to further improve outcome in patients with CKD and to decrease the burden of the disease.