In this Issue
September 2016; volume 311, issue 3
- Effect of nitrate supplementation on hepatic blood flow and glucose homeostasis: a double-blind, placebo-controlled, randomized control trial
This is the first study investigating the effect dietary nitrate supplementation on hepatic blood flow and on incretin and C-peptide concentrations in young and older adults. Despite a physiologically relevant elevation in plasma nitrite concentration following an acute dose of 11.9 mmol nitrate, there was no effect on hepatic blood flow, plasma glucose, C-peptide, or incretin concentration. Acute supplementation of nitrate does not appear to alter hepatic diffusion or modulate postprandial glucose homeostasis.
- Preterm infant gut microbiota affects intestinal epithelial development in a humanized microbiome gnotobiotic mouse model
Changes in the microbiome early in life may affect host physiology across the life span. Early life interaction between host and luminal microbes was investigated using a mouse model in which germ-free mice were transfaunated with fecal lysates from human preterm infants. Our data demonstrate that microbial communities affect differentiation of intestinal epithelial cell lineages, which may lead to significant effects on developmental, defensive, and physiological processes of the gastrointestinal epithelium.
Epithelial Biology and Secretion
- The serine protease-mediated increase in intestinal epithelial barrier function is dependent on occludin and requires an intact tight junction
We show that apical exposure of the intestinal epithelium to the serine proteases trypsin and matriptase enhances barrier function in a manner that is dependent upon the mobilization of occludin, but not upon the activation of protease-activated receptor 2. Furthermore, while serine proteases enhance barrier function in intact epithelia, they do not enhance the recovery of barriers disrupted by calcium chelation or cytokines. Proteases may be important regulators of epithelial barrier in the gut.
Neurogastroenterology and Motility
- Pilot study of small bowel mucosal gene expression in patients with irritable bowel syndrome with diarrhea
We measured mRNA expression by RT-PCR of 91 genes reflecting tight junction proteins, chemokines, innate immunity, ion channels, and transmitters in small intestinal mucosa from 15 IBS-D and 7 controls (biopsies negative for celiac disease). The following genes were significantly upregulated (q < 0.05) in irritable bowel syndrome with diarrhea (IBS-D): INADL, MAGI1, PPP2R5C, MAPKAPK5, TLR3, and IL-15. Protein expression of PPP2R5C in nuclear lysates was greater in patients with IBS-D compared with controls. Intestinal mucosal function deserves further study in IBS-D.
Liver and Biliary Tract Physiology/Pathophysiology
- Autophagy confers resistance to lipopolysaccharide-induced mouse hepatocyte injury
Autophagy is required for hepatocytes to resist injury from high concentrations of LPS. With a genetic decrease in hepatocyte autophagy, increased liver injury occurred in response to LPS from sensitization to TNF-dependent hepatocellular death in association with an impairment in Akt signaling. Human conditions such as aging and hepatic steatosis may worsen the clinical outcome from sepsis as the result of their concomitant decrease in hepatic levels of autophagy.
- A return to ad libitum feeding following caloric restriction promotes hepatic steatosis in hyperphagic OLETF rats
Caloric restriction-induced prevention of nonalcoholic fatty liver disease (NAFLD) is lost after only 4 wk of ad libitum feeding in hyperphagic Otsuka Long-Evans Tokushima fatty rats despite only modest increases in body weight and adiposity. While some beneficial hepatic mitochondrial adaptations were maintained, NAFLD development occurred in conjunction with dramatic increases in hepatic de novo lipogenesis. These findings suggest that prior caloric restriction offers little metabolic protection against future development of NAFLD should healthy eating patterns not persist.
- Macrophage colony-stimulating factor (CSF1) controls monocyte production and maturation and the steady-state size of the liver in pigs
This study is based on extensive studies in the mouse of the role of CSF1 in monocyte-macrophage production and differentiation and the function of macrophages in the control of hepatocyte proliferation. We use a novel form of CSF1, an Fc fusion protein, to demonstrate that the findings in mice can be extended to large animals. We discuss the possible role for CSF1 in homeostatic control of the size of the liver.
- PanIN-associated pericyte, glial, and islet remodeling in mice revealed by 3D pancreatic duct lesion histology
Transparent mouse pancreata with an acinar KrasG12D mutation were prepared by optical clearing to develop 3D duct lesion histology. This imaging approach identifies perilesional pericyte and glial activation and formation of pancreatic intraepithelial neoplasia (PanIN)-islet complexes, which otherwise cannot be easily portrayed by standard 2D tissue analysis. Our results highlight the cellular heterogeneity in the PanIN microenvironment and reveal anatomic details of neurovascular and endocrine links to the disease.
- Legumain is activated in macrophages during pancreatitis
Proteases are important mediators of many inflammatory diseases, including pancreatitis. With the use of recently developed chemical tools, activity of the cysteine protease legumain was found to be upregulated in acute and chronic pancreatitis. While legumain activity appears to be dispensable for initiation of pancreatitis, it serves as a biomarker for infiltrating macrophages in both mouse and human disease. Since legumain is enriched in areas of acinar-to-ductal metaplasia, it may function to promote the transition from chronic inflammation to cancer.
Inflammation, Immunity, Fibrosis, and Infection
- A long noncoding RNA signature for ulcerative colitis identifies IFNG-AS1 as an enhancer of inflammation
Long noncoding RNA (lncRNA) biology represents an exciting new field with implications in gene regulation. This field has only recently been investigated in the pathogenesis of ulcerative colitis. By utilizing high-throughput technologies on clinical samples, a lncRNA signature was generated and the lncRNA IFNG-AS1 was shown to regulate the important inflammatory cytokine interferon-γ. This work represents one of the first mechanistic studies of lncRNA biology in inflammatory bowel disease.
Microbiome and Host Interactions
- Identification of food-grade subtilisins as gluten-degrading enzymes to treat celiac disease
A novel class of gluten-degrading enzymes were isolated from Rothia bacteria, which are natural colonizers of the oral cavity. The enzymes were identified as subtilisins belonging to the S8 family of peptidases. Food-grade Bacillus species also produce such subtilisins, and these were also able to cleave and abolish gluten immunogenic epitopes. Subtilisins, cleaving after XPX↓, represent an as yet overlooked class of enzymes with great potential for enzyme therapeutic applications in celiac disease.