NAD precursors and bile acid sequestration treat preclinical refractory environmental enteric dysfunction.

Environmental enteric dysfunction (EED) is a diffuse small bowel disorder associated with poor growth, inadequate responses to oral vaccines, and nutrient malabsorption in millions of children worldwide. We identify loss of the small intestinal Paneth and goblet cells that are critical for innate immunity, reduced villous height, increased bile acids, and dysregulated nicotinamide adenine dinucleotide (NAD) synthesis signaling as potential mechanisms underlying EED and which also correlated with diminished length-for-age score. Isocaloric low-protein diet (LPD) consumption in mice recapitulated EED histopathology and transcriptomic changes in a microbiota-independent manner, as well as increases in serum and fecal bile acids.

Islet primary cilia motility controls insulin secretion.

Primary cilia are specialized cell-surface organelles that mediate sensory perception and, in contrast to motile cilia and flagella, are thought to lack motility function. Here, we show that primary cilia in human and mouse pancreatic islets exhibit movement that is required for glucose-dependent insulin secretion. Islet primary cilia contain motor proteins conserved from those found in classic motile cilia, and their three-dimensional motion is dynein-driven and dependent on adenosine 5'-triphosphate and glucose metabolism.

Mesothelium-Derived Factors Shape GATA6-Positive Large Cavity Macrophages.

The local microenvironment shapes macrophage differentiation in each tissue. We hypothesized that in the peritoneum, local factors in addition to retinoic acid can support GATA6-driven differentiation and function of peritoneal large cavity macrophages (LCMs). We found that soluble proteins produced by mesothelial cells lining the peritoneal cavity maintained GATA6 expression in cultured LCMs.

Biofilm Formation and Virulence of Shigella flexneri Are Modulated by pH of Gastrointestinal Tract.

infection remains a public health problem in much of the world. Classic models of pathogenesis suggest that microfold epithelial cells in the small intestine are the preferred initial site of invasion. However, recent evidence supports an alternative model in which primarily infects a much wider range of epithelial cells that reside primarily in the colon.

Reverse translation approach generates a signature of penetrating fibrosis in Crohn's disease that is associated with anti-TNF response.

Objective: Fibrosis is a common feature of Crohn's disease (CD) which can involve the mesenteric fat. However, the molecular signature of this process remains unclear. Our goal was to define the transcriptional signature of mesenteric fibrosis in CD subjects and to model mesenteric fibrosis in mice to improve our understanding of CD pathogenesis.

is enriched in Crohn's disease intestinal tissue and impairs healing in mice.

Alterations of the mycobiota composition associated with Crohn's disease (CD) are challenging to link to defining elements of pathophysiology, such as poor injury repair. Using culture-dependent and -independent methods, we discovered that preferentially localized to and was abundant within incompletely healed intestinal wounds of mice and inflamed mucosal tissues of CD human subjects. cultures from injured mice and inflamed CD tissues impaired colonic healing when introduced into injured conventionally raised or gnotobiotic mice.

Long-Term Culture Captures Injury-Repair Cycles of Colonic Stem Cells.

The colonic epithelium can undergo multiple rounds of damage and repair, often in response to excessive inflammation. The responsive stem cell that mediates this process is unclear, in part because of a lack of in vitro models that recapitulate key epithelial changes that occur in vivo during damage and repair. Here, we identify a Hopx colitis-associated regenerative stem cell (CARSC) population that functionally contributes to mucosal repair in mouse models of colitis.

PAI-1 augments mucosal damage in colitis.

There is a major unmet clinical need to identify pathways in inflammatory bowel disease (IBD) to classify patient disease activity, stratify patients that will benefit from targeted therapies such as anti-tumor necrosis factor (TNF), and identify new therapeutic targets. In this study, we conducted global transcriptome analysis to identify IBD-related pathways using colon biopsies, which highlighted the coagulation gene pathway as one of the most enriched gene sets in patients with IBD. Using this gene-network analysis across 14 independent cohorts and 1800 intestinal biopsies, we found that, among the coagulation pathway genes, plasminogen activator inhibitor-1 (PAI-1) expression was highly enriched in active disease and in patients with IBD who did not respond to anti-TNF biologic therapy and that PAI-1 is a key link between the epithelium and inflammation.

Temporal Regulation of the Bacterial Metabolite Deoxycholate during Colonic Repair Is Critical for Crypt Regeneration.

Colonic wound repair is an orchestrated process, beginning with barrier re-establishment and followed by wound channel formation and crypt regeneration. Elevated levels of prostaglandin E2 (PGE2) promote barrier re-establishment; however, we found that persistently elevated PGE2 hinders subsequent repair phases. The bacterial metabolite deoxycholate (DCA) promotes transition through repair phases via PGE2 regulation.

Abnormal Small Intestinal Epithelial Microvilli in Patients With Crohn's Disease.

Background & Aims: Crohn disease (CD) presents as chronic and often progressive intestinal inflammation, but the contributing pathogenic mechanisms are unclear. We aimed to identify alterations in intestinal cells that could contribute to the chronic and progressive course of CD.

Methods: We took an unbiased system-wide approach by performing sequence analysis of RNA extracted from formalin-fixed paraffin-embedded ileal tissue sections from patients with CD (n = 36) and without CD (controls; n = 32).

HIGH-RISK GASTRIC PATHOLOGY AND PREVALENT AUTOIMMUNE DISEASES IN PATIENTS WITH PERNICIOUS ANEMIA.

Objective: Pernicious anemia (PA) develops from atrophic gastritis due to autoimmune destruction of parietal cells and results in achlorhydria, vitamin B12 and iron deficiencies, anemia, neurologic deficits, and premalignant and malignant stomach lesions. We report the presentation, diagnosis and gastric complications of PA in patients from an endocrinology practice.

Methods: Thirty-four patients (31 female, 3 male) with PA who underwent esophagogastroduodenoscopy (EGD) or gastrectomy were identified.

Improving Diabetes Care with Technology and Information Management.

Patients and physicians in the 21 century require new tools to manage the growing burden of chronic illness. For providers responsible for the care of diabetic patients, developments in information management, real-time health education and feedback, and new approaches to self-monitoring and insulin delivery hold great promise to improve the quality and safety of diabetes care. This article will briefly highlight some of the major developments in the field, and the ways these technologies can be integrated into a typical practice.

Genome-wide association study of Arabidopsis thaliana leaf microbial community.

Identifying the factors that influence the outcome of host-microbial interactions is critical to protecting biodiversity, minimizing agricultural losses and improving human health. A few genes that determine symbiosis or resistance to infectious disease have been identified in model species, but a comprehensive examination of how a host genotype influences the structure of its microbial community is lacking. Here we report the results of a field experiment with the model plant Arabidopsis thaliana to identify the fungi and bacteria that colonize its leaves and the host loci that influence the microbe numbers.

Persistent gut microbiota immaturity in malnourished Bangladeshi children.

Therapeutic food interventions have reduced mortality in children with severe acute malnutrition (SAM), but incomplete restoration of healthy growth remains a major problem. The relationships between the type of nutritional intervention, the gut microbiota, and therapeutic responses are unclear. In the current study, bacterial species whose proportional representation define a healthy gut microbiota as it assembles during the first two postnatal years were identified by applying a machine-learning-based approach to 16S ribosomal RNA data sets generated from monthly faecal samples obtained from birth onwards in a cohort of children living in an urban slum of Dhaka, Bangladesh, who exhibited consistently healthy growth.

Microbial community dynamics and stability during an ammonia-induced shift to syntrophic acetate oxidation.

Anaerobic digesters rely on the diversity and distribution of parallel metabolic pathways mediated by complex syntrophic microbial communities to maintain robust and optimal performance. Using mesophilic swine waste digesters, we experimented with increased ammonia loading to induce a shift from aceticlastic methanogenesis to an alternative acetate-consuming pathway of syntrophic acetate oxidation. In comparison with control digesters, we observed shifts in bacterial 16S rRNA gene content and in functional gene repertoires over the course of the digesters' 3-year operating period.

The impact of a consortium of fermented milk strains on the gut microbiome of gnotobiotic mice and monozygotic twins.

Understanding how the human gut microbiota and host are affected by probiotic bacterial strains requires carefully controlled studies in humans and in mouse models of the gut ecosystem where potentially confounding variables that are difficult to control in humans can be constrained. Therefore, we characterized the fecal microbiomes and metatranscriptomes of adult female monozygotic twin pairs through repeated sampling 4 weeks before, 7 weeks during, and 4 weeks after consumption of a commercially available fermented milk product (FMP) containing a consortium of Bifidobacterium animalis subsp. lactis, two strains of Lactobacillus delbrueckii subsp.

Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans.

Coevolution of mammals and their gut microbiota has profoundly affected their radiation into myriad habitats. We used shotgun sequencing of microbial community DNA and targeted sequencing of bacterial 16S ribosomal RNA genes to gain an understanding of how microbial communities adapt to extremes of diet. We sampled fecal DNA from 33 mammalian species and 18 humans who kept detailed diet records, and we found that the adaptation of the microbiota to diet is similar across different mammalian lineages.

Regulation of myocardial ketone body metabolism by the gut microbiota during nutrient deprivation.

Studies in mice indicate that the gut microbiota promotes energy harvest and storage from components of the diet when these components are plentiful. Here we examine how the microbiota shapes host metabolic and physiologic adaptations to periods of nutrient deprivation. Germ-free (GF) mice and mice who had received a gut microbiota transplant from conventionally raised donors were compared in the fed and fasted states by using functional genomic, biochemical, and physiologic assays.

64Cu-azabicyclo[3.2.2]nonane thiosemicarbazone complexes: radiopharmaceuticals for PET of topoisomerase II expression in tumors.

Unlabelled: Topoisomerase II (Topo-II) is an essential enzyme in the DNA replication process and is the primary cellular target for many of the most widely used and effective anticancer agents. It has been reported that thiosemicarbazones (TSCs) are potent antitumor agents that inhibit Topo-II. The aim of this study was to investigate the relationship between the in vitro and in vivo behavior of novel (64)Cu-TSC complexes and the expression of Topo-II activity.

Electrogenerated chemiluminescence from polymer-bound ortho-metallated iridium(III) systems.

Three ortho-metallated iridium complexes whose emission maxima fall in different regions of the electromagnetic spectrum were bound in either Nafion or poly(9-vinylcarbazole) and their electrogenerated chemiluminescence (ECL) reported. The reaction of F(Ir)pic [bis(3,5-difluoro-2-(2-pyridyl)phenyl-(2-carboxypyridyl)-iridium III] with the oxidative-reductive co-reactant tri-n-propylamine (TPrA) resulted in ECL when the iridium complex was bound in Nafion. No significant ECL was observed for (btp)(2)Ir(acac) (bis[2,(2'-benzothienyl)-pyridinato-N,C3'](acetylacetonate)Ir(III)), and Ir(ppy)(3) (where ppy = 2-phenylpyridine) under these conditions.

Electrochemiluminescence of tris(8-hydroxyquinoline-5-sulfonic acid)aluminum(III) in aqueous solution.

The electrochemiluminescence (ECL) of tris(8-hydroxyquinoline-5-sulfonic acid)aluminum(III) in aqueous solution is reported. ECL is generated by complexing aluminum ions with the chelating agent 8-hydroxyquinoline-5-sulfonic acid (HQS) to form Al(HQS)3, followed by oxidation in the presence of tri-n-propylamine (TPrA). The ECL intensity peaks a potential corresponding to oxidation of both TPrA and Al(HQS)3, and the ECL emission spectrum (lambda(max) = 499 nm) matches the photoluminescence emission spectrum, indicating that the emission is from a Al(HQS)3* excited state.

Effects of poly(ethylene glycol) tert-octylphenyl ether on tris(2-phenylpyridine)iridium(III)-tripropylamine electrochemiluminescence.

The effects of the nonionic surfactant Triton X-100 (poly(ethylene glycol) tert-octylphenyl ether) on the properties of tris(2-phenylpyridine)iridium(III) (Ir(ppy)3, where ppy = 2-phenylpyridine, electrochemiluminescence (ECL) have been investigated. Anodic oxidation of Ir(ppy)3 produces ECL in the presence of tri-n-propylamine (TPrA) in aqueous surfactant solution. Increases in ECL efficiency (> or = 10-fold) and TPrA oxidation current (> or = 2.

Electrochemiluminescent detection of metal cations using a ruthenium(II) bipyridyl complex containing a crown ether moiety.

The effects of metal ions on the electrochemiluminescence (ECL) properties of (bpy)2Ru(AZA-bpy) (bpy = 2,2'-bipyridine; AZA-bpy = 4-(N-aza-18-crown-6-methyl-2,2'-bipyridine) have been investigated. The electrochemistry, photophysics and ECL of Ru(bpy)3(2+) in the presence of Pb2+, Hg2+, Cu2+, and K+ are reported. The anodic oxidation of Ru(bpy)3(2+) produces ECL in the presence of tri-n-propylamine (TPrA) in 50:50 (v/v) CH3CN:H2O solution.