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Byline: Pinar. Ural, Hümeyra. Albayrak, Oktay. Gürcan, Atilla. Kazanci, Ahmet. Gürçay, Mehmet. Özates Objective: Histopathological examination of the effects of Tisseel, Cova, Glubran and Coseal, which are used for sealing [...]

Background Rifaximin is a poorly absorbed broad-spectrum antibiotic used for hepatic encephalopathy. Although increased Lactobacillaceae and decreased Bacteroidetes abundance are characteristic of hepatic encephalopathy, rifaximin does not dramatically alter the stool microbiota. As the antimicrobial effect of rifaximin increases by micellization with bile acids, we hypothesized that rifaximin alters the microbiota in the duodenum and jejunum, where the levels of bile acids are abundant. Methods and results Eight-week-old BALB/c mice were injected with carbon tetrachloride (CCl.sub.4) intraperitoneally for 12 weeks to induce liver fibrosis. The mice were grouped into the control (n = 9), CCl.sub.4 (n = 13), and rifaximin group in which mice were treated with rifaximin for two weeks after CCl.sub.4 administration (n = 13). We analyzed the microbiota of the duodenum, jejunum, ileum, cecum, and stool using 16S ribosomal RNA gene analysis. The content of Lactobacillaceae, the most abundant bacterial family in the duodenum and small intestine, increased in the CCl.sub.4 group, especially in the jejunum (median 67.0% vs 87.8%, p = 0.03). Rifaximin significantly decreased Lactobacillaceae content in the duodenum (median 79.4% vs 19.0%, p = 0.006) and jejunum (median 87.8% vs 61.3%, p = 0.03), but not in the ileum, cecum, and stool. Bacteroidetes abundance tended to decrease on CCl.sub.4 administration and increased following rifaximin treatment in the duodenum and jejunum. S24_7, the most abundant family in Bacteroidetes, demonstrated a significant inverse correlation with Lactobacillaceae (duodenum, r = - 0.61, p < 0.001; jejunum, r = - 0.72, p < 0.001). In the ileum, cecum, and stool, the effect of rifaximin on the microbiota was minimal, with changes within the same phylum. The percentage of bacterial families, such as Lactobacillaceae and S24_7 in the duodenum and small intestine, did not correlate with that in the stool. Conclusions The abundance of Lactobacillaceae increased in the jejunum of mice with CCl.sub.4-induced liver fibrosis, while rifaximin significantly reduced it in the duodenum and jejunum. Thus, rifaximin possibly exerts its effect by altering the duodenal and jejunal microbiota. Furthermore, changes in the duodenal and small intestinal microbiota were not associated with that of stool, suggesting that the analysis of stool microbiota is insufficient to evaluate upper intestinal microbiota. Keywords: Microbiome, Liver fibrosis, Small intestine, Hepatic encephalopathy, Lactobacillaceae, Firmicutes, Bacteroidetes, Author(s): Kazuhiko Ikeuchi[sup.1], Takeya Tsutsumi[sup.1,2], Aya Ishizaka[sup.1], Taketoshi Mizutani[sup.1], Ayako Sedohara[sup.1], Michiko Koga[sup.1], Satoru Tamaoki[sup.3] and Hiroshi Yotsuyanagi[sup.1] Background Rifaximin is a semisynthetic antibiotic derived by modifying rifamycin to achieve [...]

Although the immune response within draining lymph nodes (DLNs) has been studied for decades, how their stromal compartment contributes to this process remains to be fully explored. Here, we show that donor mast cells were prominent activators of collagen I deposition by fibroblastic reticular cells (FRCs) in DLNs shortly following transplantation. Serial analysis of the DLN indicated that the LN stroma did not return to its baseline microarchitecture following organ rejection and that the DLN contained significant fibrosis following repetitive organ transplants. Using several FRC conditional-knockout mice, we show that induction of senescence in the FRCs of the DLN resulted in massive production of collagen I and a proinflammatory milieu within the DLN. Stimulation of herpes virus entry mediator (HVEM) on FRCs by its ligand LIGHT contributed chiefly to the induction of senescence in FRCs and overproduction of collagen I. Systemic administration of ex vivo-expanded FRCs to mice decreased DLN fibrosis and strengthened the effect of anti-CD40L in prolonging heart allograft survival. These data demonstrate that the transformation of FRCs into proinflammatory myofibroblasts is critically important for the maintenance of a proinflammatory milieu within a fibrotic DLN., Introduction Lymph nodes (LNs) are the quintessential organs of alloimmunity following transplantation. Recent advances in elucidating the function of specific cellular and stromal compartments in the LN have broadened our [...]

Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2.sup.+CD9.sup.+ subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1.sup.+ and PLVAP.sup.+ endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFR[alpha].sup.+ collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis. Single-cell RNA sequencing is used to characterize and compare the functional diversity of cells from liver biopsies of human scarred and normal liver, and identifies markers for scar-associated macrophages and endothelial cells., Author(s): P. Ramachandran [sup.1] , R. Dobie [sup.1] , J. R. Wilson-Kanamori [sup.1] , E. F. Dora [sup.1] , B. E. P. Henderson [sup.1] , N. T. Luu [sup.2] [sup.3] [...]

Persistent, unresolved inflammation in the liver represents a key trigger for hepatic injury and fibrosis in various liver diseases and is controlled by classically activated proinflammatory macrophages, while restorative macrophages of the liver are capable of reversing inflammation once the injury trigger ceases. Here we exhibit neutrophils as key contributors to resolving the inflammatory response in the liver using two models of liver inflammation resolution. Using two models of liver inflammatory resolution, we found that mice undergoing neutrophil depletion during the resolution phase exhibited unresolved hepatic inflammation, activation of the fibrogenic machinery, and early fibrosis. These findings were associated with an impairment of the phenotypic switch of proinflammatory macrophages into a restorative stage after removal of the cause of injury and an increased NLRP3/miR-223 ratio. Mice with a deletion of the granulocyte-specific miR-223 gene showed a similarly impaired resolution profile that could be reversed by replacing miR-223 levels using a miR-223 3p mimic or by infusion of neutrophils from wild-type animals. Collectively, our findings reveal hepatic neutrophils as resolving effector cells that induce proinflammatory macrophages into a restorative phenotype, potentially via miR-223., Introduction Liver inflammation constitutes a central contributor to liver pathology during chronic injury from varying etiologies (1, 2). While it is self-limiting, liver inflammation is considered beneficial and contributes to [...]

Idiopathic pulmonary fibrosis (IPF) is a deadly disease with limited therapies. Tissue fibrosis is associated with type 2 immune response, although the causal contribution of immune cells is not defined. The AP-1 transcription factor Fra-2 is upregulated in IPF lung sections, and Fra-2 transgenic mice (Fra-[2.sup.Tg]) exhibit spontaneous lung fibrosis. Here, we show that bleomycin-induced lung fibrosis is attenuated upon myeloid inactivation of Fra-2 and aggravated in Fra-[2.sup.Tg] bone marrow chimeras. Type VI collagen (ColVI), a Fra-2 transcriptional target, is upregulated in 3 lung fibrosis models, and macrophages promote myofibroblast activation in vitro in a ColVI- and Fra-2-dependent manner. Fra-2 or ColVI inactivation does not affect macrophage recruitment and alternative activation, suggesting that Fra-2/ColVI specifically controls the paracrine profibrotic activity of macrophages. Importantly, ColVI-KO mice and ColVI-KO bone marrow chimeras are protected from bleomycin-induced lung fibrosis. Therapeutic administration of a Fra-2/AP-1 inhibitor reduces ColVI expression and ameliorates fibrosis in Fra-[2.sup.Tg] mice and in the bleomycin model. Finally, Fra-2 and ColVI positively correlate in IPF patient samples and colocalize in lung macrophages. Therefore, the Fra-2/ColVI profibrotic axis is a promising biomarker and therapeutic target for lung fibrosis and possibly other fibrotic diseases., Introduction Fibrosis is the result of an abnormal healing process that can occur in every solid organ where hyperactive fibroblasts, called myofibroblasts, characterized by the expression of [alpha]-SMA, produce an [...]