Microbiota regulates neonatal disease tolerance to virus-evoked necrotizing enterocolitis by shaping the STAT1-NLRC5 axis in the intestinal epithelium.

Microbiota and feeding modes influence the susceptibility of premature newborns to necrotizing enterocolitis (NEC) through mechanisms that remain unknown. Here, we show that microbiota colonization facilitated by breastmilk feeding promotes NOD-like receptor family CARD domain containing 5 (Nlrc5) gene expression in mouse intestinal epithelial cells (IECs). Notably, inducible knockout of the Nlrc5 gene in IECs predisposes neonatal mice to NEC-like injury in the small intestine upon viral inflammation in an NK1.

A novel mouse model of hepatocyte-specific apoptosis-induced myeloid cell-dominant sterile liver injury and repair response.

Apoptosis, inflammation, and wound healing are critical pathophysiological events associated with various liver diseases. Currently, there is a lack of in vivo approaches to study hepatocyte apoptosis-induced liver injury and repair. To address this critical knowledge gap, we developed a unique genetically modified mouse model, namely, 3-Transgene (Tg) with inducible Hepatocyte-Specific Apoptosis Phenotype (3xTg-iHAP) in this study.

Scattered Crypt Intestinal Epithelial Cell Apoptosis Induces Necrotizing Enterocolitis Via Intricate Mechanisms.

Background & Aims: Necrotizing enterocolitis (NEC) is a life-threatening disease affecting mostly the ileum of preemies. Intestinal epithelial cell (IEC) apoptosis contributes to NEC pathogenesis. However, how scattered crypt IEC apoptosis leads to NEC with excessive villus epithelial necrosis remains unclear.

Severe gut mucosal injury induces profound systemic inflammation and spleen-associated lymphoid organ response.

Clinical evidence indicates a connection between gut injuries, infections, inflammation, and an increased susceptibility to systemic inflammation. Nevertheless, the animal models designed to replicate this progression are inadequate, and the fundamental mechanisms are still largely unknown. This research explores the relationship between gut injuries and systemic inflammation using a Dextran Sulfate Sodium (DSS)-induced colonic mucosal injury mouse model.

Feeding mode influences dynamic gut microbiota signatures and affects susceptibility to anti-CD3 mAb-induced intestinal injury in neonatal mice.

Feeding modes influence the gut microbiome, immune system, and intestinal barrier homeostasis in neonates; how feeding modes impact susceptibility to neonatal gastrointestinal (GI) diseases is still uncertain. Here, we investigated the impact of dam feeding (DF) and formula feeding (FF) on features of the gut microbiome and physiological inflammation during the first 2 days of postnatal development and on the susceptibility to intestinal injury related to the inflammatory state in neonatal mouse pups. 16S rRNA sequencing data revealed microbiome changes, lower α-diversity, and a distinct pattern of β-diversity including expansion of and in the ileum of FF pups compared with DF pups by postnatal day (P)2.

SARS-CoV-2 ORF8 Forms Intracellular Aggregates and Inhibits IFNγ-Induced Antiviral Gene Expression in Human Lung Epithelial Cells.

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a disease that involves significant lung tissue damage. How SARS-CoV-2 infection leads to lung injury remains elusive. The open reading frame 8 (ORF8) protein of SARS-CoV-2 (ORF8) is a unique accessory protein, yet little is known about its cellular function.

MFG-E8 Plays an Important Role in Attenuating Cerulein-Induced Acute Pancreatitis in Mice.

Milk fat globule-EGF factor 8 (MFG-E8) is a secreted glycoprotein that regulates tissue homeostasis, possesses potent anti-inflammatory properties, and protects against tissue injury. The human pancreas expresses MFG-E8; however, the role of MFG-E8 in the pancreas remains unclear. We examined the expression of MFG-E8 in the pancreas at baseline and during cerulein-induced acute pancreatitis in mice and determined whether MFG-E8 attenuates the progression of pancreatitis, a serious inflammatory condition that can be life-threatening.

Interferon-γ inhibits sirtuin 6 gene expression in intestinal epithelial cells through a -dependent mechanism.

Sirtuin 6 (Sirt6) is predominantly expressed in epithelial cells in intestinal crypts. It plays an important role in protecting intestinal epithelial cells against inflammatory injury. Previously, we found that colitis is associated with the downregulation of Sirt6 protein in the intestines.

In Inflamed Intestinal Tissues and Epithelial Cells, Interleukin 22 Signaling Increases Expression of H19 Long Noncoding RNA, Which Promotes Mucosal Regeneration.

Background & Aims: Inflammation affects regeneration of the intestinal epithelia; long noncoding RNAs (lncRNAs) regulate cell functions, such as proliferation, differentiation, and migration. We investigated the mechanisms by which the lncRNA H19, imprinted maternally expressed transcript (H19) regulates regeneration of intestinal epithelium using cell cultures and mouse models of inflammation.

Methods: We performed RNA-sequencing transcriptome analyses of intestinal tissues from mice with lipopolysaccharide (LPS)-induced sepsis to identify lncRNAs associated with inflammation; findings were confirmed by quantitative real-time polymerase chain reaction and in situ hybridization analyses of intestinal tissues from mice with sepsis or dextran sulfate sodium (DSS)-induced mucosal wound healing and patients with ulcerative colitis compared to healthy individuals (controls).

Sirtuin-6 preserves R-spondin-1 expression and increases resistance of intestinal epithelium to injury in mice.

Sirtuin-6 (Sirt6) is a critical epigenetic regulator, but its function in the gut is unknown. Here, we studied the role of intestinal epithelial Sirt6 in colitis-associated intestinal epithelial injury. We found that Sirt6, which is predominantly expressed in epithelial cells in intestinal crypts, is decreased in colitis in both mice and humans.

Spherical nucleic acid targeting microRNA-99b enhances intestinal MFG-E8 gene expression and restores enterocyte migration in lipopolysaccharide-induced septic mice.

Milk fat globule-EGF factor 8 (MFG-E8) maintains the intestinal homeostasis by enhancing enterocyte migration and attenuating inflammation. We previously reported that sepsis is associated with down-regulation of intestinal MFG-E8 and impairment of enterocyte migration. Here, we showed that impairment of intestinal epithelial cell migration occurred in lipopolysaccharide (LPS)-induced septic mice.

Molecular Mechanisms Underlying the Regulation of the MFG-E8 Gene Promoter Activity in Physiological and Inflammatory Conditions.

Milk fat globule-EGF factor 8 (MFG-E8) is expressed by macrophages and plays an important role in attenuating inflammation and maintaining tissue homeostasis. Previously, we and others found that lipopolysaccharide (LPS) inhibits MFG-E8 gene expression in macrophages. Here, we characterized the 5'-flanking region of the mouse MFG-E8 gene.

Dissociation of hepatic insulin resistance from susceptibility of nonalcoholic fatty liver disease induced by a high-fat and high-carbohydrate diet in mice.

Liver steatosis in nonalcoholic fatty liver disease is affected by genetics and diet. It is associated with insulin resistance (IR) in hepatic and peripheral tissues. Here, we aimed to characterize the severity of diet-induced steatosis, obesity, and IR in two phylogenetically distant mouse strains, C57BL/6J and DBA/2J.

MFG-E8 and HMGB1 are involved in the mechanism underlying alcohol-induced impairment of macrophage efferocytosis.

Efferocytosis is a unique phagocytic process for macrophages to remove apoptotic cells in inflammatory loci. This event is maintained by milk fat globule-EGF factor 8 (MFG-E8), but attenuated by high mobility group box 1 (HMGB1). Alcohol abuse causes injury and inflammation in multiple tissues.

Luminal-applied flagellin is internalized by polarized intestinal epithelial cells and elicits immune responses via the TLR5 dependent mechanism.

Bacteria release flagellin that elicits innate responses via Toll-like receptor 5 (TLR5). Here, we investigated the fate of apically administrated full length flagellin from virulent and avirulent bacteria, along with truncated recombinant flagellin proteins in intestinal epithelial cells and cellular responses. Flagellin was internalized by intestinal epithelial cell (IEC) monolayers of IEC-18.

Milk fat globule-EGF factor 8 is a critical protein for healing of dextran sodium sulfate-induced acute colitis in mice.

Milk fat globule-EGF factor 8 (MFG-E8) has been shown to play an important role in maintaining the integrity of the intestinal mucosa and to accelerate healing of the mucosa in septic mice. Herein, we (a) analyzed the expression of MFG-E8 in the gut of wild-type (WT) C57BL/6 (MFG-E8(+/+)) mice with and without dextran sulfate sodium (DSS)-induced colitis, (b) characterized the pathological changes in intestinal mucosa of MFG-E8(+/+) and MFG-E8(-/-) mice with DSS-induced colitis and (c) examined the therapeutic role of MFG-E8 in inflammatory bowel disease by using DSS-induced colitis model. Our data documented that there was an increase in colonic and rectal MFG-E8 expression in MFG-E8(+/+) mice during the development of DSS colitis.

Toll-like receptor 2-mediated peptidoglycan uptake by immature intestinal epithelial cells from apical side and exosome-associated transcellular transcytosis.

Peptidoglycan (PGN) is a potent immune adjuvant derived from bacterial cell walls. Previous investigations suggest that intestinal epithelium may absorb PGN from the lumen. Nonetheless, how PGN is taken up and crosses intestinal epithelium remains largely unclear.

Probiotic preparation VSL#3 alters the distribution and phenotypes of dendritic cells within the intestinal mucosa in C57BL/10J mice.

Probiotic nutrients have shown promise in therapy for the treatment of gastrointestinal inflammation, infection, and atopic disease. Intestinal dendritic cells (DC) play a critical role in shaping the intestinal immune response. In this study, we tested the effect of a probiotic preparation (VSL#3) on DC distribution and phenotypes within the intestinal mucosa using a lineage depletion-based flow cytometric analysis.

Milk fat globule-EGF factor 8 mRNA expression in rat splanchnic tissues during postnatal development.

Milk fat globule-EGF factor (MFG-E8) is a protein that binds to alphavbeta3/5 integrin and phosphatidylserine. It plays a role in apoptotic cell removal, tissue remodeling and intestinal epithelial wound-healing process. In the present study, we examined the expression of MFG-E8 mRNA in the small intestine, liver and lungs during postnatal development.

Milk fat globule-EGF factor 8/lactadherin plays a crucial role in maintenance and repair of murine intestinal epithelium.

Milk fat globule-EGF factor 8 (MFG-E8)/lactadherin participates in several cell surface-mediated regulatory events. Although its mRNA is present in the gut, the physiological roles of MFG-E8 in the intestinal mucosa have not been explored. Here we show that MFG-E8 was expressed in intestinal lamina propria macrophages from mice.

Lysozyme-modified probiotic components protect rats against polymicrobial sepsis: role of macrophages and cathelicidin-related innate immunity.

Severe sepsis is associated with dysfunction of the macrophage/monocyte, an important cellular effector of the innate immune system. Previous investigations suggested that probiotic components effectively enhance effector cell functions of the immune system in vivo. In this study, we produced bacteria-free, lysozyme-modified probiotic components (LzMPC) by treating the probiotic bacteria, Lactobacillus sp.

ERBP, a novel estrogen receptor binding protein enhancing the activity of estrogen receptor.

To understand the mechanism by which estrogen receptor (ER) activates transcription in a tissue specific fashion, we isolated ERalpha binding protein (ERBP) by performing yeast two-hybrid screening with human mammary gland cDNA library. ERBP is a nuclear protein and its mRNA is ubiquitously expressed. The in vitro interaction of ERBP with ERalpha was demonstrated by GST pull-down assay and this interaction was enhanced by estrogen.

Identification of a transcriptionally active peroxisome proliferator-activated receptor alpha -interacting cofactor complex in rat liver and characterization of PRIC285 as a coactivator.

Peroxisome proliferator-activated receptor alpha (PPAR alpha) plays a central role in the cell-specific pleiotropic responses induced by structurally diverse synthetic chemicals designated as peroxisome proliferators. Transcriptional regulation by liganded nuclear receptors involves the participation of cofactors that form multiprotein complexes to achieve cell- and gene-specific transcription. Here we report the identification of such a transcriptionally active PPAR alpha-interacting cofactor (PRIC) complex from rat liver nuclear extracts that interacts with full-length PPAR alpha in the presence of ciprofibrate, a synthetic ligand, and leukotriene B(4), a natural ligand.