Abstract
During sepsis, disturbed gastrointestinal motility and increased mucosal permeability can aggravate sepsis due to the increased risk of bacterial translocation. To help identify new therapeutic targets, there is a need for animal models that mimic the immunological changes in the gastrointestinal tract as observed during human sepsis. We therefore characterized in detail the gastrointestinal neuroimmune environment in the cecal ligation and puncture (CLP) model, which is the gold standard animal model of microbial sepsis. Mice were sacrificed at day 2 and day 7, during which gastrointestinal motility was assessed and cytokines were measured in the serum and the colon. In the spleen, lymph nodes, ileum, and colon, subsets of leukocyte populations were identified by flow cytometry. Septic animals displayed an impaired gastrointestinal motility at day 2 and day 7. Two days post-CLP, increased serum and colonic levels of proinflammatory cytokines were measured. Flow cytometry revealed an influx of neutrophils in the colon and ileum, increased numbers of macrophages in the spleen and mesenteric lymph nodes, and an enhanced number of mast cells in all tissues. At day 7 post-CLP, lymphocyte depletion was observed in all tissues coinciding with increased IL-10 and TGF-β levels, as well as increased colonic levels of IL-17A and IFN-γ. Thus, CLP-induced sepsis in mice results in simultaneous activation of pro- and anti-inflammatory players at day 2 and day 7 in different tissues, mimicking human sepsis.
Highlights
IntroductionIleus, defined as the inhibition of the propulsive gastrointestinal (GI) motility of the entire GI tract, is a common complication often observed following surgical manipulation (so-called postoperative ileus or “POI”) of the GI tract or during sepsis
Ileus, defined as the inhibition of the propulsive gastrointestinal (GI) motility of the entire GI tract, is a common complication often observed following surgical manipulation of the GI tract or during sepsis
By adjusting the cecal ligation and puncture (CLP) procedure, we aimed to obtain an animal model that exhibits the different immune phases that have been typically described in human sepsis, namely, the systemic inflammatory response syndrome (SIRS) and the compensatory anti-inflammatory response syndrome (CARS) or anergic phase [30]
Summary
Ileus, defined as the inhibition of the propulsive gastrointestinal (GI) motility of the entire GI tract, is a common complication often observed following surgical manipulation (so-called postoperative ileus or “POI”) of the GI tract or during sepsis. Neuronal cells as well as inflammation play a pivotal role in the initiation and maintenance of ileus [6–8]. Immune cells are able to secrete mediators that directly affect smooth muscle cells or activate neuronal reflex pathways, resulting in motility disturbances, pain, and/or hypersensitivity. Activation of mechanisms of immune homeostasis may result in inflammation [9]. Neurotransmitters secreted from neurons affect immune cells; this feature has been demonstrated for mast cells, T cells, and dendritic cells [10–14]. The role of the aforementioned mast cells and macrophages has been unraveled [15–17], but much remains to be elucidated on the role of other leukocytes, such as T cells, in the GI tract during sepsis-induced ileus. Inflammation and leukocyte recruitment play a major role during endotoxemia-induced ileus
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