Toll-Like Receptor 2–Mediated Intestinal Injury and Enteric Tumor Necrosis Factor Receptor I Contribute to Liver Fibrosis in Mice

Abstract

Background & Aims Progression of liver fibrosis in experimental models depends on gut-derived bacterial products, but little is known about mechanisms of disruption of the mucosal barrier or translocation. We used a mouse model of cholestatic liver disease to investigate mechanisms of intestinal barrier disruption following liver injury. Methods Liver fibrosis and bacterial translocation were assessed in Toll-like receptor (TLR)2- and tumor necrosis factor receptor (TNFR)I-deficient mice subjected to bile duct ligation. Epithelial and lamina propria cells were isolated and analyzed by immunoblot analyses and flow cytometry. We analyzed bone-marrow chimeras and mice with a conditional gain-of-function allele for the TNFRI receptor. By crossing TNFRIflxneo/flxneo mice with mice that expressed the VillinCre transgene specifically in intestinal epithelial cells, we created mice that express functional TNFRI specifically on intestinal epithelial cells (VillinCreTNFRIflxneo/flxneo mice). Results Following bile duct ligation, TLR2-deficient mice had less liver fibrosis and intestinal translocation of bacteria and bacterial products than wild-type mice. Mice with hematopoietic cells that did not express TLR2 also had reduced bacterial translocation, indicating that TLR2 expression by hematopoietic cells regulates intestinal barrier function. The number of TLR2+ monocytes that produce TNF_ increased in the intestinal lamina propria of wild-type mice following bile duct ligation; bacterial translocation was facilitated by TNFRI-mediated signals on intestinal epithelial cells. Conclusion Intestinal inflammation and bacterial translocation contribute to liver fibrosis via TLR2 signaling on monocytes in the lamina propria and TNFRI signaling on intestinal epithelial cells in mice. Enteric TNFRI therefore is an important mediator of cholestatic liver fibrosis.

Activated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier function

“…This is in contrast to a murine model of cholestatic liver disease where bacterial translocation was dependent on TLR-2 and TNFRI pathways, suggesting that the bile duct ligation model differs from molecular pathways associated with bacterial translocation in human non-cholestatic cirrhosis [24].…”

Bifidobacterium pseudocatenulatum CECT7765 promotes a TLR2-dependent anti-inflammatory response in intestinal lymphocytes from mice with cirrhosis

“…In fact, similar results had been obtained in the past showing the antiinflammatory properties of TLR-2 [27][28][29] and the induction of a pro-inflammatory cytokine response by B. breve after blocking TLR-2 [30]. In contrast to this and the previously mentioned studies, an inflammatory downregulation in monocytes from lamina propria in TLR2-deficient mice with bile duct ligation has been reported [31]. Several aspects, such as the distinct experimental model used and the intestinal monocyte population used rather than ILs, may explain this difference.…”

TREM-1 Promotes Survival during Klebsiella pneumoniae Liver Abscess in Mice

“…It has been suggested that intestinal inflammation mediated by inflamed cells in the lamina propria is involved in upregulation of intestinal permeability leading to enhanced translocation of bacteria or their products (38). Besides, compromised antimicrobial peptide production has also been reported to predispose hosts to bacterial translocation in experimental cirrhosis (42).…”

“…To assess bacterial translocation from gastrointestinal segments, we used a modified intestinal loop model as previously described (35)(36)(37)(38). After anesthesia, a midline laparotomy incision was made.…”