ABSTRACT
OBJECTIVES: In SLE, deregulation of haematopoiesis is characterised by inflammatory priming and myeloid skewing of haematopoietic stem and progenitor cells (HSPCs). We sought to investigate the role of extramedullary haematopoiesis (EMH) as a key player for tissue injury in systemic autoimmune disorders. METHODS: Transcriptomic analysis of bone marrow (BM)-derived HSPCs from patients with SLE and NZBW/F1 lupus-prone mice was performed in combination with DNA methylation profile. Trained immunity (TI) was induced through ß-glucan administration to the NZBW/F1 lupus-prone model. Disease activity was assessed through lupus nephritis (LN) histological grading. Colony-forming unit assay and adoptive cell transfer were used to assess HSPCs functionalities. RESULTS: Transcriptomic analysis shows that splenic HSPCs carry a higher inflammatory potential compared with their BM counterparts. Further induction of TI, through ß-glucan administration, exacerbates splenic EMH, accentuates myeloid skewing and worsens LN. Methylomic analysis of BM-derived HSPCs demonstrates myeloid skewing which is in part driven by epigenetic tinkering. Importantly, transcriptomic analysis of human SLE BM-derived HSPCs demonstrates similar findings to those observed in diseased mice. CONCLUSIONS: These data support a key role of granulocytes derived from primed HSPCs both at medullary and extramedullary sites in the pathogenesis of LN. EMH and TI contribute to SLE by sustaining the systemic inflammatory response and increasing the risk for flare.
Subject(s)
Lupus Erythematosus, Systemic , Lupus Nephritis , beta-Glucans , Humans , Animals , Mice , Hematopoiesis , Hematopoietic Stem CellsABSTRACT
Microbiota and the metabolites they produce within the large intestine interact with the host epithelia under the influence of a range of host-derived metabolic, immune, and homeostatic factors. This complex host-microbe interaction affects intestinal tumorigenesis, but established microbial or metabolite profiles predicting colorectal cancer (CRC) risk are missing. Here, we aimed to identify fecal bacteria, volatile organic compounds (VOC), and their associations that distinguish healthy (non-adenoma, NA) from CRC prone (high-risk adenoma, HRA) individuals. Analyzing fecal samples obtained from 117 participants ≥15 days past routine colonoscopy, we highlight the higher abundance of Proteobacteria and Parabacteroides distasonis, and the lower abundance of Lachnospiraceae species, Roseburia faecis, Blautia luti, Fusicatenibacter saccharivorans, Eubacterium rectale, and Phascolarctobacterium faecium in the samples of HRA individuals. Volatolomic analysis of samples from 28 participants revealed a higher concentration of five compounds in the feces of HRA individuals, isobutyric acid, methyl butyrate, methyl propionate, 2-hexanone, and 2-pentanone. We used binomial logistic regression modeling, revealing 68 and 96 fecal bacteria-VOC associations at the family and genus level, respectively, that distinguish NA from HRA endpoints. For example, isobutyric acid associations with Lachnospiraceae incertae sedis and Bacteroides genera exhibit positive and negative regression lines for NA and HRA endpoints, respectively. However, the same chemical associates with Coprococcus and Colinsella genera exhibit the reverse regression line trends. Thus, fecal microbiota and VOC profiles and their associations in NA versus HRA individuals indicate the significance of multiple levels of analysis towards the identification of testable CRC risk biomarkers.