Challenge to the Intestinal Mucosa During Sepsis

Abstract

Sepsis is a complex of life-threating organ dysfunction in critically ill patients, with a primary infectious cause or through secondary infection of damaged tissues. The systemic consequences of sepsis have been intensively examined and evidences of local alterations and repercussions in the intestinal mucosal compartment is gradually defining gut-associated changes during sepsis. In the present review, we focus on sepsis-induced dysfunction of the intestinal barrier, consisting of an increased permeability of the epithelial lining, which may facilitate bacterial translocation. We discuss disturbances in intestinal vascular tonus and perfusion and coagulopathies with respect to their proposed underlying molecular mechanisms. The consequences of enzymatic responses by pancreatic proteases, intestinal alkaline phosphatases, and several matrix metalloproteases are also described. We conclude our insight with a discussion on novel therapeutic interventions derived from crucial aspects of the gut mucosal dynamics during sepsis.

Keywords: enzymatic response; gut-barrier dysfunction; innate immunity; microbiome; perfusion disturbances; sepsis.

Figure 1

Sepsis is involved in several pathophysiological processes regarding the intestinal epithelial integrity, perfusion, coagulation, enzymatic response, and MIS. In sepsis, bacteria and their products (PAMPs), including LPS, PG, and bacterial DNA, can be recognized by PRRs (e.g., TLR2 and TLR4) upon the surface of macrophages, neutrophils, DCs, and even IECs (19, 32). Thereby, intestinal macrophages and DCs as part of the MIS can detect luminal PAMPs via transepithelial dendrites (TEDs) (26, 27, 33). Consequently, PAMPs induce a “cytokine storm” of pro-inflammatory mediators, which drive the local intestinal and systemic inflammation (32). The released mediators can lead to an upregulation of endothelial adhesion molecules (e.g., ICAM, VCAM, E-, and P-selectin), resulting in increased recruitment of neutrophils and monocytes and in turn to increased levels of pro-inflammatory cytokines and ROS (34, 35). These cellular responses aggravate vasodilatation and induce a high level of capillary leakage with the development of interstitial edema. Local DIC is frequently observed during sepsis with a decreased supply of oxygen and nutrients, but increased carbon dioxide concentration (36, 37). Hypoxia in turn leads to increased apoptosis and necrosis of IECs and the regeneration of these IECs is suppressed during sepsis (–40). Furthermore, the IEC integrity is disrupted and bacterial translocation may be facilitated. Pancreatic proteases are capable of autodigestion and potentiation of MOF and self-digestion leads to an increased release of further DAMPs (10, 19, 41, 42). MIS, mucosal immune system; PAMPs, pathogen-associated molecular patterns; DAMPs, danger-associated molecular patterns; LPS, lipopolysaccharide; PG, proteoglycan; PRR, pattern-recognition-receptors; TLR, toll-like receptor; DCs, dendritic cells; IECs, intestinal epithelial cells; TEDs, transepithelial dendrites; DIC, disseminated-intravascular-coagulation; MOF, multi-organ failure; ICAM, intercellular adhesion molecule 1; VCAM, vascular cell adhesion protein 1; ROS, reactive oxygen species; M-cells, microfold cells; AMPs, antimicrobial peptides; APC, antigen presenting cells; TJ, tight junctions; MALT, mucosa-associated-molecular pattern.

Figure 2

Sepsis-induced alterations in perfusion, vascular tonus and coagulation lead to a hypoxic microenvironment of the intestinal tissue (38). Therefore, the protective gel-forming MUC2 mucus layer becomes disrupted (22). Both, bacteria (products) and (pancreatic) proteases gain access into intestinal epithelia, inducing damage followed by increased pro-inflammatory signaling (41, 48, 70, 70, 71). Furthermore, MMPs (like MMP13) are able to cleave membrane-bound pro-TNF into sTNF, which in turn is able to stimulate caveolin-1-dependent endocytosis of TJs (72, 73). Gut barrier breakdown and dysfunction is one consequence (72). Intestinal commensal microbes regulate the maturation of the MIS and support local mucosal immunity (8, 74). During sepsis, the well-regulated interplay between the commensal microbiome, IECs and mucosal immune cells becomes imbalanced. There is a sepsis-induced shift from a physiological microbiome to a “pathobiome,” which is able to dysregulate the immune system by activating PRRs (32, 58). SP-A and SP-D can be synthetized by IECs (75, 76). These SPs are capable of increasing the permeability of bacterial membranes and in turn reduce the bacterial burden (77). IECs produce AMPs (e.g., α-defensin and lysozyme), to confer intestinal protection from pathogenic insults. Thereby, AMPs can act two ways, on the one hand directly by antimicrobial killing and on the other hand by innate immune modulation (78). Complement factors are mainly produced in the liver (79, 80), but also IECs were identified to synthesize and secrete C3 into the intestinal lumen (81), and thus may also play a role in intestinal immunity (82, 83). IECs, intestinal epithelia cells; MUC2, mucin-2; MMPs, matrix metalloproteinases; TNF, tumor necrosis factor; sTNF, soluble TNF; TJs, tight junctions; MIS, mucosal immune system; PRR, pattern recognition receptors; TLR, toll-like receptor; SP, surfactant protein; AMPs, antimicrobial peptides; C3, complement factor 3; LPS, lipopolysaccharide; DC, dendritic cell; IgA, immunoglobulin A.