Abstract
Because both endotoxemia and gut dysbiosis post-splenectomy might be associated with systemic infection, the susceptibility against infection was tested by dextran sulfate solution (DSS)-induced colitis and lipopolysaccharide (LPS) injection models in splenectomy mice with macrophage experiments. Here, splenectomy induced a gut barrier defect (FITC-dextran assay, endotoxemia, bacteria in mesenteric lymph nodes, and the loss of enterocyte tight junction) and gut dysbiosis (increased Proteobacteria by fecal microbiome analysis) without systemic inflammation (serum IL-6). In parallel, DSS induced more severe mucositis in splenectomy mice than sham-DSS mice, as indicated by mortality, stool consistency, gut barrier defect, serum cytokines, and blood bacterial burdens. The presence of green fluorescent-producing (GFP) E. coli in the spleen of sham-DSS mice after an oral gavage supported a crucial role of the spleen in the control of bacteria from gut translocation. Additionally, LPS administration in splenectomy mice induced lower serum cytokines (TNF-α and IL-6) than LPS-administered sham mice, perhaps due to LPS tolerance from pre-existing post-splenectomy endotoxemia. In macrophages, LPS tolerance (sequential LPS stimulation) demonstrated lower cell activities than the single LPS stimulation, as indicated by the reduction in supernatant cytokines, pro-inflammatory genes (iNOS and IL-1β), cell energy status (extracellular flux analysis), and enzymes of the glycolysis pathway (proteomic analysis). In conclusion, a gut barrier defect after splenectomy was vulnerable to enterocyte injury (such as DSS), which caused severe bacteremia due to defects in microbial control (asplenia) and endotoxemia-induced LPS tolerance. Hence, gut dysbiosis and gut bacterial translocation in patients with a splenectomy might be associated with systemic infection, and gut-barrier monitoring or intestinal tight-junction strengthening may be useful.
Highlights
As the largest lymphatic organ, the spleen’s functions are filtration of foreign matters from blood, antibody production, and bacteria control [1]
Gut Barrier assay, endotoxemia from gut translocation, and positive bacterial culture in the mesenThe splenectomy-induced gut barrier defect was indicated by FITC-dextran (4.4 kDa) teric lymph nodes at 14 days post-splenectomy (Figure 1A–C)
Post-splenectomy leaky gut, dysbiosis, and endotoxemia enhanced the bacteremia of dextran sulfate solution (DSS)-induced mucositis, implying the impact of the loss of microbial control due to asplenia and macrophage LPS tolerance
Summary
As the largest lymphatic organ, the spleen’s functions are filtration of foreign matters from blood, antibody production, and bacteria control [1]. Removal of the spleen (splenectomy), mostly due to blunt splenic injury [2], hypersplenism [3,4], and functional hyposplenism [5,6,7] in some conditions (coeliac disease, inflammatory bowel disease, and sickle cell anemia) [8] can lead to several bacterial infections, including Klebsiella pneumoniae, Hemophilus influenzae, and Pseudomonas aeruginosa [5,6,7]. These bacteria could be found in the environment, they are encapsulated Gram-negative bacteria that could be found in the intestine [9]. Our objective was to demonstrate and explore the clinical impact of an intestinal barrier defect post-splenectomy that might facilitate spontaneous systemic infection
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