Abstract
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.
Highlights
Traumatic hemorrhagic shock (THS) is highly prevalent and is one of the leading contributors to morbidity and mortality worldwide
All mice were gavaged with C. rodentium (Figure S1B and Figure 1(a)), and we found that in the sham-operated group, intestinal bacterial translocation into the mesenteric lymph nodes (MLNs) (Figure 1(b)) was higher in the Tlr5−/− mice than in the WT mice (p = 0:005)
More bacteria translocated into the MLNs of WT mice after THS compared with corresponding bacterial translocation in Tlr5−/− mice (p = 0:0013)
Summary
Traumatic hemorrhagic shock (THS) is highly prevalent and is one of the leading contributors to morbidity and mortality worldwide. The direct effects of traumatic injuries, secondary hemorrhage, and shock are usually severe; increasing evidence has revealed that the major cause of death after THS is severe systemic infection [1]. The details of the underlying mechanisms are not well understood, given that the immunological and biological barriers have not been fully explored. These barriers are widely acknowledged to work with the mucosal mechanical barrier in the intestine. The gut biological barrier is primarily composed of commensal anaerobic bacteria. It consists of a complex community of more than 1000 different species of commensal eukaryotes, archaea, and bacteria [3, 4]. The mechanisms involved remain largely unexplored, warranting further studies
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