Biology subjects

Pugin, J.

Publications and source records attributed to Pugin, J..

3 recordsLinked to original sources

bioRxiv2021

Excessive inflammatory and metabolic responses to acute SARS-CoV-2 infection are associated with a distinct gut microbiota composition

Protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and associated clinical sequelae requires well-coordinated metabolic and immune responses that limit viral spread and promote recovery of damaged systems. In order to understand potential mechanisms and interactions that influence coronavirus disease 2019 (COVID-19) outcomes, we performed a multi-omics analysis on hospitalised COVID-19 patients and compared those with the most severe outcome (i.e. death) to those with severe non-fatal disease, or mild/moderate disease, that recovered. A distinct subset of 8 cytokines and 140 metabolites in sera identified those with a fatal outcome to infection. In addition, elevated levels of multiple pathobionts and lower levels of protective or anti-inflammatory microbes were observed in the faecal microbiome of those with the poorest clinical outcomes. Weighted gene correlation network analysis (WGCNA) identified modules that associated severity-associated cytokines with tryptophan metabolism, coagulation-linked fibrinopeptides, and bile acids with multiple pathobionts. In contrast, less severe clinical outcomes associated with clusters of anti-inflammatory microbes such as Bifidobacterium or Ruminococcus, short chain fatty acids (SCFAs) and IL-17A. Our study uncovered distinct mechanistic modules that link host and microbiome processes with fatal outcomes to SARS-CoV-2 infection. These features may be useful to identify at risk individuals, but also highlight a role for the microbiome in modifying hyperinflammatory responses to SARS-CoV-2 and other infectious agents.

immunology↗

bioRxiv2021

Single-cell profiling in COVID-19 associated acute kidney injury reveals patterns of tubule injury and repair in human

The cellular mechanisms of kidney tubule repair are poorly characterized in human. Here, we applied single-nucleus RNA sequencing to analyze the kidney in the first days after acute injury in 5 critically ill patients with COVID-19. We identified abnormal proximal tubule cell states associated with injury, characterized by altered functional and metabolic profiles and by pro-fibrotic properties. Tubule repair involved the plasticity of mature tubule cells in a process of cell de-differentiation and re-differentiation, which displayed substantial similarities between mouse and man. In addition, in man we identified a peculiar tubule reparative response determining the expansion of progenitor-like cells marked by PROM1 and following a differentiation program characterized by the sequential activation of the WNT, NOTCH and HIPPO signaling pathways. Taken together, our analyses reveal cell state transitions and fundamental cellular hierarchies underlying kidney injury and repair in critically ill patients.

pathology↗

bioRxiv2019

Impaired renal gluconeogenesis is a major determinant of acute kidney injury associated mortality

Nature letterAcute Kidney Injury (AKI) is strongly associated with adverse outcome and mortality independently of the cause of renal damage1-3. The mechanisms determining the deleterious systemic effects of AKI are poorly understood and specific interventions, including optimization of renal replacement therapy, had a marginal effect on AKI-associated mortality in clinical trials4-8. The kidney contributes to up to 40% of systemic glucose production by gluconeogenesis during fasting and stress conditions, mainly synthesized from lactate in the proximal tubule9-12, rendering this organ a major systemic lactate disposal13. Whether kidney gluconeogenesis is impaired during AKI and how this might influence systemic metabolism remains unknown. Here we demonstrate that glucose production and lactate clearance are impaired during human AKI using renal arteriovenous catheterization in patients. Using single cell transcriptomics in mice and RNA sequencing in human biopsies, we show that glycolytic and gluconeogenetic pathways are modified during AKI in the proximal tubule specifically, explaining the metabolic alterations. We further demonstrate that impaired renal gluconeogenesis and lactate clearance during AKI are major determinants of systemic glucose and lactate levels in critically ill patients. Most importantly, altered glucose metabolism in AKI emerged as a major determinant of AKI-associated mortality. Thiamine supplementation restored renal glucose metabolism and substantially reduced AKI-associated mortality in intensive care patients. This study highlights an unappreciated systemic role of renal glucose and lactate metabolism in stress conditions, delineates general mechanisms explaining AKI-associated mortality and introduces a potential therapeutic intervention for a highly prevalent clinical condition with limited therapeutic options.

cell biology↗