Role of TLR5 in the Translocation and Dissemination of Commensal Bacteria in the Intestine after Traumatic Hemorrhagic Shock.

Enterogenous infection is a major cause of death during traumatic hemorrhagic shock (THS). It has been reported that Toll-like receptor 5 (TLR5) plays an integral role in regulating mucosal immunity and intestinal homeostasis of the microbiota. However, the roles played by TLR5 on intestinal barrier maintenance and commensal bacterial translocation post-THS are poorly understood. In this research, we established THS models in wild-type (WT) and Tlr5-/- (genetically deficient in TLR5 expression) mice. We found that THS promoted bacterial translocation, while TLR5 deficiency played a protective role in preventing commensal bacteria dissemination after THS. Furthermore, intestinal microbiota analysis uncovered that TLR5 deficiency enhanced the mucosal biological barrier by decreasing RegIIIγ-mediated bactericidal activity against G+ anaerobic bacteria. We then sorted small intestinal TLR5+ lamina propria dendritic cells (LPDCs) and analyzed TH1 differentiation in the intestinal lamina propria and a coculture system consisting of LPDCs and naïve T cells. Although TLR5 deficiency attenuated the regulation of TH1 polarization by LPDCs, it conferred stability to the cells during THS. Moreover, retinoic acid (RA) released from TLR5+ LPDCs could play a key role in modulating TH1 polarization. We also found that gavage administration of RA alleviated bacterial translocation in THS-treated WT mice. In summary, we documented that TLR5 signaling plays a pivotal role in regulating RegIIIγ-induced killing of G+ anaerobic bacteria, and LPDCs mediated TH1 differentiation via RA. These processes prevent intestinal bacterial translocation and enterogenous infection after THS, suggesting that therapeutically targeting LPDCs or gut microbiota can interfere with bacterial translocation after THS.

Effects of Short-Peptide-Based Enteral Nutrition on the Intestinal Microcirculation and Mucosal Barrier in Mice with Severe Acute Pancreatitis.

SCOPE: Short-peptide-based enteral nutrition (SPEN) is absorbed more efficiently in patients with severe acute pancreatitis (SAP). More importantly, SPEN decreases SAP-induced enterogenous infection risk. This study aims to investigate whether SPEN alleviates intestinal bacterial translocation in mice with SAP, and the underlying mechanisms. METHODS AND RESULTS: The SAP model is established after pre-treatment with SPEN or intact-protein-based enteral nutrition. Although there is no improvement in pancreas injury, as evaluated through Hematoxylin-Eosin staining or serum amylase, SPEN obviously attenuates intestinal bacterial translocation after SAP. To unveil the mechanisms, it is found that the intestinal mechanical barrier destroyed by SAP is significantly relieved by SPEN, which presents with recovered ZO-1 expression, mucus layer, and goblet cell function. Additionally, SPEN alleviates local CCR6/CCL20 induced CD11c+ dendritic cell infiltration, systemic immunosuppression, and inhibits the secretion of luminal secretory immunoglobulin A. Possibly responsible for SAP-induced mucosal dysfunctions, destroyed intestinal mucosal microcirculation and local hypoxia are largely improved in SAP+SPEN group. CONCLUSION: SPEN can improve downregulated intestinal mucosal microcirculation secondary to SAP, which may be responsible for mucosal inflammation relief, maintenance of the mechanical barrier and mucosal immunity, the correction of systemic immunosuppression, and play a protective role in defending commensal bacterial translocation after SAP.

Severe traumatic hemorrhagic shock induces compromised immune barrier function of the mesenteric lymph node leading to an increase in intestinal bacterial translocation.

Critically ill patients have increased susceptibility to translocation of gut bacteria. However, the mechanisms are complicated and remain unclear, and the aim of this study was to explore these mechanisms. Rats exposed to different levels of shock were orally administrated with bioluminescent Citrobacter. We found that severe shock caused an increase in bacterial translocation to the visceral organs, such as liver, spleen and blood, compared with mild shock. Surprisingly, bacterial translocation to mesenteric lymph node (MLN) was unchanged between the two shock groups. Various methods, including flow cytometry, a co-culture model and western blots, were used to evaluate MLN-associated immune function. Specifically, we focused on mesenteric lymph node dendritic cells (MLN-DCs), the critical antigen presenting cells involved in the construction of the immune barrier in MLN. We also found that severe shock impaired the phenotypic maturation of MLN-DCs and induced a tolerogenic phenotype. Furthermore, co-culture assays of DCs with naive CD4+ T cells showed that DCs subject to severe shock were more inclined to polarize native CD4+ T cells into Th2 and Treg cells. This study successfully reproduced the clinical phenomenon of severe shock resulting in increased bacterial translocation to extraintestinal tissues, and this may be related to the compromised immune barrier function of MLN, as maturation and function of MLN-DC's were badly impaired.